Clinical trial NCT04045613
Conditions: Urothelial Carcinoma
Keywords: metastatic urothelial cancer bladder cancer Fibroblast Growth Factor Receptor FGFR genetic aberration targeted therapy derazantinib checkpoint inhibitor immune checkpoint blockade atezolizumab Tecentriq solid tumor
Sponsor: Basilea Pharmaceutica
Start date: 2019-08-02; Completion date: 2022-10-04
Enrollment: 95 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate efficacy of derazantinib monotherapy or derazantinib-atezolizumab in combination in patients with advanced urothelial cancer harboring fibroblast growth factor receptor (FGFR) genetic aberrations (GA) of various clinical stages of disease progression and prior treatments.

Detailed description:
The study comprised five open-label substudies (1-5) in patients with advanced urothelial cancer harboring FGFR GA (with the exception of substudy 2 which did not require a FGFR GA) who were treated by derazantinib monotherapy or derazantinib in combination with atezolizumab. The study enrolled patients with cisplatin-ineligible status, or patients whose disease progressed after either first-line treatment or prior treatment with FGFR inhibitors.

Arms: arm 1: Patients with urothelial cancer were treated with derazantinib 300 mg once daily arm 2: Patients with any solid tumors were treated with derazantinib 200 mg once daily in combination with atezolizumab 1200 mg given every 3 weeks as intravenous (IV) infusion arm 3: Patients with any solid tumors were treated with derazantinib 300 mg once daily in combination with atezolizumab 1200 mg given every 3 weeks as IV infusion arm 4: Patients with urothelial cancer were treated with derazantinib 200 mg twice daily in combination with atezolizumab 1200 mg given every 3 weeks as IV infusion arm 5: Patients with FGFR inhibitor resistant urothelial cancer were treated with derazantinib 300 mg once daily arm 6: Patients with urothelial cancer were treated with derazantinib 300 mg once daily in combination with atezolizumab 1200 mg given every 3 weeks as IV infusion arm 7: Patients with urothelial cancer were treated with derazantinib 200 mg twice daily
Interventions: intervention 1: Derazantinib 300 mg once daily monotherapy intervention 2: Derazantinib 200 mg once daily + atezolizumab 1200 mg intervention 3: Derazantinib 300 mg once daily+ atezolizumab 1200 mg intervention 4: Derazantinib 200 mg twice daily + atezolizumab 1200 mg intervention 5: Derazantinib 300 mg once daily monotherapy (QD) intervention 6: Derazantinib 300 mg once daily + atezolizumab 1200 mg intervention 7: Derazantinib 200 mg twice daily monotherapy
Intervention descriptions: intervention 1: Derazantinib was administered orally at a dose of 300 mg once daily intervention 2: Derazantinib was administered orally at a dose of 200 mg once daily in combination with atezolizumab 1200 mg every 3 weeks intervention 3: Derazantinib was administered orally at a dose of 300 mg once daily in combination with atezolizumab 1200 mg every 3 weeks intervention 4: Derazantinib was administered orally at a dose of 200 mg twice daily in combination with atezolizumab 1200 mg every 3 weeks intervention 5: Derazantinib was administered orally at a dose of 300 mg once daily intervention 6: Derazantinib was administered orally at a dose of 300 mg once daily in combination with atezolizumab 1200 mg every 3 weeks intervention 7: Derazantinib was administered orally at a dose of 200 mg twice daily

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
DZB-CS-201
Derazantinib
An open-label multi-cohort Phase 1b/2 study of derazantinib and atezolizumab in 
patients with urothelial cancer expressing activating molecular FGFR aberrations 
(FIDES-02) 
Protocol Number/Version
DZB-CS-201 / Version 5.0
Compound
Derazantinib
Phase of development
1b/2
IND number
143805
EudraCT number
2019-000359-15
Date
8 March 2021
Project Physician
Clinical Pharmacologist
Project Statistician
Sponsor
Basilea Pharmaceutica International Ltd
Grenzacherstrasse 487 
CH-4058 Basel, Switzerland
Confidentiality statement
The information contained in this document is commercial confidential information which is the property 
of Basilea Pharmaceutica International Ltd, or is under its control. This information is provided to you in 
confidence as an investigator, potential investigator or consultant, for review by you, your staff and an 
applicable Independent Ethics Committee/Institutional Review Board, and may not be disclosed by the 
recipient to any other third party without prior written authorization from Basilea Pharmaceutica 
International Ltd, except to the extent necessary to obtain informed consent from potential participants in 
the clinical study to which the document refers. If it is determined that disclosure to potential participants 
or to another third party is required by applicable law or regulations or to obtain such informed consent 
from potential participants in such clinical study, the party to whom the information is disclosed must be 
informed that the information is confidential and that it may not be further disclosed without prior written 
authorization from Basilea Pharmaceutica International Ltd.
Note: This is an electronically controlled document (Document ID: Clinical-002487)


 
 
   
 
 
 
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DOCUMENT APPROVAL
The original version of this document has been electronically signed by the 
representatives of Basilea Pharmaceutica International Ltd identified on page 1, 
in compliance with the requirements of (US) 21 CFR Part 11 and other applicable 
national regulations regarding electronic records and electronic signatures.


 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
  
 
  
  
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
Derazantinib
Clinical Study Protocol
DZB-CS-201 (FIDES-02)
Version 5.0
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Protocol synopsis
TITLE
An open-label multi-cohort Phase 1b/2 study of derazantinib and 
atezolizumab in patients with urothelial cancer expressing activating 
molecular FGFR aberrations (FIDES-02)
PROTOCOL NUMBER
DZB-CS-201 / Version 5.0
SPONSOR
Basilea Pharmaceutica International Ltd, Switzerland
STUDY PHASE
1b/2
INDICATION
Urothelial cancer
IND NUMBER
143805
EUDRACT NUMBER
2019-000359-15
DATE:
8 March 2021
Overview of study design
Abbreviations: 1L: first-line treatment; 2+L: second-line or post-second line; ∆: decision for transition to Stage 2; 
FGFR: fibroblast growth factor receptor; GA: genetic aberration; mUC: locally advanced or metastatic and recurrent or 
progressing urothelial cancer; R: randomization. 
* Derazantinib 300mg QD
† Derazantinib 200 mg BID
‡ Safety interim analysis after 10 patients
§ If derazantinib 200 mg BID is not assessed as safe and tolerable, the RP2D determined in Substudy 2 will be used.
STUDY DESIGN
This study is a multiple-cohort, multi-center Phase 1b/2 study. An overview of the study design is 
provided above. The efficacy of derazantinib or derazantinib-atezolizumab in combination is 
evaluated in substudies enrolling patients with genetic aberrations (GAs) in the fibroblast growth 
factor receptor (FGFR) genes of various clinical stages of disease progression and prior treatments. 


 
 
   
 
 
 
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Effective from Protocol Version 5.0, Substudy 3 has been modified, and Substudy 5 has been 
added. Substudy 2 has been completed.
Patients with surgically unresectable or metastatic urothelial cancer (mUC) and FGFR1, FGFR2, 
or FGFR3 mutations and rearrangements / fusions (for the purposes of this protocol hereafter 
referred to as FGFR1–3 GAs) will be enrolled, and sample-size minimizing statistical designs with 
interim analyses for futility and efficacy will be used. 
All prospective study participants must test positive for FGFR1–3 GAs (see below). In Substudy 
4, it is anticipated that positive FGFR1–3 GA testing is available from the preceding FGFR 
inhibitor treatment. 
The study comprises five open-label substudies:

Substudy 1: Patients with mUC expressing FGFR1–3 GAs who have progressed on at least 
one standard chemotherapy and/or immune-checkpoint blockade and have not 
received prior FGFR inhibiting treatment. Patients in this substudy are to be 
treated with derazantinib 300 mg daily (QD) monotherapy.

Substudy 2: As of Protocol Version 5.0, enrollment to this substudy was completed, with 
interim results described in Section 1.4.1.2.

Substudy 3: As of Protocol Version 5.0, this substudy has been modified. First-line cisplatin-
ineligible patients with mUC expressing FGFR1–3 GAs are to be treated with 
derazantinib 200 mg twice daily (BID) and atezolizumab 1200 mg every 3 weeks 
(Q3W) in combination. If derazantinib 200 mg BID at the safety interim analysis 
(SIA) is not assessed as safe and tolerable, patients are to be treated with the 
RP2D determined in Substudy 2.

Substudy 4: FGFR inhibitor-resistant patients with mUC expressing FGFR1–3 GAs. Patients 
in this substudy are to be randomized (1:1) into two non-comparative cohorts: 
Cohort 4a patients will receive derazantinib 300 mg QD monotherapy, and 
Cohort 4b patients will receive derazantinib 300 mg QD and atezolizumab 
1200 mg Q3W in combination. 

Substudy 5: Patients with mUC expressing FGFR1–3 GAs who have progressed on at least 
one standard chemotherapy and/or immune-checkpoint blockade, and have not 
received prior FGFR inhibiting treatment. Patients in this substudy are to be 
treated with derazantinib 200 mg BID monotherapy.
INVESTIGATIONAL PRODUCT(S) 
Derazantinib, atezolizumab
TUMOR MOLECULAR TESTING DEVICE 
Molecular eligibility for enrollment will be established by a positive test result for eligible 
FGFR1-3 GAs (see Appendix 1). The molecular test is to be based on next generation sequencing 
(NGS) of either tumor tissue DNA and/or RNA, or plasma circulating-free DNA (cfDNA).
For patients with no access to local NGS testing, central testing will be performed in a laboratory 
in the USA designated by the Sponsor; this ‘central testing’ will be based on NGS testing of cfDNA
from a liquid biopsy obtained at Pre-screening. 
For potential prospective study participants without an available positive FGFR1–3 GA test result, 
a Pre-screening visit (see below) is to be scheduled for liquid biopsy sampling.


 
 
   
 
 
 
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Alternatively, an eligible, positive FGFR1–3 GA test result obtained from local NGS testing (‘local 
testing’, the commissioning of which is the study site’s responsibility) can be used to establish 
molecular eligibility; no Pre-screening visit is required. The commissioned NGS test for ‘local 
testing’ is to use standard protocols approved by the local IRB/IEC, Clinical Laboratory 
Improvement Amendments (CLIA), or other similar agency, or, where applicable, US FDA-
approved kits. For enrollment of patients in the EU, assays must be either fully CE-marked or CE-
marked for analytical performance; tests manufactured by health institutions and used only on their 
own patients are exempt from the Medical Devices Regulation requirements, and do not have to be 
CE-marked. 
PRE-SCREENING VISIT AND INITIATION OF CLINICAL SCREENING
A Pre-screening visit is only required for prospective study participants under consideration for 
enrollment into Substudies 1, 3 or 5, and if no documented local NGS test result with an eligible 
FGFR1–3 GA is available. If these patients have no access to local NGS testing, they are required 
to sign the Pre-screening Informed Consent Form (ICF) for molecular screening, and are not 
considered enrolled (i.e., patients are considered to be in pre-screening for the study) until receipt 
of a positive central molecular test result, and dated patient signature on the Study ICF. The Pre-
screening visit for liquid biopsy sampling should be scheduled following assessment of objective 
documented progression after prior anti-cancer treatment (e.g., rather than during prior anti-cancer 
treatment) to optimize the likelihood of capturing cfDNA shedding reflective of disease 
progression.
No Pre-screening visit is required for patients with a known and eligible FGFR1–3 GA status (see 
Appendix 1) from local NGS testing; these patients may directly initiate clinical screening 
procedures. Substudy 4 patients also do not require a Pre-screening visit if their molecular 
eligibility is known from prior FGFR-inhibiting treatment (documentation of which should be made 
available at the Screening visit, otherwise a Pre-screening visit should be scheduled).
PLANNED NUMBER OF PATIENTS
The study plans to enroll up to 272 evaluable patients in total across all five substudies.
NUMBER OF CENTERS/LOCATIONS
Up to 100 study sites in Asia-Pacific, Europe, and North America.
OBJECTIVES (as applicable to active substudies)
Primary efficacy objective

To evaluate the objective response rate (ORR) of derazantinib monotherapy (in Substudies 1 
and 5, and Cohort 4a) and of derazantinib-atezolizumab in combination (in Substudy 3 and 
Cohort 4b) in patients with mUC expressing FGFR1–3 GAs.
Primary safety objectives

To confirm derazantinib 200 mg BID plus atezolizumab 1200 mg Q3W as a safe and tolerable 
regimen (Substudy 3).

To confirm derazantinib 200 mg BID as a safe and tolerable dose regimen of derazantinib 
monotherapy (Substudy 5).


 
 
   
 
 
 
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Secondary objectives

To evaluate the efficacy of the study drugs as measured by disease control rate (DCR), duration 
of response (DOR), progression-free survival (PFS) and overall survival (OS)

To assess the safety and tolerability of the study drugs

To characterize the PK profile of derazantinib 200 mg BID (and, if applicable, derazantinib 
metabolites) as monotherapy (Substudy 5) and in combination with atezolizumab (Substudy 3).

To evaluate changes, and assess the minimally important difference, in health-related quality 
of life (HR-QoL) and symptom response from baseline by cohort, substudy and in the overall 
study population using the EORTC QLQ C30, FACT-Bl, EQ-5D (5L) visual analogue scale 
(VAS), and Health Transition Index/G-SET.
DOSE / ROUTE / REGIMEN (as applicable to active substudies)
In this study, a treatment cycle is 21 days in both monotherapy and combination cohorts.
Derazantinib is an investigational drug supplied as 100 mg immediate-release powder-filled 
capsules for oral administration. Atezolizumab is an approved medication supplied as
1200 mg/20 mL concentrate solution for intravenous (IV) infusion. The atezolizumab dose for all 
patients receiving the combination treatment will be 1200 mg Q3W.
In cohorts with a monotherapy regimen, unless a dose reduction is required to manage adverse 
events (AEs), the following doses of derazantinib are used:

In Substudy 1 and Cohort 4a, derazantinib 300 mg QD

In Substudy 5, derazantinib200 mg BID
In cohorts with derazantinib-atezolizumab in combination, unless a dose reduction is required to 
manage AEs, the following doses of derazantinib are used:

In Substudy 3, derazantinib 200 mg BID in combination with atezolizumab 1200 mg Q3W. If 
derazantinib 200 mg BID with atezolizumab 1200 mg Q3W is not assessed as safe and tolerable
at the SIA, the full cohort of 36 patients will be enrolled and treated with the RP2D determined 
in Substudy 2

In Cohort 4b, derazantinib 300 mg QD in combination with atezolizumab 1200 mg Q3W (as 
determined by Substudy 2)
KEY INCLUSION CRITERIA (as applicable to active substudies)
Inclusion criteria
(The full list of inclusion criteria is in Section 4.2 of the main protocol body)
1.
Study Informed Consent Form signed by the patient indicating that they understand the 
purpose of, and procedures required for, the study and are willing to participate in the study, 
prior to any study-related procedure.
…
3.
Histologically-confirmed transitional cell carcinoma of the urothelium of the upper or lower 
urinary tract.


 
 
   
 
 
 
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4.
Recurrent or progressing stage IV disease, or surgically unresectable, recurrent or progressing 
disease, as specified for each substudy:

Substudy 1: Patients with mUC expressing FGFR1–3 GAs who have progressed on at 
least one standard chemotherapy and/or immune-checkpoint blockade and have not 
received prior FGFR inhibiting treatment.

Substudy 3: First-line cisplatin-ineligible1 patients with mUC expressing FGFR1–3 GAs
who have not received prior FGFR inhibiting treatment.

Substudy 4: Patients with FGFR inhibitor-resistant mUC expressing FGFR1–3 GAs who 
have progressed on at least one standard regimen each of chemotherapy and immune-
checkpoint blockade2 and have received prior FGFR inhibiting treatment (excluding 
derazantinib)3.

Substudy 5: Patients with mUC expressing FGFR1–3 GAs who have progressed on at 
least one standard chemotherapy and/or immune-checkpoint blockade and have not 
received prior FGFR inhibiting treatment.
5.
An eligible FGFR1–3 GA-positive test result for enrollment (see Appendix 1 and Section 
3.1.1).
6.
Measurable disease, as defined by the Investigator using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 criteria, documented within the 28 days prior to study drug 
administration.
7.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2.
8.
Adequate organ functions as indicated by Screening visit local laboratory values.
9.
Men and women of childbearing potential must agree to avoid impregnating a partner or 
becoming pregnant, respectively, during the study, and for at least 5 months after the last dose 
of either investigational drug (see Inclusion criterion 9 in the main protocol body and Section 
4.2 for full details).
KEY EXCLUSION CRITERIA (as applicable to active substudies)
(The full list of exclusion criteria is in Section 4.3. of the main protocol body)
1.
Receipt of prior cancer treatment within specific interval periods (see Exclusion criterion 1 in 
the main protocol body).
2.
For Substudy 3 patients, prior treatment with anti-PD-1 or anti-PD-L1-therapeutic antibody, 
or PD-1/PD-L1 pathway-targeting agents.
3. Prior FGFR inhibiting treatment (except for Substudy 4 patients).
                                                
1 Cisplatin-ineligibility as defined by any one of the following criteria: 1) grade ≥ 2 peripheral neuropathy; 2) creatinine 
clearance (CLCR) calculated by Cockcroft-Gault ≥30 mL/min but < 60 mL/min; 3) hearing impairment (measured by 
audiometry) of > 25 dB at two contiguous test frequencies in at least one ear; 4) comorbidity that forbids high-volume 
hydration.
2 Prior treatment with combinations of immune-checkpoint blockade and FGFR inhibitor are not allowed; prior treatment 
with either sequential immune-checkpoint blockade and FGFR inhibitor treatment or combinations of FGFR inhibitor 
and chemotherapy are allowed.
3 Patients assessed as having progressed upon prior treatment with FGFR inhibitors must have received FGFR inhibitor 
treatment for at least 12 weeks and have undergone at least one on treatment tumor imaging assessment.


 
 
   
 
 
 
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4.
For Substudy 4 patients, prior treatment with FGFR inhibitor in combination with anti-PD-1 
or anti-PD-L1 therapeutic antibody or PD-1/PD-L1 pathway-targeting agents.
5.
Concurrent evidence of clinically significant corneal or retinal disorder likely to increase the 
risk of eye toxicity, including but not limited to bullous/band keratopathy, keratoconjunctivitis 
(unless keratoconjunctivitis sicca), corneal abrasion (unless related to trauma), 
inflammation/ulceration, confirmed by ophthalmological examination.
6.
History of clinically significant cardiac disorders, including myocardial infarction or New York 
Heart Association Class II to IV congestive heart failure, within 6 months of the first dose of 
study drug, and/or concurrent and clinically significant abnormalities on electrocardiogram 
(ECG) at Screening, including QTcF > 450 ms for males or > 460 ms for females.
…
10. Bellmunt score 3, or 2 if based on a combination of hemoglobin < 10 g/dL and presence of 
liver metastasis.
11. Any unresolved (at the time of Screening) clinically significant Common Terminology Criteria 
for Adverse Events (CTCAE) grade ≥2 toxicity (except for alopecia, grade 2 platinum-therapy 
related neuropathy, grade 2 anemia from previous anti-tumor treatment, grade 2 renal 
impairment per reduced CLCR by Cockcroft-Gault of 30–60 mL/min [which is generally 
accepted for this cancer population], and/or from medical/surgical procedures/interventions).
12. Known CNS metastases.
13. Lack of recovery from major (e.g., open abdominal) surgery after 4 weeks, or major elective 
surgery is planned during the foreseeable duration of the study.
14. Concurrent uncontrolled or active infection with human immunodeficiency virus (HIV; known 
HIV 1/2 antibodies positive).
15. Active hepatitis B or chronic hepatitis B without current antiviral therapy and an HBV 
DNA ≥100 IU/mL.
16. Active hepatitis C.
17. Active tuberculosis.
18. Severe bacterial, fungal, viral and/or parasitic infections on therapeutic oral or IV medication 
at the time of first dose of study drug administration
…
MAIN STUDY ENDPOINTS (as applicable to active substudies)
Primary endpoints
The primary endpoint for efficacy is ORR, as measured by the proportion of patients with 
confirmed complete response (CR)1or partial response (PR)2 by blinded independent central review 
(BICR).
                                                
1 Evaluating target lesions, Complete Response (CR) is defined as the disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; further details 
Appendix 3 and Eisenhauer 2009.
2 Evaluating target lesions, Partial Response (PR) is defined as at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters; further details Appendix 3 and Eisenhauer 2009.


 
 
   
 
 
 
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For the safety interim analysis in Substudy 3, the primary endpoint is the proportion of patients 
with DLTs during treatment with derazantinib 200 mg BID and atezolizumab 1200 mg Q3W in 
combination. 
For the safety interim analysis in Substudy 5, the primary endpoint is the proportion of patients 
with DLTs during treatment with derazantinib 200 mg BID monotherapy. 
Secondary endpoints
Efficacy, safety and pharmacokinetics of derazantinib will be measured overall and in prespecified 
subsets. The secondary endpoints for active substudies are provided in Section 3.2.2.
STATISTICAL ANALYSIS (as applicable to active substudies)
Key analysis populations
Safety / Intent-to-treat population: All patients with an eligible FGFR1–3 GA who received at 
least one dose of derazantinib or atezolizumab. Safety data will be summarized according to the 
treatment actually received.
Modified intent-to-treat (mITT) population: All patients who received at least one dose of 
derazantinib or atezolizumab, and have at least one post-baseline imaging assessment in accordance 
with RECIST 1.1, or documented clinical progression (every effort should be made to objectively 
assess radiographic progression). The mITT population will be used for all primary efficacy 
endpoint analyses.
Analysis of the primary efficacy endpoint 
The primary efficacy endpoint will be ORR, defined as the achievement of confirmed CR or PR 
using RECIST 1.1, as assessed by BICR. Point estimates and 2-sided 95% confidence intervals 
(CIs) will be provided. The primary analysis will be performed on the mITT population and 
repeated on the per-protocol population.
Analysis of the primary safety endpoint (Substudies 3 and 5)
Safety interim analyses will be performed once up to 10 patients have been enrolled and full safety 
data are available in Substudies 3 and 5 to determine if the revised dosing regimen of derazantinib 
200 mg BID either as monotherapy or in combination with atezolizumab is safe and tolerable. The 
safety evaluation will comprise updating a three-parameter cumulative Bayesian linear regression 
model (BLRM) with overdose control (EWOC) design with monotherapy and combination therapy
for the incidence of DLTs to strictly manage the risk of excessive toxicity (see Section 8.3.5.1). 
The prior data will comprise the current number of DLTs observed at each derazantinib dose
previously explored. With an acceptable target toxicity range for a dose defined as a probability of 
toxicity of 10% to 25% and an overdosing range of ≥25%, the posterior probability of overdosing 
will be updated over time. Data resulting in a posterior probability of overdosing for a dose in 
excess of 25% will be determined as unacceptable. This ensures a tolerable dose is chosen for 
subsequent evaluation of efficacy. 
This process also involves regular dose decision meetings to review the updated cumulative model 
results as well as safety in individual patients. Safety and tolerability of both the monotherapy and 
the combination dose regimens, and restart of enrollment in Substudy 3 and 5 will be concluded by 
joint decisions taken by the IDMC, Investigators, and the Sponsor in reviewing the aggregate of 
DLT, AE and PK data from the first 10 patients each enrolled in Substudies 3 and 5.


 
 
   
 
 
 
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Analysis of secondary endpoints
DCR will be summarized in the same way as the primary endpoint.
DOR, PFS and OS analyses will be performed using Kaplan-Meier (KM) methods. The analysis 
will be performed on the mITT population.
Sensitivity analyses within Substudy 4 will be performed according to the stratification factor 
composite score and its variables. 
ASSESSMENTS
Pharmacokinetics
Sparse derazantinib PK sampling: In the Sparse derazantinib PK sampling population, 
derazantinib plasma concentrations at each nominal time-point will be summarized by substudy 
and cohort using descriptive statistics.
Rich derazantinib PK sampling: All SIA patients in Substudies 3 and 5 will undergo Rich 
derazantinib PK sampling for measurement of plasma concentrations of derazantinib and relevant 
PK parameters. In the Rich derazantinib PK sampling population, PK parameters will be 
determined by non-compartmental analysis. The following parameters will be determined: Cmax, 
tmax, AUC0-12,, AUC0-24, AUClast. PK parameters from rich PK sampling will be summarized by 
Substudy and Cohort using descriptive statistics. Derazantinib plasma concentrations at each 
nominal time-point will be summarized by substudy and cohort using descriptive statistics.
In the atezolizumab PK population, atezolizumab and anti-drug antibodies (ADA) serum 
concentrations at each nominal time-point will be summarized by Substudy and Cohort using 
descriptive statistics.
Safety/tolerability
AE monitoring will be ongoing throughout the study and graded in severity according to the 
guidelines outlined in the National Cancer Institute CTCAE Version 5.0 (NCI CTCAE 5.0). AEs 
will be coded using the standard Medical Dictionary for Regulatory Activities (MedDRA), and 
grouped by System Organ Class and Preferred Term. Additional safety summaries will be provided 
for safety laboratory tests, vital signs, ECGs, physical examinations, ophthalmology examinations 
and ECOG PS.
Efficacy
Tumor response using RECIST 1.1 will be summarized by cohorts. Tumor response will be 
summarized using descriptive statistics and respective 95% confidence intervals. PFS, DOR, and 
OS will be summarized using KM analysis, including number and percentage of patients with 
events and of censored patients.
Biomarker analysis
The biomarker data will be summarized by treatment, using descriptive statistics. Exploratory 
analysis of the correlation between biomarkers and clinical efficacy endpoints may be performed.


 
 
   
 
 
 
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TABLE OF CONTENTS
TABLE OF CONTENTS ..................................................................................................11
LIST OF TABLES ............................................................................................................19
LIST OF FIGURES...........................................................................................................19
LIST OF APPENDICES ...................................................................................................19
LIST OF ABBREVIATIONS ...........................................................................................20
INTRODUCTION.......................................................................................................25
1.1
Background on urothelial cancer........................................................................25
1.1.1
Platinum-based chemotherapy in urothelial cancer.......................................25
1.1.2
Immune-checkpoint inhibiting agents in urothelial cancer ...........................26
1.2
FGFR inhibition in urothelial carcinoma ...........................................................27
1.2.1
Current clinical evidence...............................................................................27
1.2.2
Derazantinib...................................................................................................28
1.3
Combination of FGFR inhibition and immune-checkpoint blockade in 
urothelial carcinoma...........................................................................................28
1.4
Study rationale....................................................................................................30
1.4.1
Study design rationale ...................................................................................30
1.4.1.1
Rationale for Substudy 1..........................................................................31
1.4.1.2
Rationale for Substudy 2 (including results) ...........................................32
1.4.1.3
Rationale for Substudy 3..........................................................................32
1.4.1.4
Rationale for Substudy 4..........................................................................33
1.4.1.5
Rationale for Substudy 5..........................................................................34
1.4.1.6
Rationale for molecular testing devices...................................................34
1.4.1.7
Rationale for pharmacodynamic research................................................35
1.4.2
Rationale for patient reported outcomes........................................................35
1.4.3
Dose rationale................................................................................................36
1.4.3.1
Derazantinib.............................................................................................36
1.4.3.2
Derazantinib in combination with atezolizumab .....................................36
1.5
Risk-benefit assessment .....................................................................................37
1.5.1
Derazantinib...................................................................................................37
1.5.2
Derazantinib in combination with atezolizumab...........................................38


 
 
   
 
 
 
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1.5.3
Pharmacodynamic research...........................................................................39
1.5.4
Conclusion to risk-benefit assessment...........................................................39
STUDY OBJECTIVES ...............................................................................................39
2.1
Primary objectives and hypotheses ....................................................................39
2.1.1
Primary efficacy objective.............................................................................39
2.1.2
Primary safety objective of Substudy 3.........................................................40
2.1.3
Primary safety objective of Substudy 5.........................................................40
2.2
Secondary objectives..........................................................................................40
2.3
Exploratory objectives........................................................................................41
2.3.1
Exploratory objectives specific to efficacy-estimating substudies................41
2.3.2
Exploratory PK objectives.............................................................................41
INVESTIGATIONAL PLAN......................................................................................42
3.1
Overview of study design and study flow chart.................................................42
3.1.1
Molecular eligibility......................................................................................43
3.1.2
Pre-screening .................................................................................................44
3.1.3
Screening .......................................................................................................44
3.1.4
Treatment period............................................................................................44
3.1.5
End of Treatment / Safety Follow-up period.................................................45
3.1.6
Optional post-discontinuation study treatment crossover (Cohort 4a)..........46
3.1.6.1
Eligibility criteria for post-discontinuation study treatment 
crossover………… ..................................................................................46
3.1.6.2
Assessments during post-discontinuation study treatment crossover......46
3.1.7
Survival Follow-up period.............................................................................47
3.1.8
Beginning and end of the study.....................................................................47
3.2
Endpoints............................................................................................................47
3.2.1
Primary endpoints..........................................................................................47
3.2.1.1
Primary endpoint......................................................................................47
3.2.1.2
Primary safety endpoint (Substudies 3 and 5) .........................................48
3.2.2
Secondary endpoints......................................................................................48
3.2.3
Exploratory endpoints ...................................................................................49
3.2.3.1
Exploratory endpoints specific to efficacy-estimating substudies...........49


 
 
   
 
 
 
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3.2.3.2
Exploratory PK endpoints........................................................................49
3.3
Number of patients.............................................................................................49
3.4
Study sites ..........................................................................................................49
3.5
Independent Data Monitoring Committee..........................................................50
STUDY POPULATION..............................................................................................50
4.1
Target populations..............................................................................................50
4.2
Inclusion criteria.................................................................................................50
4.3
Exclusion criteria................................................................................................53
4.4
Method of assignment to substudy and treatment..............................................56
4.4.1
Substudy 1 .....................................................................................................56
4.4.2
Substudy 3 .....................................................................................................56
4.4.3
Substudy 4 .....................................................................................................56
4.4.4
Substudy 5 .....................................................................................................57
4.5
Discontinuation from the study treatment or study............................................57
4.5.1
Patient discontinuation from study treatment................................................57
4.5.2
Patient discontinuation from the study..........................................................58
4.5.3
Replacement of patients.................................................................................58
4.5.4
Study discontinuation ....................................................................................58
SCHEDULE OF ASSESSMENTS AND PROCEDURES.........................................59
5.1
Summary of schedule of assessments ................................................................59
5.2
Study visits .........................................................................................................64
5.2.1
Screening/enrollment period .........................................................................64
5.2.1.1
Informed consent .....................................................................................64
5.2.1.2
Pre-screening visit....................................................................................64
5.2.1.3
Screening visit..........................................................................................64
5.2.2
Treatment period............................................................................................66
5.2.2.1
Cycle 1, Day 1 (all patients) ....................................................................66
5.2.2.2
Cycle 1, Day 8 (±3 days) (SIA patients in Substudies 3 and 5) ..............67
5.2.2.3
Cycle 1, Day 15 (±3 days) (all patients) ..................................................67
5.2.2.4
Cycle 2+, Day 1 (+3 days) (all patients)..................................................67
5.2.2.5
Cycle 2, Day 8 (±3 days) (SIA patients in Substudies 3 and 5) ..............69


 
 
   
 
 
 
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5.2.2.6 Cycle 2, Day 15 (±3 days) (SIA patients in Substudy 3 and 5)...............69
5.2.2.7
End of Treatment assessment (≤ 7 days after last dose) (all patients).....69
5.2.2.8
Safety follow-up (28 days after last dose; ± 3 days)................................70
5.2.2.9
Safety follow-up (90 days after last dose; ± 3 days)................................71
5.2.3
Survival follow-up period..............................................................................71
5.2.3.1 Overall survival follow-up (at least every 3 months ± 14 days)..............71
5.3
Study procedures................................................................................................72
5.3.1
Screening procedures.....................................................................................72
5.3.1.1 Medical history / baseline medical conditions.........................................72
5.3.1.2
Demography.............................................................................................72
5.3.1.3
Prior cancer history..................................................................................72
5.3.1.4 Prior and concomitant medications..........................................................72
5.3.2
Safety assessments.........................................................................................72
5.3.2.1
Physical examination ...............................................................................73
5.3.2.2 Eastern Cooperative Oncology Group performance status......................73
5.3.2.3
Complete ophthalmological examination ................................................73
5.3.2.4
Electrocardiogram (12-lead) triplicates ...................................................74
5.3.2.5 Clinical safety laboratory blood tests.......................................................74
5.3.2.6 Urinalysis……………….........................................................................75
5.3.2.7 Pregnancy testing.....................................................................................75
5.3.2.8 Adverse event monitoring........................................................................76
5.3.2.9 Concomitant medications ........................................................................76
5.3.3
Efficacy assessments .....................................................................................76
5.3.3.1
Tumor imaging and assessment of disease..............................................76
5.3.3.2 Tumor measurement and response evaluations .......................................77
5.3.4
Pharmacokinetic assessments........................................................................79
5.3.4.1 Pharmacokinetic assessments for derazantinib........................................79
5.3.4.2
Assessments for pharmacokinetics and anti-therapeutic antibodies of 
atezolizumab............................................................................................81
5.3.5
Biomarker assessments..................................................................................81
5.3.5.1 Research liquid biopsy.............................................................................81


 
 
   
 
 
 
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5.3.5.2
Archival tumor tissue...............................................................................82
5.3.5.3
Pharmacodynamic research (optional).....................................................82
5.3.5.4
Future biomedical research......................................................................82
5.3.6
PRO assessments...........................................................................................82
STUDY TREATMENTS.............................................................................................85
6.1
Investigational products .....................................................................................85
6.1.1
Derazantinib...................................................................................................85
6.1.1.1
Derazantinib administration.....................................................................85
6.1.1.2
Labeling and packaging...........................................................................85
6.1.1.3
Drug accountability..................................................................................85
6.1.1.4
Shipping and storage conditions..............................................................86
6.1.1.5
Dose modifications ..................................................................................86
6.1.1.6
Missed-dose management........................................................................90
6.1.1.7
Overdose 90
6.1.2
Atezolizumab.................................................................................................90
6.1.2.1
Atezolizumab administration...................................................................90
6.1.2.2
Labeling and packaging...........................................................................90
6.1.2.3
Drug accountability..................................................................................90
6.1.2.4
Shipping and storage conditions..............................................................91
6.1.2.5
Preparation and stability of study drug....................................................91
6.1.2.6
Dose modifications ..................................................................................92
6.1.2.7
Missed-dose management........................................................................92
6.1.2.8
Overdose 92
6.1.3
Dosing schedule of study drugs.....................................................................92
6.1.4
Duration of treatment.....................................................................................93
6.2
Treatment compliance........................................................................................93
6.2.1
Treatment compliance for derazantinib.........................................................93
6.2.2
Treatment compliance for atezolizumab .......................................................94
6.3
Prior treatment....................................................................................................94
6.4
Concomitant treatments......................................................................................94
6.4.1
Permitted treatment........................................................................................94


 
 
   
 
 
 
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6.4.2
Prohibited treatment / Treatment to be avoided or used with caution...........95
SAFETY ......................................................................................................................97
7.1
Warnings and precautions..................................................................................97
7.1.1
Derazantinib...................................................................................................97
7.1.1.1
Treatment-emergent adverse events ........................................................97
7.1.1.2
Identified and potential risks....................................................................97
7.1.2
Atezolizumab.................................................................................................97
7.1.3
Contraception and pregnancy........................................................................97
7.1.3.1
Contraception...........................................................................................98
7.1.3.2
Pregnancy testing.....................................................................................98
7.1.3.3
Nursing mothers.......................................................................................98
7.2
Definitions..........................................................................................................98
7.2.1
Adverse event ................................................................................................98
7.2.2
Serious adverse event ....................................................................................98
7.2.3
Unexpected adverse event or serious adverse event......................................99
7.2.4
Suspected adverse event or serious adverse event.........................................99
7.2.5
Suspected unexpected serious adverse reaction ............................................99
7.2.6
Adverse events of special interest ...............................................................100
7.2.7
Treatment-emergent adverse events............................................................100
7.3
Evaluation of adverse events............................................................................100
7.3.1
Grading of Severity .....................................................................................100
7.3.2
Assessment of causality...............................................................................101
7.3.3
Dose-limiting toxicities (applicable to Substudies 3 and 5)........................101
7.4
Handling of safety information and collection periods....................................102
7.4.1
Responsibilities and procedures ..................................................................102
7.4.2
Handling of safety data during the pre-treatment period.............................102
7.4.3
Handling of safety data during the treatment period and up to the last 
scheduled follow-up ....................................................................................102
7.4.3.1
Adverse event management...................................................................103
7.4.3.2
Serious adverse event and AESI reporting ............................................104
7.4.4
Handling of post-study safety data..............................................................105


 
 
   
 
 
 
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7.4.5
Reporting and handling of pregnancies.......................................................105
7.5
Adverse events associated with an overdose or error in drug administration
106
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ......................107
8.1
Sample size considerations by substudy ..........................................................107
8.1.1
Substudy 1 ...................................................................................................107
8.1.2
Substudy 3 ...................................................................................................108
8.1.3
Substudy 4, Cohorts 4a and 4b....................................................................108
8.1.4
Substudy 5 ...................................................................................................109
8.2
Analysis populations ........................................................................................109
8.2.1
Safety analysis population / Intent-to-treat population................................109
8.2.2
Modified intent-to-treat population .............................................................109
8.2.3
Per-protocol population...............................................................................110
8.2.4
Pharmacokinetic analysis population ..........................................................110
8.3
Statistical and analytical methods ....................................................................110
8.3.1
Patient demographics, medical history, and other baseline characteristics
.....................................................................................................................110
8.3.2
Study treatment exposure and compliance..................................................111
8.3.3
Prior and concomitant treatments................................................................111
8.3.4
Efficacy analysis..........................................................................................111
8.3.4.1
Primary endpoint....................................................................................111
8.3.4.2
Secondary efficacy endpoints ................................................................112
8.3.5
Safety data analysis .....................................................................................113
8.3.5.1
Dose-limiting toxicity (Substudies 3 and 5 only) ..................................113
8.3.5.2
Other safety parameters .........................................................................115
8.3.6
Pharmacokinetic analysis ............................................................................115
8.3.7
Pharmacodynamics analyses .......................................................................116
8.3.8
PRO analysis ...............................................................................................116
8.3.9
Crossover analysis.......................................................................................116
8.3.10 Handling of missing data and discontinuations...........................................116
STUDY ADMINISTRATION AND REGULATORY ASPECTS ..........................117


 
 
   
 
 
 
 
 
 
 
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9.1
Study records....................................................................................................117
9.1.1
Investigator Site File....................................................................................117
9.1.2
Case report forms ........................................................................................117
9.1.3
Patient source documents ............................................................................117
9.1.4
Document retention and archiving ..............................................................117
9.2
Sample retention...............................................................................................118
9.3
Clinical monitoring ..........................................................................................118
9.4
Audits and inspections .....................................................................................118
9.5
Protocol amendments.......................................................................................119
9.6
Premature termination of the study..................................................................119
9.7
Publication policy.............................................................................................119
ETHICS AND GOOD CLINICAL PRACTICE .......................................................121
10.1 Good Clinical Practice .....................................................................................121
10.2 Informed consent..............................................................................................121
10.3 Patient confidentiality and data protection.......................................................122
10.4 Independent Ethics Committees / Institutional Review Boards.......................122
PROTOCOL VERSION HISTORY..........................................................................122
REFERENCES ..........................................................................................................123
APPENDICES ...........................................................................................................132


 
 
   
 
 
 
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LIST OF TABLES
Table 1
Schedule of assessments...........................................................................60
Table 2 
ECOG performance status ........................................................................73
Table 3
Imaging and treatment after first radiologic evidence of PD if 
iRECIST is followed.................................................................................79
Table 4
Derazantinib dose reduction schema ........................................................87
Table 5
Dose delays/reductions for drug-related toxicity......................................88
Table 6
Dosing schedule of study drugs by substudy............................................92
Table 7 
Summary of sample size and required responses of proposed two-
stage Fleming design ..............................................................................108
Table 8 
Summary of sample size and required responses of proposed two-
stage Fleming design ..............................................................................109
LIST OF FIGURES
Figure 1
Overview of study design .........................................................................42
LIST OF APPENDICES
Appendix 1
Eligible FGFR genetic aberrations .........................................................132
Appendix 2
Assessment of anti-tumor activity per RECIST v. 1.1 ...........................133
Appendix 3
Comparison of RECIST 1.1 and iRECIST criteria.................................142
Appendix 4
Management of atezolizumab-specific adverse events..........................143
Appendix 5
Collection and Management of Specimens for Future Biomedical 
Research..................................................................................................154
Appendix 6
Understanding the intent, scope and public health benefits of 
exploratory biomarker research ..............................................................157
Appendix 7
Examples of in vivo substrates, inhibitors, and inducers for specific 
CYP enzymes..........................................................................................169
Appendix 8
Examples of in vivo substrates, inhibitors, and inducers of 
P-glycoprotein.........................................................................................173
Appendix 9
Drugs with the potential to prolong QT and/or cause Torsades de 
Pointes.....................................................................................................174
Appendix 10
Criteria for evaluating relationship between adverse events and study 
treatment .................................................................................................178
Appendix 11
Investigator’s protocol signature page....................................................180


 
 
   
 
 
 
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LIST OF ABBREVIATIONS
(i)CPD1
Confirmed progressive disease
(i)CR1
Complete response
(i)PR1
Partial response
(i)RECIST1
Response Evaluation Criteria In Solid Tumors
(i)SD1
Stable disease
(i)UPD1
Unconfirmed progressive disease 
1L
First-line treatment
2+L
Second-line or post-second line treatment
ADA
Anti-drug antibodies
ADR
Adverse drug reaction
AE
Adverse event
AESI
AE of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase 
ANC
Absolute neutrophil count 
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase 
AUC
Area under the plasma concentration versus time 
curve
AZB
Atezolizumab
BICR
Blinded independent central review 
BLRM
Bayesian linear regression model
CI
Confidence interval
CLCR
Creatinine clearance
Cmax
Maximum plasma concentration
CNS
Central nervous system
CRP
C-reactive protein
CRS
Cytokine-release syndrome
CSF1R
Colony-stimulating factor-1 receptor 
CT
Computed tomography
                                                
1 Where predicated by the letter ‘i´, abbreviation refers to the equivalent acronym under RECIST adapted to account for 
the unique tumor response seen with immunotherapeutic drugs.


 
 
   
 
 
 
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CTCAE
Common Terminology Criteria for Adverse 
Events 
ctDNA
Circulating tumor DNA
cfDNA
Cell-free DNA
CxDx
Cycle (cycle number), Day (day number), e.g. 
C4D1 = Cycle 4, Day 1
CyTOF
Cytometry by time of flight
D0
Pretreatment phase
D1
Day 1
DCR
Disease control rate
DL
Dose Level
DLT
Dose limiting toxicity
DMC
Data Monitoring Committee
DOR
Duration of response 
DZB
Derazantinib
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EU
European Union
EWB
Emotional well-being
EWOC
Escalation with overdose control
FACT-G
FACT General
FDA
Food and Drug Administration
FFPE
Formalin-fixed paraffin-embedded 
FGF
Fibroblast growth factor 
FGFR
Fibroblast growth factor receptor 
FISH
Fluorescence in-situ hybridization
FSH
Follicle stimulating hormone 
fT3
Tri-iodothyronine
fT4
Thyroxine
FWB
Functional well-being
GA
Genetic aberration
GC
Gemcitabine/carboplatin


 
 
   
 
 
 
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GCP
Good Clinical Practice
GEP
Gene-expression profile 
GLP
Good Laboratory Practice
GPP3
Good Publication Practice
H0
Null hypothesis 
HA
Alternative hypothesis 
HBV
Hepatitis B virus
hCG
Local serum pregnancy test 
HCV
Hepatitis C virus
HIV
Human imunodeficiency virus
HR
Hazard ratios
HR-QoL
Health-related quality of life 
IB
Investigator’s Brochure
IC
Immune cell
IC50
50% inhibition
iCCA
Intrahepatic cholangiocarcinoma 
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee 
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
INR
International normalized ratio
IPCW
Inverse Probability of Censoring Weighted
IRB
Institutional Review Board
IRT
Interactive response technology 
IRR
Immune-related reaction
ISF
Investigator Site File
ITT
Intent-to-treat
iUPD
Immunotherapy-treated unconfirmed progression
IV
Intravenous(ly)
IWRS
Interactive Web Response System
KM
Kaplan-Meier
LFT
Liver function test
MAPK
MAP-Kinase


 
 
   
 
 
 
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M-CAVI
Methotrexate/carboplatin/vinblastine 
MedDRA
Medical Dictionary for Regulatory Activities 
Mid-C2
Middle of Cycle2
mITT
Modified intent-to-treat 
MMR-D
Mismatch repair-deficient 
MRI
Magnetic resonance imaging 
MSI-H
High-frequency microsatellite instability
MTD
Maximum tolerated dose
mUC
Locally advanced or metastatic and recurrent or 
progressing urothelial cancer  
n
Number
NCI
National Cancer Institute 
NCI CTCAE 5.0
National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0
NE
Not evaluable
NGS
Next-generation sequencing 
OCT
Ocular coherence tomography
ORR
Objective response rate
OS
Overall survival
PCR
Polymerase chain reaction
PD
Progressive disease
PD
Pharmacodynamics
PD-1
Programmed cell death receptor-1 
PD-L1
Programmed death ligand-1 
PDR
Pharmacodynamics Research Group
PDX
Patient-derived xenograft 
PE
Polyethylene
PFS
Progression-free survival
P-gp
P-glycoprotein
PI
Prescribing Information
PK
Pharmacokinetic(s)
PO
Orally
POS
Positive (molecular status)
PopPK
Population PK


 
 
   
 
 
 
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PP
Per protocol
PRO
Patient-reported outcome
PVC
Polyvinyl chloride 
PWB
Physical well-being
Q3W
Every 3 weeks
QALY
Quality-adjusted life-year
QD
Once daily
QOD
Every other day
QTc
Corrected QT interval
QTcF 
Difference between QTc corrected by Fridericia's 
formula
RNA
Ribonucleic acid
RNAseq
RNA sequencing
RP2D
Recommended Phase 2 dose
RSI
Reference Safety Information 
SAE
Serious adverse event
SAP
Statistical Analysis Plan 
SEER
Surveillance, Epidemiology, and End Results
(Program)
SIA
Safety interim analysis
SmPC
Summary of Product Characteristics
SoC
Standard of care
SOP
Standard Operating Procedure
SUSAR
Suspected unexpected serious adverse reaction
SWB
Social well-being
TAM
Tumor-associated macrophage
TEAE
Treatment-emergent adverse event
tmax
Time to peak (maximum) plasma concentration
TSH
Thyroid stimulating hormone
UC
Urothelial cancer 
ULN
Upper limit of normal
USA
United States of America
VAS
Visual analog scale 


 
 
   
 
 
 
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INTRODUCTION
1.1
Background on urothelial cancer
Urothelial cancer (UC) is the most common cancer of the urinary system worldwide, with 
UC of the bladder being the predominant histologic type and location. Although less 
common, UC may also originate in the renal pelvis, ureter, or urethra. It has been estimated 
that in 2019, there would be 80,470 new cases of bladder cancer and 17,670 deaths in the 
USA. Similar worldwide data estimate that there were 549,000 new cases and 199,922
deaths in 2018 (Bray 2018). The gender-specific estimates were 424,082 new cases and 
148,270 deaths in men, and 125,311 new cases and 51,652 deaths in women (Bray 2018).
In a structured literature search, the crude incidence rate of UC reported for the USA, EU,
and Japan was derived to be 25.7, 25.7 and 18.6 per 100,000 (83,662; 129,977; and 23,567 
patients), respectively. The incidence of locally-advanced or metastatic UC was 3.8, 3.8 
and 2.8 per 100,000 (12,494; 19,411 and 3,520 patients), respectively (Bharmal 2017).
Based on patients diagnosed with urothelial cancer since 1975 in the USA, the
Surveillance, Epidemiology, and End Results (SEER) Program’s Cancer Statistics Review 
1975–2017 reported a 5.5% 5-year relative survival rate for patients diagnosed with 
primary metastatic UC (Howlader 2020). Poor prognostic factors for survival in patients 
with metastatic UC include advanced stage of disease at the time of initial diagnosis, 
Karnofsky Performance Status < 80%, and visceral metastasis (i.e., lung, liver, or bone; 
Bajorin 1999). The presence of these unfavorable features was associated with a median 
survival of 4 months, compared with 18 months in patients without these features 
(Loehrer 1992).
Current choices for standard treatment of patients with locally-advanced or metastatic and 
recurrent or progressing UC (hereafter identified by the acronym mUC) are cisplatin-based 
chemotherapy, immune-checkpoint blockade, and combinations thereof. Specifically 
identified subgroups of mUC patients represent the indications investigated in this study. 
No targeted agents directed against oncogenic driver mutations have yet been fully 
approved in these indications.
1.1.1
Platinum-based chemotherapy in urothelial cancer
Prior to the advent of programmed cell death receptor-1 (PD-1)/programmed death ligand-
1 (PD-L1) checkpoint inhibitors, systemic chemotherapy with cisplatin-based regimens 
was the standard of care (SoC), leading to median survival of around 1 year 
(von der Maas 2000, Sternberg 2001). However, for patients with platinum-refractory 
disease, median survival was only 6–9 months (Lorusso 1998, McCaffrey 1997,
Papamichael 1997, Vaughn 2002).
Due to a variety of factors, including renal or hearing impairment, poor performance status, 
and neuropathies, 30% to 50% of patients with chemotherapy-naïve mUC are not 
candidates for cisplatin-based chemotherapy (Galsky 2011), and prior to the advent of 
therapeutic immune-checkpoint blockade, cisplatin-ineligibility limited treatment options 
to carboplatin-based regimes (Dash 2006, Galsky 2011, Bellmunt 2016). 


 
 
   
 
 
 
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Among the few randomized studies investigating how to best treat cisplatin-ineligible 
patients, a Phase 2/3 study compared two carboplatin-based chemotherapy regimens in 
mUC patients who were clinically considered ineligible (‘unfit’) for cisplatin 
chemotherapy as first-line treatment (De Santis 2009, De Santis 2011). Study participants 
received either gemcitabine/carboplatin (GCa) or methotrexate/carboplatin/vinblastine 
(M-CAVI). There were no significant differences in efficacy between the two treatment 
groups. The incidence of severe acute toxicities1 was higher for those receiving M-CAVI. 
Patients treated with GCa attained an Objective Response Rate (ORR) of 36%. The median 
duration of treatment was 4 cycles and 14 weeks, respectively. The most common grade 3 
to 4 toxicities with GCa were neutropenia (53%), febrile neutropenia (4%), 
thrombocytopenia (48%), and infection (12%), limiting the administration of the full six
planned cycles to a minority of approximately one third of the platinum-ineligible 
population. The proportion of patients with severe acute toxicity-related death was 9% for 
patients treated with GCa. It is noted, however, that carboplatin is not a formally-approved 
drug for the treatment of cisplatin-ineligible patients.
1.1.2
Immune-checkpoint inhibiting agents in urothelial cancer
UC is a highly immunogenic tumor, partly as a result of the relatively high level of 
nonsynonymous mutations, which represents at least one mechanism for the generation of 
tumor neoantigens for the host immune system to recognize (Alexandrov 2013). PD-L1 
overexpression in the tumor microenvironment and its binding to PD-1 on tumor antigen-
specific T-cells is a mechanism for immune escape in UC. After decades of slow progress 
in drug development in UC, the advent of immune-checkpoint blockade has rapidly 
become an indispensable tool for its treatment. To date, atezolizumab, durvalumab, and 
avelumab (PD-L1 inhibitors), and pembrolizumab and nivolumab (PD-1 inhibitors), have 
been approved by the Food and Drug Administration (FDA) for mUC. In the post-platinum 
refractory setting, these five checkpoint blocking agents generated response rates between 
15–21% (Balar 2017a, Balar 2017b and Suzman 2018, O’Donnell 2017, Sharma 2017,
Powles 2017, Apolo 2017, Balar 2017), while ORR in the cisplatin-ineligible frontline 
setting was approximately 24% and 29% for atezolizumab and pembrolizumab, 
respectively. 
In the two ongoing clinical studies, of atezolizumab (IMvigor130) and pembrolizumab 
(KEYNOTE-361), the Data Monitoring Committee (DMC) for each study performed an 
early review and found that patients in the monotherapy arms of both studies with 
PD-L1-low status had higher mortality compared with patients who received cisplatin- or 
carboplatin-based chemotherapy. The sponsors of both studies stopped enrolling patients 
whose tumors have PD-L1-low status to the atezolizumab or pembrolizumab monotherapy 
arms, in accordance with the DMCs’ recommendations (Suzman 2018).
As a consequence, patients with mUC and PD-L1-low expression are without a standard
and well-tolerated first-line treatment option beyond cytotoxic regimens which are often 
poorly tolerated in this indication (De Santis 2011).
                                                
1 Severe acute toxicity was defined as death as a result of toxicity, renal toxicity (grade 3 to 4), febrile neutropenia (grade 
3 to 4), hemorrhage/bleeding with thrombocytopenia (grade 4), or mucositis (grade 3 to 4).


 
 
   
 
 
 
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1.2
FGFR inhibition in urothelial carcinoma
1.2.1
Current clinical evidence
Activation of the fibroblast growth factor receptor (FGFR) is a common oncogenic 
mechanism, occurring in a subset of nearly all common cancers (Babina 2017,
Turner 2010). Genetic aberrations (GAs) in the FGFR genes in carcinomas result in 
receptor amplification, mutation, and generation of aberrant receptor fusions through 
translocation (Babina 2017, Turner 2010).
It is estimated that approximately 15-20% of patients with advanced/metastatic urothelial 
cancer have genomic FGFR aberrations (Necchi 2018, di Martino 2016, Helsten 2016). 
FGFR3 mutations, and FGFR1, FGFR2, or FGFR3 gene rearrangements and fusions (for 
the purposes of this protocol hereafter referred to as FGFR1–3 GAs) are the most frequent 
FGFR GA among patients with UC and are found predominantly among patients whose 
tumors are allocated to the luminal subgroup (Choi 2017).
FGFR inhibitors have therefore been proposed for the treatment of patients whose tumors 
harbor FGFR GAs, and a number of FGFR inhibitors are currently under development in 
Phase 1–3 studies. Patients with mUC and FGFR GAs treated with FGFR inhibitors 
achieved an ORR ranging from 21–40% in uncontrolled clinical Phase 1/2 studies. The 
current evidence for FGFR-inhibiting treatment in mUC patients was generated with the 
following compounds: 

Erdafitinib (Balversa®) was granted an accelerated approval from the U.S. FDA in 
2019 for the treatment of adult patients with locally advanced or metastatic urothelial 
carcinoma that have susceptible FGFR3 or FGFR2 genetic alterations and who 
progressed during or following at least one line of prior platinum-containing 
chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-
containing chemotherapy (Balversa USPI) based on a Phase 2 study, reporting an ORR 
of 32% (N=87) ; of note, erdafitinib achieved an ORR of 59% (13 responses) in 22 UC 
patients unresponsive to immune-checkpoint blockade and an ORR of 35% (27 
responses) in 77 UC patients without prior immune-checkpoint blockade (Loriot 2019).

Infigratinib (BGJ398) achieved an ORR of 25% (N=67) in patients with confirmed 
FGFR3 GAs (Pal 2018).

Pemigatinib (INCB054828) is being investigated in an ongoing Phase 2 study of UC 
patients with fibroblast growth factor (FGF)/FGFR GAs (NCT02872714). Interim 
results from 61 patients with FGFR3 mutations/fusions have demonstrated an ORR of 
21% (Necchi 2018).

Rogaratinib achieved an ORR of 24% (N=51) in patients with mRNA-ISH/NanoString 
confirmed FGFR1/3 mRNA overexpression (Phase 1 expansion cohort) (Joerger 2018). 
For derazantinib, preclinical data from a number of patient-derived xenograft mouse 
models in UC expressing FGFR mutations suggested a similar or superior efficacy with 
derazantinib in a direct comparison to erdafitinib using previously described equivalent 
dosing schedules (Perera 2017, Basilea data on file). In these experiments, similar or less 
body weight loss was observed with derazantinib.


 
 
   
 
 
 
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Clinical anti-tumor activity with FGFR inhibitors was found in studies with patients 
identified by various methods (including but not limited to PCR, FM NGS™,
RNAscope™/NanoString™) as carrying FGFR GAs, and applying differential definitions 
of the intended target population (mutations, fusions and ribonucleic acid [RNA]
overexpression). In recent studies with erdafitinib (Loriot 2019), targeting mUC patients 
carrying FGFR2/3 GAs has been shown to be a successful approach (Balversa USPI).
Based on a recent search in Foundation Medicine’s FoundationInsight™ database of 
FGFR1–3 GAs in 2,405 urothelial carcinoma test specimens, known or likely activating 
missense point mutations followed by rearrangements and copy number changes were 
found at a prevalence of approximately 18%, 4% and 3% of specimens, respectively. 
The frequency of known or likely activating FGFR3, FGFR2 and FGFR1 mutations and/or 
rearrangements/fusion eligible for  this protocol is approximately 20%, 0.8% and 0.4%, 
respectively (Basilea data on file, Foundation Medicine Insight database, January 2019 –
see Appendix 1). Due to the uncertainty around the oncogenic nature of FGFR
amplification (Pearson 2016), FGFR amplifications are currently not included in the 
evaluation of derazantinib in patients with mUC expressing FGFR1–3 GAs.
1.2.2
Derazantinib
Derazantinib is a spectrum-selective FGFR inhibitor with multi-kinase activity. In 
biochemical studies, derazantinib showed potent activity against both wild-type and 
variants of the FGFR kinases (FGFR1–3), and to a lesser extent against FGFR4, with 
inhibitor concentration values required for 50% inhibition (IC50) in the low nM range. Less 
activity, but within 2–10 fold of FGFR2 activity, was observed for a number of other 
kinases relevant to anti-tumor treatment, i.e., VEGF-R2, PDGF-R, KIT, RET, DDR2, 
colony-stimulating factor-1 receptor (CSF1R), and the Src family kinases (Hall 2016).
In an autophosphorylation assay, derazantinib inhibited autophosphorylation of FGFR1
and FGFR2 in a dose-dependent manner, suggesting that, in addition to inhibiting the 
active (phosphorylated) form of the kinase, derazantinib binds to the unphosphorylated or 
inactive form of the kinase and delays its activation. Across a large panel of cell-lines, IC50s 
for inhibition of proliferation ranged from 0.1–10 µM, with the more sensitive lines being 
associated with high FGFR expression (1/2/3, or specific activating mutations). Preclinical 
studies demonstrated potent inhibition of tumor growth in FGFR pathway-activated 
models, including in FGFR2-driven (amplification/fusion/mutation) tumor xenografts
grown subcutaneously in nude mice (Hall 2016). Furthermore, in a Phase I study, one 
derazantinib-treated evaluable UC patient with FGFR2 and FGF19 amplification achieved 
a partial response (PR) (Papadopoulos 2017).
Consequently, it is hypothesized that derazantinib may be a suitable treatment option for 
mUC patients expressing FGFR1–3 GAs.
1.3
Combination of FGFR inhibition and immune-checkpoint blockade in 
urothelial carcinoma
Derazantinib is an investigational drug and is not yet registered in any indication globally. 
Atezolizumab (Tecentriq®) is a PD-L1 blocking antibody indicated (amongst others) for 


 
 
   
 
 
 
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the treatment of patients with locally surgically unresectable or metastatic UC, including 
those who were not eligible for frontline cisplatin-containing chemotherapy if their tumors 
express PD-L1 on more than 5% of tumor-infiltrating immune cells (ICs), as determined 
by an FDA-approved test1, or are not eligible for any platinum-containing chemotherapy 
regardless of PD-L1 status, or have disease progression during or following any platinum-
containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy.
Since pembrolizumab, the second drug approved for the treatment of specified 
mUC indications in the frontline setting, has received the same restriction of its indication 
for the frontline treatment of cisplatin-ineligible mUC patients whose tumors have 
PD-L1-low status, there is currently no strategic approach for mUC patients who express 
FGFR GAs and are considered cisplatin-ineligible in the frontline setting. Consequently, 
the availability of effective and tolerable treatment regimens for mUC patients with both 
FGFR GAs and PD-L1-low expression, which comprise approximately 20% of the 
frontline patient population, is limited. PD-L1-low expression together with expression of 
FGFR GAs is frequently seen in luminal-I-type tumors (Moreno 2020, Rosenberg 2020, 
Choi 2017, Siefker-Radtke 2018b, Loriot 2019). Interim results recently published from 
two  ongoing Phase 2 studies using either rogaratinib and atezolizumab (Rosenberg 2020) 
or erdafitinib and cetrelimab (Moreno 2020) in combination demonstrated ORRs of 44% 
each in patients selected for FGFR1/3 mRNA expression and specific FGFR2/3 alterations, 
respectively, and unselected for PD-L1 expression.
The immunogenicity of UC is well documented (Babina 2017, Alexandrov 2013) and 
immune-checkpoint blockade has been demonstrated to generate long-term responses in 
several studies to date (Felsenstein 2018, Stenehjem 2018). However, recent research has 
identified an association between PD-L1-low expression and an increased probability of 
concurrent expression of FGFR GAs in UC patients (Choi 2017, Siefker-Radtke 2018b,
Loriot 2019). In addition, redundancy in immunosuppressive pathways involves further 
mechanisms that could explain the observation that only certain subsets of UC patients 
respond to immune-checkpoint blockade; one example for such a pathway is the CSF1R
interaction that leads to a phenotype switch of macrophages in the tumor 
microenvironment. A predominant M2-phenotype of tumor-associated macrophages 
(TAMs) has been shown to be associated with unfavorable patient outcomes, and to abolish 
susceptibility to therapeutic immune-checkpoint blockade (Rizvi 2018, Yang 2017,
Hasita 2010). Conversely, it has been shown that CSF1R inhibition may bypass tumor-
induced immunosuppression, restore T-cell activity, downregulate immunosuppressive 
macrophage activity and improve susceptibility to therapeutic immune checkpoint 
blockade using anti-PD-1/PD-L1 antibodies (Fleming 2018, Kim 2015, Ries 2014). 
                                                
1 For atezolizumab, a low PD-L1 expression level is less than 5% of immune cells staining positive for PD-L1 by 
immunohistochemistry. Information on FDA-approved tests for the determination of PD-L1 expression in 
locally-advanced or metastatic urothelial carcinoma or triple-negative breast cancer is available at: 
http://www fda.gov/CompanionDiagnostics.


 
 
   
 
 
 
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In comparative kinase screens of known FGFR inhibitors, CSF1R kinase inhibition seems
to be a unique characteristic of derazantinib (Basilea, data on file, 2019). Structural 
analyses suggest that conformations of FGFR- and CSF1R-structures are such that 
derazantinib can efficiently occupy the CSF1R kinase sub-pocket as well as the ATP-
binding site of both FGFR and CSF1R (Basilea, data on file, 2019). Derazantinib reduced 
ligand-stimulated phospho-CSF1R in mouse macrophages in a concentration-dependent 
manner, with a maximum effect similar to the CSF1R inhibitor BLZ945 (Li 2019). In 
addition, studies found a frequent co-incidence of FGFR GAs (mainly FGFR3 mutations) 
and low PD-L1 expression in UC patient samples (Choi 2017, Siefker-Radtke 2018b, 
Loriot 2019). These observations form the rationale to combine targeting FGFR-driven 
tumor cells with dual targeting of immunosuppressive stromal cells via CSF1R and PD-L1 
to revert immune escape of tumor cells. Therefore, the administration of derazantinib in 
combination with atezolizumab may provide additional benefit, which is investigated in 
Substudies 2, 3 and 4 of this protocol.
1.4
Study rationale
1.4.1
Study design rationale
Several 
immune-checkpoint 
inhibitors, 
including 
atezolizumab 
(Balar 
2017a,
Rosenberg 2016), have already been approved for use in mUC, putting immune- inhibitors 
along-side 
standard 
platinum-based 
combination 
chemotherapy 
regimens 
(Felsenstein 2018). For patients with mUC expressing FGFR GAs, FGFR inhibitors are 
considered emerging treatment options in addition to standard chemotherapy regimens and 
immune-checkpoint inhibitors. Both preclinical and clinical data from derazantinib studies 
(Basilea, data on file, 2019, Papadopoulos 2017) and emerging clinical data from other 
studies with FGFR inhibitors (Joerger 2018, Pal 2018, Loriot 2019) have shown activity of 
FGFR inhibiting treatment in mUC patients. In addition, FGFR inhibitors in combination 
with anti-PD-(L)1 treatment have shown activity in patients with mUC, with ORRs of 44% 
for both rogaratinib in combination with atezolizumab (first-line cisplatin ineligible) and 
erdafitinib in combination with cetrelimab (second line or greater) (Rosenberg 2020; 
Moreno 2020).
Accordingly, this study is designed as a multiple cohort, multi-center Phase 1b/2 study to 
investigate the efficacy of derazantinib monotherapy or derazantinib-atezolizumab in 
combination in distinct populations of patients with either advanced solid tumors or 
upper/lower urinary tract mUC expressing any FGFR GAs. The study comprises the 
following five open-label substudies:

Substudy 1: This substudy will enroll patients with mUC expressing FGFR1–3 GAs 
who have progressed on at least one standard chemotherapy and/or immune-checkpoint 
blockade and have not received prior FGFR inhibiting treatment. Patients in this 
substudy are to receive derazantinib 300 mg QD monotherapy, with the primary 
objective of assessing efficacy of this treatment regimen in this patient population (for
substudy rationale see Section 1.4.1.1).

Substudy 2: As of Protocol Version 5.0, enrollment to this substudy was completed, 
with interim results described in Section 1.4.1.2. 


 
 
   
 
 
 
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
Substudy 3: As of Protocol Version 5.0, this substudy has been modified. First-line 
cisplatin-ineligible patients with mUC expressing FGFR1–3 GAs are to be treated with 
derazantinib 200 mg BID and atezolizumab 1200 mg Q3W in combination, with the 
co-primary objectives of assessing the safety and efficacy of this regimen in this patient 
population (for substudy rationale see Section 1.4.1.3). If derazantinib 200 mg BID at 
the safety interim analysis (SIA) is not assessed as safe and tolerable, patients are to be 
treated with the RP2D determined in Substudy 2 (see Section 1.4.1.2). 

Substudy 4: This substudy will enroll FGFR inhibitor-resistant patients with 
mUC expressing specific FGFR1–3 GAs. Patients in this substudy are to be 
randomized (1:1) into two non-comparative cohorts: Cohort 4a patients will receive
derazantinib 300 mg QD monotherapy, and Cohort 4b patients will receive 
derazantinib 300 mg QD and atezolizumab in combination. The primary objective of 
this substudy is to assess the efficacy of derazantinib monotherapy and derazantinib-
atezolizumab in combination in this patient population (for substudy rationale see 
Section 1.4.1.4).

Substudy 5: This substudy will enroll patients with mUC expressing FGFR1–3 GAs 
who have progressed on at least one standard chemotherapy and/or immune-checkpoint 
blockade, and have not received prior FGFR-inhibiting treatment. Patients in this 
substudy are to receive derazantinib 200 mg BID monotherapy, with the primary 
objective of assessing efficacy of this treatment regimen in this patient population (for
substudy rationale see Section 1.4.1.5).
1.4.1.1
Rationale for Substudy 1
For derazantinib, preclinical data from a number of patient-derived xenograft mouse 
models in UC expressing FGFR mutations suggested a similar or superior efficacy with 
derazantinib in a direct comparison to erdafitinib using previously described equivalent 
dosing schedules (Perera 2017, Basilea data on file). In these experiments similar or less 
body weight loss was observed with derazantinib, suggesting a potential advantage in 
tolerability.
In clinical studies, patients with mUC and FGFR GAs treated with FGFR inhibitors 
achieved an ORR ranging from 21–40% in uncontrolled clinical trials (Joerger 2018,
Necchi 2018, Pal 2018, Papadopoulos 2017, Loriot 2019). Additionally, in a subgroup of 
mUC patients expressing FGFR GAs and previously exposed to immune-checkpoint 
blockade, FGFR inhibition achieved a higher ORR of 59% (Loriot 2019). Of note, only 
one of these patients had an objective response to the prior immune-checkpoint blockade. 
While the range of activating FGFR GAs conferring oncogene addiction is still under 
investigation, there is evidence of activity of various FGFR inhibitors in mUC patients, and 
it appears that progression following immune-checkpoint blockade may comprise a patient 
subpopulation particularly susceptible to FGFR inhibitor treatment. The efficacy of 
derazantinib will be investigated in second-line or post second-line mUC patients 
expressing FGFR1–3 GAs.


 
 
   
 
 
 
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1.4.1.2
Rationale for Substudy 2 (including results)
Both derazantinib and atezolizumab have been studied in a substantial number of patients 
to understand their toxicity profile (see Section 1.4.3.2) (Papadopoulos 2017, 
Mazzaferro 2019, O’Donnell 2017, Balar 2017a, Rosenberg 2016). This substudy 
functions as a safety run-in cohort, with the aim of identifying the appropriate RP2D for 
the derazantinib-atezolizumab combination, before commencement of Substudy 3 and 
Substudy 4.
The sample size of approximately 12 patients per dose level has been based on recent 
contemporary studies with safety run-in cohorts for immune checkpoint blockade in 
combination with a tyrosine tyrosine kinase inhibitor in various solid tumors 
(Levy 2019,Bonomo 2018, Choueiri 2018, Atkins 2018).
Up to 24 evaluable patients will be included into two dose cohorts using a modified rolling-
six design in order to characterize dose-limiting toxicities (DLTs) and the safety and 
tolerability profile of derazantinib when combined with atezolizumab, and identify 
potentially overlapping toxicities. The dose of atezolizumab will be 1200 mg (Q3W) while 
the starting dose of derazantinib will be 200 mg QD (Dose Level [DL] 1) which may be 
escalated to 300 mg (DL 2). Each dose-level will enroll up to 12 patients. 
Results
The Intent-To-Treat (ITT) and Safety populations for the interim analysis of Substudy 2
comprised 26 patients, 14 in dose-level (DL) 1, and 12 in DL2. Across the two dose levels, 
13 patients were enrolled in the maximum tolerated dose (MTD) cohorts to determine 
DLTs, seven in DL1 and six in DL2. To further assess safety and tolerability, 13 patients 
were additionally enrolled in the expansion cohorts, seven in DL1 and six in DL2. There 
were no DLTs assessed in either DL1 or DL2. The RP2D of derazantinib-atezolizumab in 
combination was determined to be 300 mg QD derazantinib plus 1200 mg atezolizumab 
Q3W.
The most commonly-reported AEs were fatigue/asthenia (31%), nausea (27%), and 
diarrhea (23%). Three patients (15%) had serious adverse drug reactions (ADRs), 
and six patients (23%) had ADRs of grade 3 or higher. Only one event of nephritis was
reported as an immune-related AE. No ADRs leading to death were reported; the only AEs 
with a fatal outcome were two events of disease progression. 15% of patients experienced 
an AE that led to permanent discontinuation of study treatment. Overall, derazantinib-
atezolizumab in combination was well tolerated without apparent differences in frequency 
and severity between both dose levels, and AEs were manageable for both dose levels 
(Abdul-Karim 2021, Basilea, data on file 2021). 
1.4.1.3
Rationale for Substudy 3
The activity seen with erdafitinib in patients unresponsive to immune-checkpoint blockade 
generated the hypothesis that these patients may respond particularly well to FGFR 
inhibition, as PD-L1-low expression is frequently found in FGFR GAs expressing 
advanced urothelial cancers (Loriot 2019, Choi 2017, Siefker-Radtke 2018b). However, 
studies of both erdafitinib and rogaratinib in combination with immune-checkpoint 


 
 
   
 
 
 
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blockade also pursued an alternative hypothesis that immune-cell infiltration may be 
required for successful treatment resulting in target populations of mUC patients unselected 
for PD-L1 (Rosenberg 2020, Moreno 2020). The inhibiting effect of derazantinib on the 
CSF1R kinase (McSheehy 2019) regulating the phenotype of TAMs (Mantovani 2017, 
Ries 2014) may improve the immune-response to immune-check point inhibitors.
Substudy 3 will therefore investigate whether first-line cisplatin-ineligible mUC patients 
derive a clinical benefit from derazantinib-atezolizumab in combination. 
The dose regimen of derazantinib 300 mg QD plus atezolizumab 1200 mg Q3W was well 
tolerated and showed almost no increased toxicity over derazantinib monotherapy (see 
Section 1.4.1.2), suggesting that the benefit-risk may be further improved. Therefore, in 
line with the rationale for Substudy 5 (see Section 1.4.1.5), a higher dose of derazantinib 
(400 mg per day, given as 200 mg BID) will be explored. 
1.4.1.4
Rationale for Substudy 4
Based on available literature of retrospective data and/or small cohorts of uncontrolled 
studies (Di Lorenzo 2015, Soga 2010), it is estimated that patients with mUC expressing 
FGFR1–3 GAs treated with third or fourth-line single-agent chemotherapy and with 
progressive disease (PD) following platinum-containing chemotherapy, immune-
checkpoint blockade, and/or FGFR inhibitor treatment, will attain an ORR of
approximately 7% with single-agent chemotherapy regimens (e.g., taxanes or 
gemcitabine). 
Acquired resistance to tyrosine kinase inhibitors, including FGFR inhibitors, remains an 
issue for patients receiving these targeted therapies, and several mechanisms of resistance 
to FGFR-directed therapy have been postulated (Chen 2011, Datta 2017, 
von der Maas 2000, Wang 2017). Current understanding of acquired resistance to FGFR-
inhibiting treatment includes emergence of de novo or preexisting mutations conferring 
resistance at the drug binding site and activation of alternative pathways of receptor 
activation bypassing the FGFR-inhibiting effect, and has been clinically shown in patients 
with UC (Pal 2018). 
There is some evidence that patients treated with FGFR inhibitors who experience 
progression may benefit from re-treatment with a different FGFR inhibitor 
(Meric-Bernstam 2018), and molecular modeling and in vitro studies have indicated that 
mutations leading to resistance to one FGFR inhibitor may be surmountable by treatment 
with a structurally distinct FGFR inhibitor (Goyal 2017), which is investigated by 
derazantinib monotherapy in Cohort 4a. Given the inhibiting effect of derazantinib on the 
CSF1R kinase (as described above), derazantinib may lead to an enhanced response to 
immune checkpoint inhibitors by dual targeting of the FGFR and CSF1R which may 
provide clinical benefit to this patient population, which is investigated in Cohort 4b.
The derazantinib dose in this substudy will be maintained at 300 mg QD since this substudy 
will enroll patients after at least three prior lines of treatment for mUC who are considered 
to benefit from the favorable benefit-risk profile of the current dose regimens. 


 
 
   
 
 
 
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1.4.1.5
Rationale for Substudy 5
Substudy 5 will include a similar target population as ongoing Substudy 1, however will 
explore a higher dose of derazantinib (400 mg per day, given as 200 mg BID) compared to 
the dose used in Substudy 1 (300 mg QD).
The rationale for exploring a higher dose of derazantinib is to assess whether a higher dose 
further improves the benefit-risk profile for derazantinib in patients with mUC and is based 
on observed safety and efficacy with derazantinib 300 mg QD in the ongoing current study, 
safety data with derazantinib 400 mg QD in the Phase 1 part of study ARQ 087-101, and 
new clinical pharmacology data. A dose regimen of 200 mg BID instead of 300 mg QD is 
anticipated to increase exposure and to enable a faster achievement of efficacious drug 
concentration levels in plasma and as such in tumor within a 1- or 2-week timeframe. 
1.4.1.6
Rationale for molecular testing devices
Molecular eligibility for enrollment will be established by a positive test result for eligible 
FGFR1-3 GAs (see Appendix 1). The molecular test is to be based on NGS of either tumor 
tissue DNA and/or RNA, or plasma circulating cell-free DNA (cfDNA).
Analysis of plasma cfDNA is an evolving technology that permits rapid and non-invasive 
genotyping of tumors. Plasma cfDNA is a subset of cell-free DNA that can be found in 
plasma, and represents genetic material from the primary tumor as well as metastases. 
cfDNA released by tumor cells undergoing apoptosis, necrosis, and in extracellular vesicles 
(exosomes) secreted from tumor cells is highly fragmented, ranging between 100 and 
200 base pairs in size, and is rapidly cleared from the peripheral circulation with a short
half-life (Sabari 2018, Diaz 2014). Plasma cfDNA harboring somatic mutations has 
been found to be highly specific for cancers, in some cancers (e.g., mUC) even highly 
prognostic (Vandekerkhove 2021), and has been proposed as a useful surrogate of tumor 
burden, intratumor heterogeneity, and response to therapy (Vandekerkhove 2021, 
Vandekerkhove 2019, Sabari 2018, Wyatt 2017, Pearson 2016, Diehl 2008).
Molecular testing of somatic mutations in ctDNA from liquid biopsies is feasible, with a 
short diagnostic turnaround time. It appears to be sufficiently sensitive to identify 
oncogenic driver DNA alterations present in matched metastatic tissue, which supports the 
utilization of plasma-derived DNA biomarkers to guide treatment eligibility for somatic 
FGFR GAs in this study.
Alternatively, and to account for the logistical constraints for some sites and patients, and 
the fact that in numerous investigational sites tissue remains the gold standard for 
molecular profiling of mUC (Vandekerkhove 2021), a local NGS testing using tissue DNA 
and/or RNA or plasma cfDNA will be accepted for patent enrollment. The NGS test 
commissioned at the study site’s responsibility is to use standard protocols approved by 
the local IRB/IEC, Clinical Laboratory Improvement Amendments (CLIA), or other 
similar agency, or, where applicable, US FDA-approved kits. For enrollment of patients in 
the EU, assays must be either fully CE-marked or CE-marked for analytical performance; 
tests manufactured by health institutions and used only on their own patients are exempt 
from the Medical Devices Regulation requirements, and do not have to be CE-marked. 


 
 
   
 
 
 
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1.4.1.7
Rationale for pharmacodynamic research
Colony-stimulating factor 1 (CSF1)-mediated signaling via its receptor (CSF1R) is a key 
regulator of the proliferation, migration, survival, and differentiation of macrophages and 
their precursors (Stanley 2014). CSF1 is highly expressed by several tumors, and is 
associated with the presence of tumor-associated macrophages (TAMs) that closely 
resemble the M2-polarized functional phenotype. The presence of TAMs appears to be an 
adverse prognostic factor associated with poor survival in patients with solid tumors and 
hematological malignancies (Yang 2017). Targeting CSF1R signaling in TAMs may 
therefore be a promising therapeutic approach, by inhibiting tumor-promoting 
macrophages in the tumor microenvironment.
Derazantinib is a multikinase inhibitor that in addition to FGFR1–3 kinases also inhibits
the CSF1R kinase. It has been shown in non-clinical studies that the CSF1R inhibitory 
effect of derazantinib on CSF1 stimulated mouse bone-marrow-derived macrophages is 
similar to known CSF1R inhibitors like pexidartinib and BLZ945 (Basilea data on file).
To investigate the pharmacodynamics (PD) of derazantinib, both as monotherapy and in 
combination with atezolizumab in patients with mUC, it is planned to investigate the role 
of CSF1R inhibition by derazantinib using a skin biopsy and blood sampling for monocyte 
subsets prior to the first dose of study drug at the Screening visit and on C2D1. Skin has 
been described as a surrogate tissue for PD dose selection, and as a sign of the anticipated 
mode of action reflective of changes in TAMs in paired tumor biopsies under CSF1R 
inhibiting treatment (Gomez-Roca 2019).
1.4.2
Rationale for patient reported outcomes
Patient-reported outcomes (PROs) provide an understanding of the impact a treatment has 
on a patient.
The EORTC QLQ-C30 is a validated instrument that has been widely used in assessing 
quality of life in patients with cancer. This instrument assesses global health status/quality 
of life, functions (physical, role, emotional, cognitive, and social), and general cancer 
symptoms.
The FACT-Bl is a validated instrument that was developed for patients with bladder cancer 
and consists of the five subscales: physical well-being, functional well-being, emotional 
well-being, social well-being and an additional scale specific to bladder cancer.
The EQ-5D (5L) is a standardized instrument for use as a measure of health outcome. The 
EQ-5D will provide data for use in economic models and analyses including developing 
health utilities or quality-adjusted life-years (QALYs). The five health state dimensions in 
this instrument include the following: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression. The EQ-5D also includes a graded (0 to 100) vertical visual analog 
scale (VAS) on which the patient rates his or her general state of health at the time of the 
assessment.


 
 
   
 
 
 
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Health Transition Index/G-SET is a patient-rated change in health between two time 
periods using a five-point ordinal scale (single item) and will be used as an external anchor 
to determine the minimal important difference of the EQ-5D visual analogue scale, EORTC 
QLQ-C30 scales and FACT-Bl scales. It will be administered twice during the study. 
1.4.3
Dose rationale
The cycle duration of derazantinib will be adapted from 4 weeks to 3 weeks continuous 
oral administration to match the cycle duration of the registered atezolizumab dosage of 
every 3 weeks (Q3W) and in order to harmonize study procedures and assessment intervals 
across all substudies and to reduce the likelihood of errors in dosing and deviations from 
prescribed protocol procedures.
1.4.3.1
Derazantinib
In clinical studies, the maximum tolerated dose of derazantinib monotherapy was assessed,
and the RP2D was determined as continuous daily oral administration of 300 mg 
derazantinib (Papadopoulos 2017). In a Phase 2 study, derazantinib demonstrated 
encouraging anti-tumor activity and a manageable safety profile in patients with advanced, 
unresectable iCCA with FGFR2
fusion who progressed after chemotherapy
(Mazzaferro 2019).
Based on the data from completed and ongoing clinical studies with derazantinib, the most 
commonly reported drug-related adverse events (AEs) are transaminases elevations, 
fatigue /asthenia, gastrointestinal side effects (nausea, vomiting, diarrhea, constipation), 
xerostomia, hyperphosphatasemia, dysgeusia, decreased appetite, ocular side effects 
(xerophthalmia and blurred vision) and alopecia (see Section 7.1.1). Adverse events 
reported in derazantinib-treated patients have largely been mild to moderate in severity, 
and have infrequently required concomitant treatments (e.g., phosphate reducing agents) 
or study drug discontinuation. 
New clinical pharmacology data from a food-effect study (Study DZB-CS-103) and from 
a mass balance study (Study DZB-CS-102) became available and simulations from a new 
two-compartment population PK model, which included data from these two new studies 
and from a previous clinical Phase 1 study (Study ARQ 087-101), was completed recently. 
The data from these analyses suggest that the half-life of derazantinib is in a range of 8 to 
10 days compared to a previous assumption of only 5 days, and that the dose-exposure is 
linear across a dose range of 100 mg to 400 mg QD derazantinib. 
The available safety data with derazantinib across the dose range of 100 mg to 400 mg QD 
together with the revised assumption on dose-linearity and half-life of derazantinib, support 
the exploration of a higher dose of 400 mg per day (given as 200 mg BID) as an additional 
option to assess whether the benefit to risk profile may be further improved in mUC 
patients (Derazantinib Investigator’s Brochure [IB] - Edition 9.0, dated 29 January 2021).
1.4.3.2
Derazantinib in combination with atezolizumab
To date, the safety profiles of derazantinib (see Section 1.4.3.1) and atezolizumab have 
only been studied individually (Mazzaferro 2019, Petrylak 2018, Papadopoulos 2017, 
O’Donnell 2017, Balar 2017a, Herbst 2014). 


 
 
   
 
 
 
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In the first-in-human study of atezolizumab (formerly known as MPDL3280A), the PK for 
atezolizumab were shown to be consistent with those of typical immunoglobulins, with a 
mean terminal serum half-life of approximately 3 weeks. Dose-limiting toxicities were not 
reported, neither was a maximum tolerated dose (MTD) (Herbst 2014), indicating that 
atezolizumab was well tolerated up to a dose of 20 mg/kg body weight, including a flat 
1200-mg dose, which was then used in further studies (Petrylak 2018).
For atezolizumab monotherapy, the incidence of SAEs in a pooled population from eight 
studies (N=3178) was 41.2%. The most common SAEs were pneumonia (3.1%), dyspnea 
(2.8%),pyrexia (2.5%), UTI (1.9%) and pleural effusion, pulmonary embolism, and sepsis 
(1.3%); urinary tract infections occurred more frequently in UC patients, while pneumonia 
was more common in lung cancer patients.  In the overall population, Grade 3-4 AEs were 
reported by 46.5% of patients. The most common (>3% of patients) events were anaemia 
(5.0%), dyspnea (3.7%), fatigue (3.4%), hyponatremia (3.1%), and pneumonia (3.0%). In 
the overall pooled population, 7.1% of patients experienced an AE that led to withdrawal 
of study treatment. The most common AEs leading to withdrawal of study treatment were 
pneumonitis, pneumonia, death, sepsis, septic shock, dyspnea, and AST increased.
The results obtained from Substudy 2 confirmed the safety and tolerability of the novel 
derazantinib-atezolizumab combination (see Section 1.4.1.2) and the resulting RP2D 
allows combination of the full doses established for monotherapy treatment with either 
study treatment. In any cohort using the combination of derazantinib and atezolizumab, the 
clinical decision on continuation or withholding treatment within a combination setting
will be based on current guidelines for immune checkpoint inhibitor treatment 
(Brahmer 2018). 
1.5
Risk-benefit assessment
1.5.1
Derazantinib
Derazantinib is a potent FGFR inhibitor that shows strong anti-proliferative activity in cell 
lines harboring FGFR2 alterations. In clinical trials in iCCA (Mazzaferro 2019,
Papadopoulos 2017), derazantinib has been shown to be active with a manageable safety 
profile. In exploratory PDX studies of derazantinib and erdafitinib, the degree of anti-tumor 
activity and the level of toxicity appeared to be frequently similar, and with sometimes 
superior efficacy, to erdafitinib (Basilea data on file 2019). In clinical studies, patients with 
mUC and FGFR GAs treated with FGFR inhibitors achieved an ORR ranging from 21–
40% in uncontrolled clinical trials (Joerger 2018,
Necchi 2018,
Pal 2018,
Papadopoulos 2017, Loriot 2019). Additionally, in a subgroup of mUC patients expressing 
FGFR GAs and previously exposed to immune-checkpoint blockade, FGFR inhibition 
achieved a higher ORR of 59% (Loriot 2019). It is therefore expected that patients may
derive a substantial benefit from derazantinib monotherapy. 
In the event that derazantinib monotherapy does not meet the efficacy target, the proposed 
two-stage designs with interim analyses provide a reliable method for minimizing the 
number of patients enrolled to each study cohort and exposed to a potentially futile study 
drug.


 
 
   
 
 
 
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Hyperphosphatemia, fatigue, ocular disorders, gastrointestinal disorders (constipation,
diarrhea, nausea, vomiting, stomatitis, and dry mouth), transaminase elevations,
hypertension, creatinine increased / renal disorders, hyponatremia, nail toxicity and 
alopecia are the most frequently reported adverse drug reactions (ADRs) with FGFR 
inhibitor treatments (Chae 2017, Katoh 2019, Balversa USPI, Pemazyre USPI, Abou-Alfa 
2020, Loriot 2019), and are considered to be FGFR inhibitor class effects.
With regard to derazantinib, transaminase elevations is assessed as an important identified 
risk, and hyperphosphatemia, fatigue, ocular disorders, blood creatinine increased/renal 
disorders, hyponatremia, and nail toxicities are assessed as important potential risks. The
following events are assessed as potential risks: gastrointestinal disorders, hypertension, 
alopecia1, and QT prolongation2. 
As the safety data are accumulating and remain subject to final evaluation for ongoing 
studies with derazantinib, the Sponsor continues monitoring for the potential risks. In the 
current study, an Independent Data Monitoring Committee (IDMC) will assess safety data
and provide recommendations to the Sponsor (see Section 3.5). Based on emerging 
information, the Sponsor will continue to evaluate safety data to characterize further 
potential risks and assess identified risks. 
1.5.2
Derazantinib in combination with atezolizumab
Treatment with atezolizumab offers the potential for clinical benefit in patients with mUC. 
Atezolizumab is generally well tolerated, with reported AEs with potentially immune-
related causes being consistent with an immunotherapeutic agent. These include rash, 
hypothyroidism, hepatitis/transaminitis, colitis, and myasthenia gravis, which have been 
observed in ongoing studies, and which to date have been monitorable and treatable.
Detailed guidance on the management of immune-related AEs (see Section 7.1.1) is 
provided in the atezolizumab IB.
Both derazantinib and atezolizumab are generally well tolerated and treatment-related 
toxicities of both study drugs can be monitored and clinically managed. The results 
obtained from Substudy 2 confirmed the safety and tolerability of the novel derazantinib-
atezolizumab combination (see Section 1.4.1.2) and the resulting RP2D allows 
combination of the full doses established for monotherapy with either drug.
It is expected that patients may derive a substantial benefit from a derazantinib-
atezolizumab combination in Substudies 3 and 4 to balance any potentially increased 
toxicity from a combination of two drugs. In the event that the combination does not meet 
the efficacy targets, the proposed two-stage designs provide a reliable method to minimize 
the enrollment of patients to each study cohort and their exposure to a futile study drug.
                                                
1 Gastrointestinal disorders, and hypertension can be monitored and are clinically manageable, and the event alopecia has 
no significant impact on the physical condition of the patients.
2 Based on available and centrally reviewed ECG data from study ARQ 087-101, QT prolongation is assessed as a non-
important potential risk for derazantinib, because these data rule out a large effect (mean > 20 ms) on QTcF; there have 
been no SARs/arrhythmias reported as being consequent to QT prolongation, and the risk is mostly preventable with the 
routine risk minimization measures, which have been implemented (ECG triplicates for averaged QTcF within normal 
ranges prior to dosing, and monitoring of electrolyte abnormalities, concomitant medications, or other clinical factors, 
such as cardiac ischemia).


 
 
   
 
 
 
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1.5.3
Pharmacodynamic research
Participation in the Pharmacodynamics Research (PDR) Group remains voluntary for 
patients. Similar PD evaluations have been performed in recently published study reports 
and have not reported an excess increase in AEs (e.g., Gomez-Roca 2019).
Patients willing to accept the extended schedule of assessments for the PD research, will 
sign a separate specific Informed Consent Form (ICF), which will detail the additional risks 
and benefits in relation to undergoing an extended schedule of study assessments. 
1.5.4
Conclusion to risk-benefit assessment
Patients in clinical studies generally cannot expect to receive direct benefit from treatment 
during participation, as clinical studies are designed to provide information about the safety 
and effectiveness of an investigational medicine.
The available safety data for derazantinib (both at the current dose regimen of 300 mg QD 
and at the MTD of 400 mg QD, the latter being proposed to being explored as a revised 
dose regimen of 200 mg BID) do not indicate significant risks to study patients that require 
termination or modification of the ongoing derazantinib development program, and the 
safety profile for atezolizumab, which is a licensed medicine in UC, is well characterized.
The proposed two-stage designs permit the minimization of patient accrual in case of study 
drug futility, and an IDMC will assess safety data and provide recommendations to the 
Sponsor.
The safety and tolerability profile of the novel combination treatment with derazantinib 
and atezolizumab has been assessed as clinically manageable in Substudy 2. No DLTs were 
observed, and no ADRs leading to death were reported; 15% of patients experienced an 
AE that led to permanent discontinuation of study treatment.
All substudies will include close safety monitoring through AE collection, and assessment 
of clinical safety laboratory tests, pregnancy testing, vital signs, centrally-read ECGs, 
physical examinations, ophthalmology examinations and Eastern Cooperative Oncology 
Group (ECOG) Performance Status (PS). 
The risk-benefit balance is therefore expected to be favorable in the intended mUC patient 
populations.
STUDY OBJECTIVES
Effective Protocol Version 5.0, only substudy objectives and hypotheses applicable to 
active substudies are included in this section.
2.1
Primary objectives and hypotheses
2.1.1
Primary efficacy objective 
To evaluate the ORR of derazantinib monotherapy (in Substudies 1 and 5, and Cohort 4a) 
and of derazantinib-atezolizumab in combination (in Substudy 3 and Cohort 4b) in patients 
with mUC (i.e., surgically unresectable or metastatic UC) expressing FGFR1–3 GAs. 


 
 
   
 
 
 
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
Hypothesis of Substudy 1: Patients with mUC expressing FGFR1–3 GAs treated with 
derazantinib 300 mg QD will attain a clinically meaningful ORR (e.g., ~34%), which 
is superior to the estimated ORR of 21% attained with pemigatinib, which is the lowest 
ORR currently reported from studies with FGFR-inhibiting treatment of UC patients 
(Loriot 2019, Necchi 2018, Pal 2018). 

Hypothesis of Substudy 3: Patients with mUC expressing FGFR1–3 GAs treated with 
derazantinib 200 mg BID in combination with atezolizumab 1200 mg Q3W will attain 
a clinically meaningful ORR (e.g., ~45%), which is superior to the estimated ORR of 
up to 25% obtained with treatments investigated/licensed for use this patient population 
(Pal 2018, Rosenberg 2016). 

Hypothesis of Substudy 4: Patients with mUC and disease progression after failure of 
prior FGFR inhibitor treatment treated with either derazantinib 300 mg QD or 
derazantinib 300 mg QD in combination with atezolizumab 1200 mg Q3W will attain 
a clinically meaningful ORR (e.g., ~20%), which is superior to the estimated ORR of 
up to 7% obtained with treatments (e.g., monotherapy taxanes in fourth-line or greater 
treatment) available for this patient population (Di Lorenzo 2015, Soga 2010).

Hypothesis of Substudy 5: Patients with mUC expressing FGFR1–3 GAs treated with 
derazantinib 200 mg BID will attain a clinically meaningful ORR (e.g., ~30%), which 
is superior to an ORR of 10%, which is acknowledged to be a benchmark whereby no 
further clinical investigation is warranted. 
2.1.2
Primary safety objective of Substudy 3
To confirm derazantinib 200 mg BID with atezolizumab 1200 mg Q3W as a safe and 
tolerable dose regimen.

Hypothesis: Derazantinib at a dose of 200 mg BID with atezolizumab 1200 mg Q3W 
is sufficiently well-tolerated to permit further clinical investigation.
2.1.3
Primary safety objective of Substudy 5
To confirm derazantinib 200 mg BID as a safe and tolerable dose regimen of derazantinib
monotherapy.

Hypothesis: Derazantinib at a dose of 200 mg BID is sufficiently well-tolerated to 
permit further clinical investigation.
2.2
Secondary objectives

To evaluate the efficacy of the study drugs as measured by disease control rate (DCR), 
duration of response (DOR), PFS and overall survival (OS)

To assess the safety and tolerability of the study drugs

To characterize the PK profile of derazantinib 200 mg BID (and, if applicable, 
derazantinib metabolites) as monotherapy (Substudy 5) and in combination with 
atezolizumab (Substudy 3).


 
 
   
 
 
 
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
To evaluate changes, and assess the minimally important difference, in health-related 
quality of life (HR-QoL) and symptom response from baseline by cohort, substudy and 
in the overall study population using the EORTC QLQ C30, FACT-Bl, EQ-5D (5L)
visual analogue scale (VAS), and Health Transition Index/G-SET.
2.3
Exploratory objectives
2.3.1
Exploratory objectives specific to efficacy-estimating substudies 

To describe the type of FGFR1–3 GAs in responders and non-responders

To explore the concordance between molecular FGFR assessments from plasma-based 
and tissue-based NGS testing 

To explore the efficacy of derazantinib-atezolizumab in combination following 
documented disease progression in patients who previously received derazantinib 
monotherapy and crossed over to combination treatment (Substudy 4)

To explore the efficacy of derazantinib-atezolizumab in combination by iRECIST (see 
Section 5.3.3.2.4) as measured by ORR, DCR, DOR and PFS

To compare the efficacy of derazantinib with that of derazantinib-atezolizumab in 
combination to generate potential hypotheses for future comparative studies
(Substudy 4)

To explore the efficacy of derazantinib and of derazantinib-atezolizumab in 
combination by response-indicating molecular biomarkers, as measured by ORR, DCR, 
DOR, PFS and OS

To explore the effect of derazantinib on CSF1R expressing cells in blood samples and 
skin biopsies

To characterize utilities in patients treated with derazantinib or derazantinib-
atezolizumab in combination using the EQ-5D (5L) for health economic modeling.
2.3.2
Exploratory PK objectives

To explore the exposure of 300 mg QD derazantinib monotherapy (and, if applicable, 
derazantinib metabolites) and in combination with atezolizumab

To explore the exposure of atezolizumab and anti-drug antibodies (ADA) directed 
against atezolizumab, in the context of atezolizumab combination with derazantinib


 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
  
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
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INVESTIGATIONAL PLAN
3.1
Overview of study design and study flow chart
This study is a multiple cohort, multi-center Phase 1b/2 study. An overview of the overall 
study design is provided in Figure 1. The efficacy of derazantinib or derazantinib-
atezolizumab in combination is evaluated in cohorts addressing various clinical stages of 
disease progression and prior treatments. 
Effective from Protocol Version 5.0, Substudy 3 has been modified, and Substudy 5 has 
been added. Substudy 2 has been completed.
In all efficacy-estimating cohorts, sample-size minimizing statistical designs with interim 
analyses for futility and efficacy will be used.
Figure 1
Overview of study design
Abbreviations: 1L: first-line treatment; 2+L: second-line or post-second line; ∆: decision for transition to Part 2 / Stage 
2; FGFR: fibroblast growth factor receptor; GA: genetic aberration; mUC: locally advanced or metastatic and recurrent 
or progressing urothelial cancer; R: randomization. 
* Derazantinib 300mg QD
† Derazantinib 200 mg BID
‡ Safety interim analysis after 10 patients
§ If derazantinib 200 mg BID is not assessed as safe and tolerable, the RP2D determined in Substudy 2 will be used.
Only patients with mUC expressing FGFR1–3 GAs will be enrolled (see Section 3.1.1).
As of Protocol Version 5.0, this study comprises five open-label substudies (of which four 
are ongoing; see Figure 1):

Substudy 1: This substudy will enroll patients with mUC expressing  FGFR1–3 GAs 
who have progressed on at least one standard chemotherapy and/or immune-checkpoint 
blockade and have not received prior FGFR inhibiting treatment. Patients in this 


 
 
   
 
 
 
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substudy are to receive derazantinib 300 mg QD monotherapy, with the primary 
objective of assessing of this treatment regimen treatment efficacy in this patient 
population.

Substudy 2: As of Protocol Version 5.0, enrollment to this substudy was completed, 
with interim results described in Section 1.4.1.2. 

Substudy 3: As of Protocol Version 5.0, this substudy has been modified. First-line 
cisplatin-ineligible patients with mUC expressing FGFR1–3 GAs are to be treated with 
derazantinib 200 mg BID and atezolizumab 1200 mg Q3W in combination, with the 
co-primary objectives of assessing the safety and efficacy of this regimen in this patient 
population. If derazantinib 200 mg BID at the SIA is not assessed as safe and tolerable, 
patients are to be treated with the RP2D determined in Substudy 2.

Substudy 4: This substudy will enroll FGFR inhibitor-resistant patients with 
mUC expressing FGFR1–3 GAs. Patients in this substudy are to be randomized (1:1)
into two non-comparative groups: Cohort 4a patients will receive derazantinib 300 mg 
QD monotherapy, and Cohort 4b patients will receive derazantinib 300 mg QD and 
atezolizumab 1200 mg Q3W in combination. The primary objective of this substudy is 
to assess the efficacy of derazantinib monotherapy and derazantinib-atezolizumab in 
combination in this patient population.

Substudy 5: This substudy will enroll patients with mUC expressing FGFR1–3 GAs 
who have progressed on at least one standard chemotherapy and/or immune-checkpoint 
blockade and have not received prior FGFR-inhibiting treatment. Patients in this 
substudy are to receive derazantinib 200 mg BID monotherapy, with the co-primary 
objectives of assessing the safety and efficacy of this treatment regimen in this patient 
population.
Patients enrolled in Substudies 3, 4 and 5 have the option of participating in exploratory 
PD research to investigate the role of CSF1R inhibition by derazantinib. This will comprise
a skin biopsy and blood sampling for monocyte subsets prior to the first dose of study drug 
(Screening Visit) and on C2D1 (see Section 5.3.5.3).
3.1.1
Molecular eligibility
Molecular eligibility for enrollment will be established by a positive test result for eligible 
FGFR1-3 GAs (see Appendix 1). The molecular test is to be based on NGS of either tumor 
tissue DNA and/or RNA, or plasma cfDNA.
For patients with no access to local NGS testing, central testing will be performed in a 
laboratory in the USA designated by the Sponsor; this ‘central testing’ will be based on 
NGS testing of cfDNA from a liquid biopsy obtained at Pre-screening. 
For potential prospective study participants without available positive FGFR1–3 GA test 
result, a Pre-screening visit (see Section 3.1.2) is to be scheduled for liquid biopsy 
sampling.
Alternatively, an eligible, positive FGFR1–3 GA test result obtained from local NGS 
testing (‘local testing’, the commissioning of which is the study site’s responsibility) can 


 
 
   
 
 
 
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be used to establish molecular eligibility; no Pre-screening visit is required. The 
commissioned NGS test for ‘local testing’ is to use standard protocols approved by the 
local IRB/IEC, Clinical Laboratory Improvement Amendments (CLIA), or other similar 
agency, or, where applicable, US FDA-approved kits. For enrollment of patients in the EU, 
assays must be either fully CE-marked or CE-marked for analytical performance; tests 
manufactured by health institutions and used only on their own patients are exempt from 
the Medical Devices Regulation requirements, and do not have to be CE-marked. 
3.1.2
Pre-screening 
A Pre-screening visit is only required for prospective study participants under 
consideration for enrollment into Substudies 1, 3 or 5, and if no documented local NGS 
test result with an eligible FGFR1–3 GA is available. If these patients have no access to 
local NGS testing, they are required to sign the Pre-screening Informed Consent Form 
(ICF) for molecular screening, and are not considered enrolled (i.e., patients are considered 
to be in pre-screening for the study) until receipt of a positive central molecular test result, 
and dated patient signature on the Study ICF. The Pre-screening visit for liquid biopsy 
sampling should be scheduled following assessment of objective documented progression 
after prior anti-cancer treatment (e.g., rather than during prior anti-cancer treatment) to 
optimize the likelihood of capturing cfDNA shedding reflective of disease progression.
No Pre-screening visit is required for patients with a known and eligible FGFR1–3 GA 
status (see Appendix 1) from local NGS testing; these patients may directly initiate clinical 
screening procedures. Substudy 4 patients also do not require a Pre-screening visit if their 
molecular eligibility is known from prior FGFR-inhibiting treatment (documentation of 
which should be made available at the Screening visit, otherwise a Pre-screening visit 
should be scheduled).
3.1.3
Screening
Clinical Screening procedures are required to confirm study-treatment eligibility (see 
Section 5.3.1). For the baseline study imaging assessment of measurable disease, RECIST 
1.1 criteria apply (Appendix 2, Eisenhauer 2009). 
Re-screening for molecular inclusion criteria is not permitted unless the tissue biopsy or 
liquid biopsy was not evaluable for technical reasons.
Under rare conditions and contingent upon Sponsor approval, patients may be given the 
possibility to be re-screened after initially failing screening.
3.1.4
Treatment period
Patients will be evaluated regularly during the treatment period as per the schedule of 
assessments shown in Table 1. If a patient visit deviates from the permitted protocol 
window, the next visit must be performed at the correct timing based on the date of Cycle 
1 Day 1 (C1D1).
Blood samples for PK measurements of derazantinib and atezolizumab will be collected in 
accordance with the schedule set out in Table 1 and Section 5.3.4.1 (for derazantinib), and 
Section 5.3.4.2 (for atezolizumab).


 
 
   
 
 
 
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Efficacy is to be evaluated by blinded independent central review (BICR) using 
RECIST 1.1 criteria every 9 weeks (±7 days) for the first 27 weeks, and every 12 weeks 
(±7 days) thereafter (see Section 5.3.3.2). Ideally, efficacy assessments are scheduled to 
permit treatment decision for D1 of the subsequent cycle.
Dose delays and/or reductions are permitted with derazantinib if a derazantinib-related 
toxicity is observed (see Section 6.1.1.5). No dose reductions are permitted with 
atezolizumab; however, dose delays are acceptable if an atezolizumab-related toxicity is 
observed (see Section 6.1.2.6). A related toxicity is defined as any toxicity considered 
related to derazantinib and/or atezolizumab, i.e., probably, or possibly related.
Substudies 3 and 5 will include a SIA for ADRs indicative of DLT (see Section 7.3.3) in 
the first 10 treated patients each. The process involves regular dose decision meetings 
(see Section 8.3.5.1). The schedule of AE assessments, including central ECGs and 
ophthalmological examinations, clinical safety laboratory blood sampling, and urinalysis 
has been expanded to a weekly schedule of assessments for the first two treatment cycles 
(see Table 1). Rich PK profiling will be performed for all patients during the safety run-in 
phase. The PK sampling schedule is provided in the Table 1. 
In Substudy 3, if derazantinib 200 mg BID plus atezolizumab 1200 mg Q3W is considered 
a tolerable and safe at the safety interim analysis (endorsed by the IDMC), enrollment of 
Stage 1 will be completed for the efficacy interim analysis of patients. If the dose regimen
is not tolerated, further enrollment will be revised and Stage 1 of Substudy 3 will enroll 
patients to be treated with the RP2D of derazantinib 300 mg QD plus atezolizumab 
1200 mg Q3W, as determined in Substudy 2.
In Substudy 5, if derazantinib 200 mg BID is considered tolerable and safe at the interim 
analysis (endorsed by the IDMC), and also improves exposure as expected, enrollment of 
Stage 1 will be completed for the efficacy interim analysis of patients. If derazantinib 
200mg BID is not considered tolerable and safe, other regimens may be investigated if 
needed following a protocol amendment.
3.1.5
End of Treatment / Safety Follow-up period
Patients will continue to receive study treatment until disease progression, patient 
withdrawal, lost to follow up, unacceptable toxicity, or until the Investigator’s decision to 
remove the patient from treatment; or until the substudy, cohort or the study is terminated 
by the Sponsor (see Section 4.4.4 for further details and reasons to stop receiving study 
treatment), whichever occurs first.
The End of Treatment visit will be conducted within 7 days after the administration of the 
last dose of study drug(s). Two Safety Follow-up visits will be conducted, 28 days 
(±3 days) and 90 days (±3 days) after the administration of the last dose of study drug(s).
See Section 5.2.2.8 and Section 5.2.2.9 for further details.
Once patients have been discontinued from treatment with the initially assigned study drug, 
other treatment options will be at the discretion of the Investigator. All concomitant 
medications should continue to be recorded on the appropriate electronic case report form 
(eCRF) until last Safety Follow-up visit.


 
 
   
 
 
 
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For further details on treatment and study discontinuation, see Section 4.4.4.
3.1.6
Optional post-discontinuation study treatment crossover (Cohort 4a)
Patients from Cohort 4a with PD (as assessed by BICR) will have the opportunity to 
receive treatment with derazantinib-atezolizumab in combination in a Crossover Phase. 
Crossover patients may initiate treatment with derazantinib-atezolizumab within 2 months 
of their last dose of derazantinib, regardless of the time of progression. 
Crossover is optional and is at the discretion of the Investigator (with the Sponsor’s and 
patient agreement). 
3.1.6.1
Eligibility criteria for post-discontinuation study treatment crossover
Patients who permanently discontinue derazantinib due to an AE, withdraw consent, or for 
any reason other than PD, will not be eligible for crossover. 
Patients who meet the following inclusion criteria are eligible for crossover:
1. Documented PD on derazantinib (as confirmed by BICR) as a participant of Cohort 4a
2. All ongoing AEs must have resolved to baseline or Common Terminology Criteria for 
Adverse Events (CTCAE) Grade ≤1 (except alopecia and peripheral neuropathy) 
3. No new central nervous system (CNS) metastases
4. ECOG PS of 0–2
5. Patient has not received any other systemic anti-cancer therapies after derazantinib 
administration during the treatment phase.
6. If required, completed palliative radiotherapy (30 Gy or less) ≥ 7 days before the first 
dose of crossover study treatment.
7. Patient has adequate organ function, as indicated by the laboratory values detailed in 
Section 4.2.
3.1.6.2
Assessments during post-discontinuation study treatment crossover
Once eligibility is confirmed, crossover patients will follow the same schedule of 
assessments as Cohort 4b patients (as detailed in Table 1), including atezolizumab PK and 
ADA sampling, but without further derazantinib PK sampling. In particular, safety-
oriented assessments detailed in Section 5.3.2 need to be followed as specified.
Screening procedures need to be completed within 28 days of confirmed PD (or up to 
42 days from last dose if recovering from an AE). Procedures and assessments completed 
at the time of withdrawal from the main study may be used for the start of the Crossover 
Phase of the study. 
The tumor imaging used to determine PD can be used as the new baseline image for the 
Crossover Phase if this was obtained within the 28 days prior to receiving the first dose of 
derazantinib-atezolizumab combination. 
Patients who crossover and then achieve a complete response (CR) per RECIST 1.1 criteria 
have the option to hold treatment with derazantinib and atezolizumab in combination while 
continuing in the study with the potential to resume treatment upon recurrence at the 


 
 
   
 
 
 
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discretion of the Investigator. Patients will receive the RP2D of derazantinib-atezolizumab 
unless their last dose of derazantinib was reduced according to dose modification 
prescribed by this protocol (see Section 6.1.1.5); derazantinib dose re-escalation in the 
crossover phase of this protocol is not permitted.
3.1.7
Survival Follow-up period
Patients who are permanently discontinued from study treatment for reasons other than 
death and consent withdrawal for further safety and survival follow-up, regardless of the 
reason, will enter the survival follow-up period (see Section 5.2.3). 
Survival Follow-up (at least every 3 months ± 14 days from last dose of study drug) will 
start on the day of the last dose of either study drug and will continue until the study has 
completed (see Section 3.1.8) or other discontinuation criteria are met (see Section 4.4.4).
All subsequent anticancer therapies should continue to be recorded on the appropriate 
electronic case report form (eCRF) for the duration of the patient’s survival follow up.
3.1.8
Beginning and end of the study
The study begins when the first patient signs any ICF. 
The study ends when the last patient completes the last study-related phone-call or visit, 
discontinues from the study, or is lost to follow-up (i.e., the patient is unable to be contacted 
by the investigator). 
In addition, the Sponsor may decide to terminate the study at any time (see Section 4.5.4).
For patients who continue to derive benefit (per Investigator assessment) from any of the 
study treatment regimens at the time of study closure, the Sponsor aims to provide 
continued individual access to study drug, either under a rollover study protocol, or in the 
context of compassionate use/named patient access, where applicable.
3.2
Endpoints
Effective Protocol Version 5.0, only endpoints applicable to active substudies are listed is 
this section.
3.2.1
Primary endpoints
3.2.1.1
Primary endpoint 

ORR, as measured by the proportion of patients with confirmed CR1 or PR2 by BICR.
                                                
1 Evaluating target lesions, CR is defined as the disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm; further details Appendix 3 and 
Eisenhauer 2009.
2 Evaluating target lesions, PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters; further details Appendix 3 and Eisenhauer 2009.


 
 
   
 
 
 
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3.2.1.2
Primary safety endpoint (Substudies 3 and 5)

For the safety interim analysis in Substudy 3, the primary endpoint is the proportion 
of patients with DLTs during treatment with derazantinib 200 mg BID and 
atezolizumab 1200 mg Q3W in combination. 

For the safety interim analysis in Substudy 5, the primary endpoint is the proportion 
of patients with DLTs during treatment with derazantinib 200 mg BID monotherapy. 
Safety and tolerability of both the monotherapy and the combination dose regimens will be 
concluded by joint decisions taken by the IDMC, Investigators, and the Sponsor in 
reviewing the aggregate of DLT, AE and PK data from the first 10 patients enrolled in 
Substudy 3 and 5.
3.2.2
Secondary endpoints

DCR, as measured by the proportion of patients with confirmed CR, PR or stable 
disease (SD)1 by BICR

DOR, as calculated from the first date of documented tumor response to disease 
progression by BICR

Median PFS and PFS at 6 months, as determined by BICR and measured from time of 
first dose to time of objective tumor progression or death, and the proportion of patients 
alive and free of objective tumor progression 6 months after cohort assignment, 
respectively

Median OS and OS at 6 months, as measured from time of first dose until time of death 
and the proportion of patients alive 6 months after cohort assignment, respectively

Safety and tolerability of study drugs as measured by the frequency and severity of 
AEs, clinical laboratory parameters, vital signs, ECOG PS, physical examinations 
(including eye examinations), and ECG parameters over time, and graded by 
NCI CTCAE 5.0

Derazantinib (and – if applicable –derazantinib metabolites) plasma concentrations, 
Cmax, tmax, AUC0-12, AUC0-24, AUClast assessed by measurements in blood samples 
during treatment as monotherapy (Substudy 5) or in combination (Substudy 3)

Changes in HR-QoL and symptom response, measured by global, functional and 
symptom scores obtained from patient reported outcome instruments at baseline and 
over time (EORTC QLQ C30, FACT-Bl, EQ-5D [5L] VAS), and Health Transition 
Index/G-SET.
                                                
1 Evaluating target lesions, SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for Progressive Disease (PD, see following definition), taking as reference the smallest sum of diameters while 
on study. PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression).


 
 
   
 
 
 
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3.2.3
Exploratory endpoints
3.2.3.1
Exploratory endpoints specific to efficacy-estimating substudies

Responding and non-responding patients are to be analyzed by type of FGFR1–3 GA.

The proportion of patients with concordant molecular assessment from plasma-based 
and tissue-based testing measuring FGFR GAs in matched tumor-liquid biopsy samples 
obtained at baseline and during treatment will be described.

The ORR, DCR, DOR, PFS and OS of patients treated with derazantinib-atezolizumab 
in combination will be evaluated for patients crossing over after documented disease 
progression on derazantinib monotherapy (Substudy 4).

The ORR, DCR, DOR and PFS of patients treated with derazantinib-atezolizumab in 
combination will be evaluated by iRECIST (applicable to Substudies 3 and 4).

In Substudy 4, the ORR, DCR, DOR, PFS and OS of patients treated with derazantinib 
will be compared to that of patients treated with derazantinib-atezolizumab in 
combination to generate potential hypotheses for future comparative studies.

The ORR, DCR, DOR, PFS and OS of patients treated with derazantinib and 
derazantinib-atezolizumab in combination, respectively, will be evaluated by molecular 
profile, gene expression profile, and biomarkers.

The proportion of patients with a specific reduction of immunosuppressive 
macrophages in skin biopsies or peripheral blood monocytes on derazantinib 
monotherapy and derazantinib-atezolizumab combination treatment.

EQ-5D (5L) health status data will be used for obtaining utility measures for economic 
modeling. For the EQ-5D (5L), further scoring and analysis may be reported in a 
separate document.
3.2.3.2
Exploratory PK endpoints

Derazantinib plasma concentrations, assessed by measurements in blood samples.

Plasma concentrations of derazantinib metabolites (if applicable), assessed by 
measurements from blood samples.

Atezolizumab serum concentrations, assessed by measurements from blood samples 
(Substudy 3, Cohort 4b, and Crossover).

Serum ADA assayed from blood samples (Substudy 3, Cohort 4b and Crossover).

Derazantinib plasma concentrations (Cmax, tmax, AUC0-24, AUClast), assessed by 
measurements from blood samples (applicable to Substudies with 300 mg QD).
3.3
Number of patients
The study plans to enroll up to 272 evaluable patients across all five substudies. 
3.4
Study sites
Up to 100 study sites in Asia-Pacific, North America, and Europe.


 
 
   
 
 
 
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3.5
Independent Data Monitoring Committee
An IDMC will be established by the Sponsor to evaluate accumulating safety data in 
patients enrolled in the study, to ensure their safety and wellbeing, and to provide 
recommendations to the clinical teams in charge of conducting the study.
For Substudy 2, the IDMC will be additionally responsible for determining the RP2D of 
derazantinib-atezolizumab in combination. This decision will be taken in an open session 
in which study Investigators and Sponsor representatives will be able to participate.
For Substudy 3 and 5, the IDMC will be additionally responsible for determining whether
derazantinib 200 mg BID, either as monotherapy or in combination with atezolizumab, can 
be declared as tolerable regimens. This decision will be taken in an open session in which 
study Investigators and Sponsor representatives will be able to participate.
As detailed in the IDMC Charter, the IDMC will comprise experts in the field of oncology
and biostatistics, who will be required to disclose their relevant financial interests to the 
Sponsor. None of the IDMC members may be involved in the conduct or reporting of any 
ongoing clinical study of which Basilea is the Sponsor.
STUDY POPULATION
Effective Protocol Version 5.0, only information applicable to active substudies is provided
in this section.
4.1
Target populations
The target population is patients with surgically unresectable, metastatic, recurrent and/or 
progressing UC (i.e. mUC) expressing known and/or likely activating and/or oncogenic 
FGFR1–3 GAs (see Appendix 1).
4.2
Inclusion criteria
Each patient must meet all of the following inclusion criteria (patients may repeat the 
screening procedures within the screening period after initially failing to meet the clinical 
inclusion criteria; rescreening for molecular inclusion criteria is not permitted unless the 
tissue biopsy or liquid biopsy was not evaluable for technical reasons):
1. Study ICF signed by the patient indicating that they understand the purpose of, and 
procedures required for, the study and are willing to participate in the study, prior to 
any study-related procedure.
2. Male or female aged ≥ 18 years.
3. Histologically-confirmed transitional cell carcinoma of the urothelium of the upper or 
lower urinary tract 
Note: Minor components (< 50% overall) of variant histology such as glandular or squamous 
differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary 
change, are acceptable.
4. Recurrent or progressing stage IV disease, or surgically unresectable, recurrent or 
progressing disease, as specified for each substudy:


 
 
   
 
 
 
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
Substudy 1: Patients with mUC expressing FGFR1–3 GAs who have progressed 
on at least one standard chemotherapy and/or immune-checkpoint blockade and 
have not received prior FGFR inhibiting treatment.

Substudy 3: First-line cisplatin-ineligible patients with mUC expressing FGFR1–
3 GAs, and have not received prior FGFR-inhibiting treatment.
Cisplatin-ineligibility as defined by any one of the following criteria: 1) grade ≥ 2 peripheral 
neuropathy; 2) CLCR calculated by Cockcroft-Gault >30 mL/min but < 60 mL/min; 3) hearing 
impairment (measured by audiometry) of > 25 dB at two contiguous test frequencies in at least one 
ear; 4) comorbidity that precludes high-volume hydration.

Substudy 4: Patients with FGFR inhibitor-resistant, mUC expressing FGFR1–3
GAs who have progressed on at least one standard regimen each of chemotherapy 
and immune-checkpoint blockade and have received FGFR inhibiting treatment
(excluding derazantinib).
Patients assessed as having progressed upon prior treatment with FGFR inhibitors must have 
received FGFR inhibitor treatment for at least 12 weeks and have undergone at least one on 
treatment tumor imaging assessment. 
Prior treatment with immune-checkpoint blockade and FGFR inhibitor in combination are not 
allowed; prior treatment with either sequential immune-checkpoint blockade and FGFR inhibitor 
treatment or combinations of FGFR inhibitor and chemotherapy are allowed. 

Substudy 5: Patients with mUC expressing FGFR1–3 GAs who have progressed 
on at least one standard chemotherapy and/or immune-checkpoint blockade and 
have not received prior FGFR inhibiting treatment.
5. Eligible FGFR1–3 GA-positive test result (see Appendix 1 and Section 3.1.1)
6. Measurable disease, as defined by the Investigator using RECIST 1.1 criteria, 
documented within the 28 days prior to study drug administration.
7. ECOG PS of 0, 1 or 2
8. Adequate organ functions as indicated by the following Screening visit local laboratory 
values:

Hemoglobin ≥ 9 g/dL

Absolute neutrophil count (ANC) ≥ 1.5 × 109/L

Platelets ≥ 75 × 109/L

International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or 3 for 
patients receiving anticoagulant therapy

Total bilirubin ≤ 2 × ULN

Aspartate 
aminotransferase 
(AST)
and 
alanine 
aminotransferase 
(ALT) ≤3 × ULN, or ≤ 5 × ULN for study patients with liver metastasis

Albumin ≥ 2.5 g/dL

CLCR ≥30 mL/min (as calculated by the Cockcroft-Gault formula)


 
 
   
 
 
 
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
For women of childbearing1 potential only, negative serum human chorionic 
gonadotropin (hCG)2
9. Men and women of childbearing potential must agree to avoid impregnating a partner 
or becoming pregnant, respectively, during the study, and for at least 5 months after the 
last dose of either investigational drug.
Male patients are considered not to be of child-producing potential if they have 
azoospermia (whether due to vasectomy or an underlying medical condition). Female 
patients are considered not to be of child-producing potential if they are:

postmenopausal3, or

have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy, or bilateral tubal ligation/occlusion, at least 6 weeks prior to 
Screening, or 

have a congenital or acquired condition that prevents childbearing.
Male or female patients of child-producing potential must agree to comply with one of 
the following until at least 150 days after the last dose of derazantinib or atezolizumab:
a) Abstinence from heterosexual activity4
b) Using (or having their partner use) a highly effective method of contraception 
during heterosexual activity. Highly effective methods of contraception are5:

an intrauterine device

vasectomy of a female patient’s male partner

a contraceptive rod implanted into the skin.

any combination of hormonal contraceptive and a barrier method (diaphragm 
with spermicide, cervical cap with spermicide, contraceptive sponge, male 
condom or female condom)
                                                
1 Women who are defined as not being of childbearing potential are: any female who is postmenopausal (age ≥55 years 
with cessation of menses for 12 or more months, or less than 55 years but without spontaneous menses for at least 2 
years, or less than 55 years with spontaneous menses during the last 1 year but currently amenorrhoeic, e.g.,
spontaneous or secondary to hysterectomy, AND with postmenopausal gonadotropin levels (luteinizing hormone and 
follicle-stimulating hormone levels < 40 IU/L), or postmenopausal estradiol levels (< 5 ng/L) or according to the 
definition of “postmenopausal range” for the laboratory involved), or who have had a hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy.
2 Spurious positive serum beta-hCG values may be caused by the underlying urothelial cancer; plausibility of pregnancy 
should be established for women of childbearing potential with urothelial cancer and positive serum beta-hCG values.
3 Postmenopausal is defined as at least 12 months with no menses without an alternative medical cause; in 
women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a post -menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is not sufficient.
4 Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the patient’s preferred and usual lifestyle and if it is employed during the entire period of risk associated 
with the study treatment and if it is considered highly effective by local regulatory agencies and ERCs/IRBs. Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not highly 
effective methods of contraception.
5 If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as a highly 
effective method of contraception for patients participating at sites in this country/region.


 
 
   
 
 
 
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
combined (estrogen and progestogen containing) or progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral 
contraceptive pill [estrogen/progestin pill or progestin-only pill], contraceptive 
skin patch/implant, vaginal contraceptive ring, or subcutaneous contraceptive 
injection)
4.3
Exclusion criteria
Patients who meet any of the following criteria at Screening must not be enrolled in the 
study (patients may repeat the screening procedures within the screening period after 
initially failing to comply with exclusion criteria; rescreening for molecular inclusion 
criteria is not permitted unless the tissue biopsy or liquid biopsy was not evaluable for 
technical reasons):
Prior cancer treatment
1. Receipt of treatment before the first dose of study drug (Cycle 1 Day 1) within an 
interval shorter than the following, as applicable:

One chemotherapy or biological (e.g., antibody) cycle interval

Five half-lives of any small molecule investigational or licensed medicinal product

Two weeks, for any investigational medicinal product (IMP) with an unknown half-
life

Four weeks of curative radiotherapy 

Seven days of palliative radiotherapy 

12 months of neo-adjuvant or adjuvant chemotherapy or radiation (only applies to 
Substudy 3)
2.
For Substudy 3 patients, any prior treatment with anti-PD-1 or anti-PD-L1-therapeutic 
antibody, or PD-1/PD-L1 pathway-targeting agents 
3.
Prior FGFR inhibiting treatment (except Substudy 4).
4.
For Substudy 4 patients, prior treatment with FGFR inhibitor in combination with
anti-PD-1 or anti-PD-L1 therapeutic antibody or PD-1/PD-L1 pathway-targeting 
agents.
Critical organ impairments
5.
Concurrent evidence of clinically significant corneal or retinal disorder likely to 
increase the risk of eye toxicity, including but not limited to bullous/band keratopathy, 
keratoconjunctivitis (unless keratoconjunctivitis sicca), corneal abrasion (unless 
related to trauma), inflammation/ulceration, confirmed by ophthalmological 
examination.
6.
History of clinically significant cardiac disorders: 

Myocardial infarction, or New York Heart Association Class II to IV congestive 
heart failure, within 6 months of the first dose of study drug

Concurrent and clinically significant abnormalities on ECG at Screening, including 
QTcF > 450 ms for males or > 460 ms for females (mean values from triplicate 
ECGs; see Section 5.3.2.4)


 
 
   
 
 
 
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7.
Serum electrolyte abnormalities defined as follows:

Hyperphosphatemia: serum phosphate > institutional ULN 

Hyperkalemia: serum potassium > institutional ULN 

Hypokalemia: serum potassium < institutional LLN 

Hypercalcemia: corrected serum calcium > 3.1 mmol/L (> 12.5 mg/dL)

Hypocalcemia: corrected serum calcium < 1.75 mmol/L (< 7.0 mg/dL)

Hypomagnesemia: < 0.4 mmol/L (< 0.9 mg/dL)
8.
History of major thrombotic and clinically relevant bleeding event in the last 6 months 
before Screening which in the assessment of the Investigator puts the patient at high 
risk of bleeding during the study
9.
Uncontrolled tumor-related hypercalcemia
Medical history
10. Bellmunt score 3, or 2 if based on a combination of hemoglobin < 10 g/dL and 
presence of liver metastasis.1
11. Any unresolved (at the time of Screening) clinically significant CTCAE grade ≥ 2 
toxicity (except for alopecia, grade 2 platinum-therapy related neuropathy, grade 2 
anemia from previous anti-tumor treatment, grade 2 renal impairment per reduced 
CLCR by Cockcroft-Gault of 30–60 mL/min [which is generally accepted for this 
cancer population], and/or medical/surgical procedures/interventions). 
12. Known CNS metastases
13. Lack of recovery from major (e.g., open abdominal) surgery after 4 weeks, or major 
elective surgery is planned during the foreseeable duration of the study
14. Concurrent uncontrolled or active infection with human immunodeficiency virus 
(known HIV 1/2 antibodies positive)
15. Active hepatitis B or chronic hepatitis B without current antiviral therapy and an HBV 
DNA ≥100 IU/mL
Note: Active hepatitis B is defined as a known positive hepatitis B surface antigen (HBsAg) result. 
16. Active hepatitis C
Note: Active hepatitis C is defined by a known positive Hep C antibody result and known quantitative 
hepatitis C virus (HCV) RNA results greater than the lower limits of detection of the assay.
17. Active tuberculosis 
18. Severe bacterial, fungal, viral and/or parasitic infections on therapeutic oral or IV 
medication at the time of first dose of study drug administration 
19. Significant gastrointestinal disorders that could, in the opinion of the Investigator, 
interfere with the absorption, metabolism, or excretion of derazantinib (e.g., Crohn’s 
                                                
1 Bellmunt scores (0–3) (Bellmunt 2010) are derived from three adverse risk factors (ECOG PS of ≥ 1, hemoglobin level 
< 10 g/dL, and presence of liver metastasis), and are based on the presence of zero, one, two, or three of the prognostic 
factors.


 
 
   
 
 
 
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disease, ulcerative colitis, diarrhea, extensive gastric resection, functionally relevant 
gastrointestinal obstruction, or vomiting)
20. History of additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin that has undergone potentially curative therapy, or in situ cervical cancer. 
Note: An incidental finding of prostate cancer (identified upon resection of the prostate) is acceptable, 
provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤ 6, and prostate-
specific antigen below lower limit of normal by local laboratory. 
21. Chronic leg ulcers, decubitus ulcers, or unhealed incisions.
General patient disposition
22. Known hypersensitivity or allergy any component of the derazantinib formulation.
23. Unable or unwilling to swallow the complete daily dose of study drug, or 
contraindicated to receive study drug.
24. Any other uncontrolled intercurrent illness that would unduly increase the risk of 
toxicity or limit compliance with study requirements, including but not limited to 
ongoing or active symptomatic infection, uncontrolled diabetes mellitus, or hepatic, 
renal, respiratory, or psychiatric illness.
25. A history or evidence of psychiatric, substance abuse, or any other clinically 
significant disorder, condition or disease that, in the opinion of the Investigator or the 
Sponsor if consulted, would pose a risk to the safety of the patient, or would interfere 
with the study evaluation, procedures, or completion.
26. Pregnant or breast feeding.
In addition, the following exclusion criteria related to atezolizumab are applicable only to
patients to be enrolled into Substudies 3 and 4:
27. Treatment with systemic corticosteroids (except for steroidal replacement therapy) or 
other systemic immunosuppressive medications (including but not limited to 
prednisone, 
dexamethasone, 
cyclophosphamide, 
azathioprine, 
methotrexate, 
thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to first dose 
of study drug or anticipated requirement for systemic immunosuppressive medications 
during the study. Generally, inhaled, intranasal, intraocular, topical, and intra-articular 
joint injections are allowed.
28. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently).
29. History of allogeneic stem cell or solid organ transplantation.
30. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric 
or humanized antibodies or fusion proteins.
31. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster 
ovary cells or any component of the atezolizumab formulation


 
 
   
 
 
 
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32. Hypersensitivity to atezolizumab or to any of the excipients
33. Patients requiring systemic treatment within the past 3 months or a documented history 
of clinically severe autoimmune disease that requires systemic steroids or 
immunosuppressive agents. (Exceptions include any patient on 10 mg or less of 
prednisone or equivalent, patients with vitiligo, hypothyroidism stable on hormone 
replacement, Type I diabetes, Graves’ disease, Hashimoto's disease, alopecia areata, 
eczema)
34. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic 
organizing pneumonia), or evidence of active pneumonitis on Screening chest CT scan
4.4
Method of assignment to substudy and treatment
Patients will be assigned to a specific substudy based on the appropriate eligibility criteria.
For all substudies, a unique enrollment code will be assigned after written informed consent 
has been obtained, using the centralized Interactive Web Response System (IWRS). If a 
patient withdraws from participation in the study, his or her enrollment code will not be 
reused. 
4.4.1
Substudy 1
All eligible patients will receive derazantinib 300 mg QD monotherapy. Treatment 
assignment is performed on C1D1, or as close as possible to the date on which treatment 
is to be administered.
4.4.2
Substudy 3
All eligible patients will receive derazantinib 200 mg BID and atezolizumab 1200 mg 
Q3W in combination. If derazantinib 200 mg BID at the safety interim analysis is not 
assessed as safe and tolerable, patients will be treated with the RP2D determined in 
Substudy 2 (i.e., derazantinib 300 mg QD and atezolizumab 1200 mg Q3W in 
combination). Treatment assignment is done on C1D1, or as close as possible to the date 
on which treatment is to be administered.
4.4.3
Substudy 4
Patients in Substudy 4 are to be randomized (1:1) to receive study treatment with either  
derazantinib 300 mg QD monotherapy (Cohort 4a), or derazantinib 300 mg QD and 
atezolizumab 1200 mg Q3W in combination (Cohort 4b), based on a computer-generated 
randomization schedule via IWRS. Patients in Substudy 4 will be randomized on C1D1, or 
as close as possible to the date on which treatment is allocated. Randomization will be
stratified for key prognostic factors according to the following algorithms:

The presence of visceral metastasis, an ECOG PS of 2, or a preceding FGFR inhibitor 
treatment interval of less than 6 months (i.e., less than 24 full weeks) will be credited 
with one point, and patients will be stratified according to their composite score values 
of 0–1 versus 2–3 points.


 
 
   
 
 
 
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4.4.4
Substudy 5
All eligible patients will receive derazantinib 200 mg BID monotherapy. Treatment 
assignment is performed on C1D1, or as close as possible to the date on which treatment 
is to be administered.
4.5
Discontinuation from the study treatment or study
4.5.1
Patient discontinuation from study treatment
Patients should be discontinued from study treatment at any time if they experience 
documented radiographic progression of disease. Patients will be permitted to remain on 
study treatment after RECIST 1.1 criteria for PD are met only if, in the opinion of the 
Investigator and with the agreement of the Medical Monitor, they continue to derive benefit 
from derazantinib or derazantinib-atezolizumab in combination. 
In particular, for patients in Cohort 4a, every effort should be undertaken to obtain BICR 
confirmation on disease progression, in order to establish a baseline for a potential 
crossover.
Furthermore, patients should be discontinued from study treatment should any of the 
following occur: 

Any clinically unacceptable treatment-emergent toxicity occurring in patients treated 
with derazantinib monotherapy that persist despite optimal treatment or dose reduction

Any clinically unacceptable treatment-emergent toxicity clearly attributable to 
derazantinib occurring in patients treated with derazantinib-atezolizumab in 
combination that persist despite optimal treatment or derazantinib dose reduction. In 
this instance derazantinib should be discontinued, whilst continuation of atezolizumab 
is at the discretion of the Investigator

Any clinically unacceptable treatment-emergent toxicity clearly attributable to 
atezolizumab occurring in patients treated with derazantinib and atezolizumab in 
combination that require respective management, as detailed in Appendix 4

Both study drugs (derazantinib and atezolizumab) should be discontinued for instances 
of overlapping toxicity (e.g., ophthalmological and/or hepatic adverse events) that 
cannot be clearly attributed to either drug

Pregnancy (see Section 7.4.5)

Patient decision to discontinue treatment and study visits

Withdrawal of consent from treatment and study follow up calls

Non-compliance with any part of the study, as assessed by the Investigator or Medical 
Monitor

Investigator’s decision after discussion with the Medical Monitor or designee

Death


 
 
   
 
 
 
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For all patients who discontinue derazantinib, AE monitoring must be continued for at least 
28 days after the last dose of study drug (see Section 5.2.2.8); for patients discontinuing 
atezolizumab, AE monitoring must be continued for at least 90 days after the last dose (see 
Section 5.2.2.9). 
For patients who fail to return for the End of Treatment visit and/or the Safety Follow-up 
visit(s), the Investigator must make every effort to contact the patient (by telephone or mail 
correspondence). The outcome of this contact must be documented by the Investigator and 
filed in the Investigator Site File (ISF). The reasons for discontinuation of treatment must 
be recorded in the eCRF.
4.5.2
Patient discontinuation from the study
Patients who discontinue from study treatment will be followed for survival until the end 
of the study criteria are met (see Section 3.1.8), either through direct contact with the 
patient or the patient’s relatives, or collection of public records (e.g., death certificate) in 
accordance with local laws, unless they meet any of the following criteria:

Withdrawal of consent for study treatment including safety and survival follow up

Withdrawal of consent for long-term (survival) follow-up

Lost to follow-up

Death
4.5.3
Replacement of patients
Patients who are non-evaluable for efficacy (see Section 8.2.2) are to be replaced.
4.5.4
Study discontinuation
The Sponsor reserves the right to temporarily or permanently discontinue the cohort, 
substudy or study at any site or at any time. Reasons for study discontinuation may include, 
but are not limited to, the following:

Safety concerns (i.e. an identified risk or potential risk that could have an impact on the 
risk-benefit balance of the product or have implications for public health)

Poor enrollment

Non-compliance with the protocol, Good Clinical Practice (GCP) guidelines, or other 
regulatory requirements by the Investigator(s)

Request to discontinue the study by regulatory or health authority
The Sponsor and/or designee will promptly inform all Investigators and the appropriate 
regulatory authorities if the study is suspended or terminated for safety reasons. In the case 
of such a termination, the Investigator will notify the IRB or Independent Ethics Committee 
(IEC), as appropriate.


 
 
   
 
 
 
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SCHEDULE OF ASSESSMENTS AND PROCEDURES
Effective Protocol Version 5.0, only assessments and procedures applicable to active 
substudies are provided in this section.
5.1
Summary of schedule of assessments
Study patients will be assessed in accordance with the items and schedules provided in
Table 1. All applicable assessments must be documented in the eCRF for each patient.
Patients will be closely monitored for safety and tolerability throughout the study. Patients 
should be assessed for toxicity prior to the start of each cycle; and study drug dosing should 
occur only if the clinical assessment and local clinical safety blood test values are 
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1.
Deviations from the visit schedule by +3 days are permitted for reasons other than toxicity, e.g., for administrative reasons or to accommodate travel logistics. If a patient 
visit deviates from the permitted protocol window, the next visit must be performed at the correct timing based on the date of C1D1.
2.
Only applicable to Cycle 2.
3.
Applicable to all patients who received atezolizumab as part of their study treatment.
4.
Applicable to Substudies 1, 3 and 5 only (see Section 3.1.1).
5.
Screening procedures (see Section 5.2.1.3) comprise assessment of eligibility criteria; medical history of cancer diagnosis and treatment; demographics, medical history, 
prior medications, baseline medical conditions, including weight and height; Bellmunt score assessment, tuberculosis blood test (e.g., interferon-γ release assay) if 
clinically indicated to rule out clinical suspicion of active tuberculosis; serology for human immunodeficiency virus, hepatitis B, and hepatitis C. 
6.
Patients will have complete ophthalmological examination, including optical coherence tomography (OCT), during Screening, the first four cycles (i.e., Day 1 [±7d] of 
Cycles 2–5) and the End of Treatment visit. A complete ophthalmological examination is to be repeated if new ocular symptoms occur or vision is impaired (see Section 
5.3.2.3).
7.
For all patients, a standard, triplicate, 12-lead ECG must be performed and read locally at all study visits; central reading of all ECG results will be performed (see 
Section 5.3.2.4). Note that the on-treatment ECGs (up to Cycle 4) should be performed as close as possible to the corresponding PK blood collection timepoint during 
those visits (see Footnote 16); if possible, ECG should be performed first, and then blood collected for PK within 5–10 minutes. Subsequently, ECGs will be performed 
pre-dose on Day 1 of every cycle, at End of Treatment and at Safety Follow-up.  
8.
Safety laboratory blood samples will be tested locally at all study visits . The results of these assessments must be reviewed prior to dosing (see Section 5.3.2.5).
9.
Comprising specific gravity, pH, glucose, protein, ketones, and blood (see Section 5.3.2.6).
10.
Women of child-bearing potential must have a negative local serum pregnancy test (hCG) at the SV and within 72 hours prior to dosing at C1D1.  Subsequently, serum 
pregnancy testing will be performed prior to study drug dosing on Day 1 of every cycle, at the End of Treatment visit, and serum or urine pregnancy testing will be 
performed monthly for 150 days (5 months) following the last administration of study treatment. Monthly pregnancy testing after the end of treatment may be performed 
by the patient’s local gynecologist to reduce the burden related to study visits at the site, but must be communicated to the study Investigator.
11.
Research liquid biopsies are requested from all patients enrolled in Substudies 1, 3, 4 and 5 at Screening and End of Treatment visits, and at the time point of the 
confirmatory CT scan (for complete response/partial response). 


 
 
 
 
 
 
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12.
Archival tumor tissue (FFPE block; or a minimum of two H&E-stained slides plus at least 10 consecutive, unstained, 4 ± 1 µm thick sections, placed on positively charged 
slides) should be collected at the SV from all enrolled patients for biomarker assessment (including PD-L1 testing). If archival tumor tissue is not available, de novo
biopsy may be performed but only if considered by the Investigator as safe and tolerable for the patient.
13.
Tumor assessments performed as SoC prior to obtaining informed consent and within 28 days of the first dose of study treatment on C1D1 may be used rather than 
repeating tests. The first on-study tumor imaging assessments will be performed after 9 weeks on study, and will be repeated every 9 weeks (±7) from C1D1 (i.e., at C4D1, 
C7D1, C10D1) and every 12 weeks (±7) from C10D1 (i.e., at C14D1, C18D1, etc.) thereafter (with additional scans as clinically indicated and as per RECIST 1.1 criteria) 
until disease progression, death, or loss of follow-up. A tumor assessment should be performed at the End-of-Treatment visit only if the prior scan was not done within 4 
weeks (28 days) prior to this visit, or if the prior scan did not show radiographic disease progression (see Sections 5.2.2.7 and 5.3.3.2). The same radiographic procedure 
as used at the SV must be used throughout the study for each patient to follow target lesions, and results must be reviewed by the Investigator before dosing at the next 
cycle. Imaging timing should be based on the first dose at C1D1, should follow calendar days, and should not be adjusted for delays in cycle starts.
14.
For pre-dose PK blood sampling at C1D15 (all substudies), and C1D8, C2D8 and C2D15 (safety interim analysis patients in Substudies 3 and 5), administer derazantinib 
at the study site. 
15.
Derazantinib PK blood (plasma) sampling will be performed according to the following schedule: 
a.
Rich PK profiling - Applicable to safety interim analysis patients in Substudy 3 and 5 only:
C1D1, prior to derazantinib dose, and 1 hour (± 5 minutes), 2hours (± 5 minutes), 4 hours (± 15 minutes), 8 hours (± 30 minutes), 10 hours (± 30 minutes), 
12 hours (± 30 minutes; prior to the second dose administration), 24 hours after first derazantinib administration (i.e., 12 hours post second dose administration 
but within 1 hour prior to the third dose). 
C1D8, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib administration.
C1D15, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib administration.
C2D1, prior to derazantinib (within 1 hour prior to the next dose), and 1 hour (± 5 minutes), 2 hours (± 5 minutes), 4 hours (± 15 minutes), 8 hours
(± 30 minutes), 10 hours (± 30 minutes), 12 hours (± 30 minutes; prior to the second dose administration), 24 hours after derazantinib administration (i.e., 
12-hour post previous dose administration but within 1 hour prior to the next dose). 
C2D8, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib administration.
C2D15, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib administration
C3D1, prior to derazantinib (within 1 hour prior to the next dose), and 6–8 hours after derazantinib administration.
C4D1, prior to derazantinib administration (within 1 hour prior to the next dose).
28-day Safety Follow-up visit
b.
Sparse PK – Applicable to all patients (except safety interim analysis patients in Substudy 3 and 5; see rich PK sampling):
C1D1 and C1D15, prior to derazantinib (within 1 hour prior to next dose), and 6–8 hours after the study drug administration.


 
 
 
 
 
 
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C2D1, prior to derazantinib (within 1 hour prior to next dose)
C3D1, prior to derazantinib (within 1 hour prior to next dose), and 6–8 hours after the study drug administration.
C4D1, prior to derazantinib administration (within 1 hour prior to next dose)
28-day Safety Follow-up visit
16.
For all patients in Substudy 3 and Cohort 4b and Crossover, atezolizumab PK and ADA (serum) blood sampling will be performed according to the following schedule:
C1D1, prior to atezolizumab administration; and for PK only, 30 minutes after end of atezolizumab infusion 
C2D1, C3D1, C4D1, prior to atezolizumab administration
C8D1, C12D1, C16D1, prior to atezolizumab administration
28-day Safety follow-up visit
17.
Non-serious and serious changes in or worsening of a patient’s condition that occur between any informed consent and first study-drug administration, as well as any AEs 
in conjunction with tumor/liquid biopsies or imaging studies, will be captured in the eCRF (see Section 7.4.2). 
18.
AEs occurring between C1D1 and C1D21 in patients during the DLT observation period of Substudy 3 and 5 will be assessed against the DLT definitions (outlined in 
Section 7.3.3) prior to study drug administration on C2D1. DLTs are also to be recorded in the eCRF. 
19.
PRO instruments should be self-administered at the study site before the patient sees the physician (i.e., at the start of the visit) and prior to the completion of other study 
assessments and the administration of study treatment (see Section 5.3.6).
20.
(Optional) PD assessments in Substudy 3, 4 or 5 (i.e., blood sampling and skin biopsy) to be performed at screening, and on C2D1.
21.
Survival contact can be in person, via phone, or, where applicable, by checking regional/national death registries.


 
 
   
 
 
 
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5.2
Study visits
5.2.1
Screening/enrollment period
5.2.1.1
Informed consent
Eligible patients may only be included in the study after providing written 
IEC/IRB-approved informed consent. Written informed consent must be obtained from 
each patient by the Investigator or designee prior to initiation of any study procedures (see 
Section 10.2 for details). A patient may only participate in the overall study once. 
Patients who agree to participate in the study will sign the most recently approved ICF and 
will be provided with a copy of the document. Informed consent must be obtained within 
the 28 days prior to the first dose of study treatment on C1D1. 
For patients in Substudies 1, 3, or 5 with no documented local NGS test result with an 
eligible FGFR1–3 GA, a separate Pre-screening ICF must first be signed by each 
prospective study participant to permit central testing for eligible FGFR1–3 GAs. 
For patients who are to be enrolled into the optional PDR of Substudies 3, 4 and 5, a 
separate specific PDR ICF providing consent for the additional study assessments 
applicable to this group must be signed.
5.2.1.2
Pre-screening visit 
A Pre-screening visit is only required for prospective study participants under 
consideration for enrollment into Substudies 1, 3 or 5, if no documented local NGS test 
result with an eligible FGFR1–3 GA (Appendix 1) is available at the Screening visit (see 
Section 3.1.1). 
During the Pre-screening visit, a liquid biopsy blood sample for molecular central testing 
will be collected after written informed consent for pre-screening is obtained. The central 
testing will be performed in a laboratory in the USA designated by the Sponsor and will be 
based on NGS testing of cfDNA from a liquid biopsy obtained at Pre-screening visit. The 
liquid biopsy should be obtained following assessment of objective documented 
progression after prior anti-cancer treatment to optimize the likelihood of capturing cfDNA 
shedding reflective of disease progression. Liquid biopsy re-screening for molecular 
inclusion criteria is not permitted, unless the liquid biopsy was not evaluable for technical 
reasons.
For patients considered for enrollment into Substudy 4, a positive FGFR1–3 GA test result 
from the prior FGFR inhibiting treatment is sufficient to initiate clinical screening 
procedures; documentation of the FGFR1–3 GA-positive status should be made available 
at the Screening visit, otherwise a Pre-screening visit must be scheduled and confirmation 
by a positive central FGFR1–3 GA test result should be sought. 
5.2.1.3
Screening visit
The screening window for clinical screening procedures will be 28 days. 
At the Screening visit, clinical eligibility of prospective study participants and baseline 
disease status will be assessed. Patients who fail to meet the eligibility criteria should not, 


 
 
   
 
 
 
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under any circumstances, be enrolled into the study and must be withdrawn from the study 
as a screen failure.
Patients who satisfy all of the inclusion criteria (see Section 4.2) and none of the exclusion 
criteria (see Section 4.3) may be enrolled in the study. After written informed consent is 
obtained, the following will be evaluated within 28 days prior to the first dose of study 
treatment and documented in the eCRF: 

Demographics/medical history/baseline medical conditions (see Sections 5.3.1.1 and 
5.3.1.2)

Medical history of cancer diagnosis and treatment (see Section 5.3.1.3)

Record prior and concomitant medications (medications used within 30 days prior to 
Screening) (see Section 5.3.1.4)

Physical examination, including height, weight and vital signs (see Section 5.3.2.1)

ECOG PS (see Inclusion criterion 7 and Section 5.3.2.2)

Bellmunt score (see Exclusion criterion 10)

Complete ophthalmic examination, including OCT (see Exclusion criterion 5 and 
Section 5.3.2.3)

Triplicate 12-lead ECG (see Exclusion criterion 6 and Section 5.3.2.4)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)
Note: CLCR should be calculated by the Cockcroft-Gault equation; prothrombin time, INR, and partial 
thromboplastin time are required at the Screening and End of Treatment visits.

Tuberculosis blood test (e.g., interferon-release assay) if clinically indicated to rule 
out clinical suspicion of active tuberculosis (see Exclusion criterion 17)

Serology for human immunodeficiency virus, hepatitis B, and hepatitis C (see 
Exclusion criteria 15 and 16)

Urinalysis (see Section 5.3.2.6)

Serum pregnancy test, if applicable (see Exclusion criterion 26, Section 5.3.2.7, and 
Section 7.1.3).

Tumor measurement according to RECIST 1.1 (see Section 5.3.3.2 and Appendix 2) 
Note: Tumor assessments performed as SoC prior to obtaining informed consent and within 28 days of 
the first dose of study treatment on C1D1 may be used rather than repeating tests (if tumor assessment 
was performed after administration of the last dose of prior anti-tumor treatment).

Research liquid biopsy (see Section 5.3.5.1)


 
 
   
 
 
 
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
Archival tumor tissue for molecular biomarker assessments, including PD-L1 testing
(FFPE block; or a minimum of two H&E-stained slides plus at least 10 consecutive, 
unstained, 4 ± 1 µm thick sections, placed on positively charged slides) 
Note: If archival tumor tissue is not available, de novo biopsy may be performed but only if considered 
by the Investigator as safe and tolerable for the patient.

Skin biopsy and blood samples for monocyte subsets (optional for patients enrolled in 
Substudies 3, 4, and 5 only; see Section 5.3.5.3).
Patients may repeat the clinical screening procedures within the screening period after 
initially failing to meet the clinical inclusion criteria. Under rare conditions and contingent 
upon Sponsor approval, patients may be given the possibility to be re-screened after
initially failing screening.
5.2.2
Treatment period
Enrolled patients will be evaluated regularly, as indicated in Table 1. All visits are based 
on the date of the first dose at C1D1 regardless of drug holds. If a patient visit deviates 
from the protocol permitted window, the next visit must be done at the correct time based 
on the date of C1D1.
AEs and concomitant medications will be recorded on an ongoing basis during the 
treatment period, and at the selected time points as summarized in Table 1.
5.2.2.1
Cycle 1, Day 1 (all patients)
The following assessments will be made during this visit (all assessments except for AE 
assessment, post-dose 12-lead ECG, and post-dose PK blood collection [where applicable; 
see Section 5.3.4.1]) must be performed prior to the first dose):

PRO instruments (questionnaires should be completed by the patient prior to being 
evaluated by the physician) (see Section 5.3.6)

Physical examination (see Section 5.3.2.1)

ECOG PS (see Section 5.3.2.2)

Triplicate 12-lead ECGs (performed pre-dose and 6–8 hours after the first dose of study 
drug) (see Section 5.3.2.4)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)
Note: 25-hydroxy vitamin D is required at C1D1, C3D1, C5D1, and the End of Treatment visit only.
CRP is required at C1D1 only and thereafter if infection is suspected. TSH, fT3 and fT4 is required at 
C1D1 and subsequently every 4 cycles.

Blood samples for derazantinib PK (see Section 5.3.4.1 for details of sampling 
schedule)

Blood samples for atezolizumab PK and ADA (Substudy 3, Cohort 4b and Crossover 
only; see Section 5.3.4.2 for details of sampling schedule)


 
 
   
 
 
 
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
Urinalysis (see Section 5.3.2.6)

Serum pregnancy test, if applicable, within 72 hours prior to dosing
(see 
Section 5.3.2.7, and Section 7.1.3) 

Dispense and administer derazantinib capsules (see Section 6.1.1.1)

Dispense and administer atezolizumab (if applicable) (see Section 6.1.2.1)

Assess and record any AEs after study medication administration (see Section 5.3.2.8)

Record concomitant medications (see Section 5.3.2.9)
5.2.2.2
Cycle 1, Day 8 (±3 days) (SIA patients in Substudies 3 and 5)
The following assessments will be made during this visit:

ECOG PS (see Section 5.3.2.2)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)

Blood samples for derazantinib PK (see Section 5.3.4.1 for details of sampling 
schedule) 

Triplicate 12-lead ECGs (performed pre-dose and 6–8 hours post-derazantinib dosing) 
(see Section 5.3.2.4)

Record concomitant medications (see Section 5.3.2.9)

Administer derazantinib capsules (see Section 6.1.1.1)

Assess and record any AEs after study medication administration (see Section 5.3.2.8)
5.2.2.3
Cycle 1, Day 15 (±3 days) (all patients)
The following assessments will be made during this visit:

ECOG PS (see Section 5.3.2.2)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)

Blood samples for derazantinib PK (see Section 5.3.4.1 for details of sampling 
schedule) 

Triplicate 12-lead ECGs (performed pre-dose and 6–8 hours post-derazantinib dosing) 
(see Section 5.3.2.4)

Record concomitant medications (see Section 5.3.2.9)

Administer derazantinib capsules (see Section 6.1.1.1)

Assess and record any AEs after study medication administration (see Section 5.3.2.8)
5.2.2.4
Cycle 2+, Day 1 (+3 days) (all patients)
The following assessments will be made during this visit (all assessments except for AE 
assessment, post-dose 12-lead ECG, and post-dose PK blood collection [where applicable; 
see Section 5.3.4.1]) must be performed prior to study drug dosing):


 
 
   
 
 
 
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
PRO instruments (questionnaires should be completed by the patient prior to being 
evaluated by the physician) (see Section 5.3.6)

Complete ophthalmological examination, including OCT, for the first four treatment 
cycles (i.e., Day 1 of Cycles 2–5), and if clinically indicated thereafter (see 
Section 5.3.2.3)

Physical examination, including weight and vital signs (see Section 5.3.2.1)

ECOG PS (see Section 5.3.2.2)

Triplicate 12-lead ECG (required on D1 of all cycles prior to dosing, or if clinically 
indicated; see Section 5.3.2.4)
Note: On C3D1, ECGs should be performed pre-dose and approximately 6-8 hours 
post-dose.  

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5). 
Note: Thyroid panel (Thyroid stimulating hormone [TSH], tri-iodothyronine [fT3], 
thyroxine [fT4]) are required every 4 cycles from C1D1; and 25-hydroxy vitamin D is 
required at C1D1, C3D1, C5D1 and the End of Treatment visit only.

Urinalysis (see Section 5.3.2.6)

Serum pregnancy test, if applicable, within 72 hours prior to dosing 
(see 
Section 5.3.2.7, and Section 7.1.3)

Blood samples for derazantinib PK (See Section 5.3.4.1 for details of sampling 
schedule) 

Blood samples atezolizumab PK and ADA (Substudy 3, Cohort 4b, and Crossover 
only; see Section 5.3.4.2 for details of sampling schedule)

Research liquid biopsy at the time point of the CT/MRI scan confirming response (see 
Section 5.3.5.1).

Tumor imaging assessment, every 9 weeks from C1D1 (±7 days) for 27 weeks (i.e., 
prior to C4D1, C7D1, C10D1) then every 12 weeks (±7 days, i.e., at C14, C18, etc.) 
(see Section 5.3.3.2 and Appendix 2)

Assess and record any DLTs (SIA patients in Substudies 3 and 5 only) (see Section 
7.3.3)

Record concomitant medications (see Section 5.3.2.9)

Dispense derazantinib capsules and perform drug accountability of returned drug (see 
Section 6.1.1.1 and Section 6.1.1.3). 
Note: To avoid unnecessary waste of study drug, in cases where treatment was interrupted and/or dose 
was reduced, the patient can continue dosing from the previously dispensed bottle until the next drug 
dispensing visit where re-supply is needed to maintain the protocol dosing regimen. 

Administer derazantinib capsules (see Section 6.1.1.1)

Administer atezolizumab (if applicable) (see Section 6.1.2.1)

Assess and record any AEs after study medication administration (see Section 5.3.2.8)


 
 
   
 
 
 
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
Skin biopsy and blood samples for monocyte subsets on C2D1 only (optional for 
patients enrolled in Substudies 3, 4, and 5 only; see Section 5.3.5.3)
5.2.2.5
Cycle 2, Day 8 (±3 days) (SIA patients in Substudies 3 and 5)
The following assessments will be made during this visit (all assessments except for AE 
assessment, post-dose 12-lead ECG, and post-dose PK blood collection [where applicable; 
see Section 5.3.4.1]) must be performed prior to study drug dosing):

ECOG PS (see Section 5.3.2.2)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)

Blood samples for derazantinib PK (see Section 5.3.4.1 for details of sampling 
schedule) 

Triplicate 12-lead ECGs (performed pre-dose and 6–8 hours post-derazantinib dosing) 
(see Section 5.3.2.4)

Record concomitant medications (see Section 5.3.2.9)

Administer derazantinib capsules (see Section 6.1.1.1)

Assess and record any AEs after study medication administration (see Section 5.3.2.8)
5.2.2.6
Cycle 2, Day 15 (±3 days) (SIA patients in Substudy 3 and 5)
The following assessments will be made during this visit (all assessments except for AE 
assessment, post-dose 12-lead ECG, and post-dose PK blood collection [where applicable; 
see Section 5.3.4.1]) must be performed prior to study drug dosing):

ECOG PS (see Section 5.3.2.2)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)

Blood samples for derazantinib PK (see Section 5.3.4.1 for details of sampling 
schedule) 

Triplicate 12-lead ECGs (performed pre-dose and 6–8 hours post-derazantinib dosing) 
(see Section 5.3.2.4)

ECOG PS (see Section 5.3.2.2)

Record concomitant medications (see Section 5.3.2.9)

Administer derazantinib capsules (see Section 6.1.1.1)

Assess and record any AEs after study medication administration (see Section 5.3.2.8)
5.2.2.7
End of Treatment assessment (≤7 days after last dose) (all patients)
End of Treatment assessments are to be performed in patients who no longer receive study
drug(s) (for any reason), and must take place within 7 days of the decision to permanently 
discontinue all study drug(s). 


 
 
   
 
 
 
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The following assessments will be performed during the End of Treatment visit:

PRO instruments (questionnaires should be completed by the patient prior to being 
evaluated by the physician) (see Section 5.3.6)

Physical examination, including weight and vital signs (see Section 5.3.2.1)

ECOG PS (see Section 5.3.2.2)

Complete ophthalmological examination, including OCT (see Section 5.3.2.3)

Triplicate 12-lead ECG (Section 5.3.2.4)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)
Note: 25-hydroxy vitamin D is required at C1D1, C3D1, C5D1, and the End of Treatment visit only.

Urinalysis (see Section 5.3.2.6)

Serum pregnancy testing

Research liquid biopsy (see Section 5.3.5.1)

Tumor imaging assessment, if the prior scan was not done within four weeks (28 days) 
prior to this visit or if the prior scan did not show radiographic disease progression (see 
Section 5.3.3.2 and Appendix 2). For patients who discontinue study treatment without 
documented radiologic disease progression, every effort should be made to perform 
radiologic imaging.

Assess and record any AEs (see Section 5.3.2.8)

Record concomitant medications (see Section 5.3.2.9)

Perform drug accountability of returned derazantinib (see Section 6.1.1.3)
5.2.2.8
Safety follow-up (28 days after last dose; ± 3 days)
All patients will be followed for a minimum of 28 days after the last dose of all study 
treatment. During the 28-day safety follow-up period, all AEs/SAEs and changes in 
concomitant medication should be reported. 
Patients with unresolved study drug-related AEs (which occurred during the study 
treatment period or in the 28-day safety follow-up period; see Section 7.2.4 for the 
definition of a suspected AE) will be followed until, in the opinion of the Investigator, 
study drug-related toxicities have resolved to baseline, CTCAE grade 1, stabilized, or are 
deemed to be irreversible. 
In addition, at the 28-day safety follow-up visit, the following assessments will be made:

Physical examination, including weight and vital signs (see Section 5.3.2.1)

ECOG PS (see Section 5.3.2.2)

Triplicate 12-lead ECG (Section 5.3.2.4)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)


 
 
   
 
 
 
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
Serum or urine pregnancy testing (to be performed monthly until 150 days after the last 
administration of study drug) (see Section 5.3.2.7, and Section 7.1.3)

Blood samples for derazantinib PK, if applicable (See Section 5.3.4.1 for details of 
applicable patients/ sampling schedule) 

Blood samples atezolizumab and ADA (Substudy 3 Cohort 4b, and Crossover; see 
Section 5.3.4.2 for details of applicable patients/ sampling schedule)
5.2.2.9
Safety follow-up (90 days after last dose; ± 3 days)
All patients who receive atezolizumab in Substudy 3, Cohort 4b, and Crossover will be 
followed for a minimum of 90 days after the last dose of all study treatment. During the 
90-day safety follow-up period, all AEs/SAEs, changes in concomitant medication, and 
new anticancer treatment should be reported. 
Patients with unresolved study drug-related AEs (which occurred during the study 
treatment period or in the 90-day safety follow-up period; see Section 7.2.4 for the 
definition of a suspected AE) will be followed until, in the opinion of the Investigator, 
study drug related toxicities have resolved to baseline, CTCAE Grade 1, stabilized, or are 
deemed to be irreversible. 
In addition, at the 90-day safety follow-up visit, the following assessments will be made:

Physical examination (see Section 5.3.2.1)

ECOG PS (see Section 5.3.2.2)

Triplicate 12-lead ECG (Section 5.3.2.4)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)

Serum or urine pregnancy testing (to be performed monthly until 150 days after the last 
administration of study drug) (see Section 5.3.2.7, and Section 7.1.3)
5.2.3
Survival follow-up period
5.2.3.1
Overall survival follow-up (at least every 3 months ± 14 days)
Survival follow-up will start the day of the last dose of study drug. 
All patients and/or family will be contacted at 3-month intervals (±14 days) and record the 
patient status as Alive (date); Dead (date); Alive, but withdrew consent for further follow 
up (last date under consent); or Lost to Follow Up (date of last contact), and subsequent 
anticancer therapies. 
Survival updates may be made more often than every 3 months if the patient is seen at the 
investigational site for other reasons and for study level survival sweep(s). The survival 
follow-up period will continue until the study has completed (see Section 4.5.4) or other 
discontinuation criteria are met (see Section 4.4.4).
Note: Survival follow-up can be done either over the telephone, or by collection of public 
records in accordance with local laws. For some patients the first survival contact may 


 
 
   
 
 
 
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occur at the time of the 90-day Safety-Follow-up visit (i.e. 90 days after the last dose had 
been administered).
Note: Pregnancy testing after 90 days (e.g., on Day 150) after the last dose of study drug 
may be performed at the patient’s local gynecologist to reduce the burden related to study 
visits at the site, but must be communicated to the study Investigator.
5.3
Study procedures
5.3.1
Screening procedures
5.3.1.1
Medical history / baseline medical conditions
A full medical history, including relevant conditions, abnormalities, surgeries, diseases, or 
disorders, must be obtained at Screening and recorded in the eCRF. Medical history also 
includes any relevant worsening of a patient’s condition which occurs after any informed 
consent, but prior to the start of first study-drug administration.
5.3.1.2
Demography
Demography should also be collected and recorded in the eCRF, including year of birth, 
gender, race (unless local regulations do not permit), and ethnicity (US patients).
5.3.1.3
Prior cancer history
Details regarding prior cancer history, current cancer diagnosis, tumor stage at the time of 
diagnosis and at Screening, and previous cancer-related surgical procedures, including type 
of the procedure and dates are also required. 
Prior anti-cancer treatments must be recorded during Screening and documented for each 
patient in the eCRF, including:

Previous anti-cancer agents received since the diagnosis of cancer (if relevant), 
including dates, duration and outcome of treatment.

Previous radiation therapy received since the diagnosis of cancer, including anatomic 
site, dose and dates of treatment.
5.3.1.4
Prior and concomitant medications
All non-antineoplastic medications or significant non-drug therapies (including herbal 
medicines) taken within 30 days of the Screening visit must be documented for each patient 
in the eCRF.
5.3.2
Safety assessments
The Investigator will evaluate safety by AE monitoring (type, nature, severity, according 
to NCI CTCAE 5.0), physical examination (including vital signs), ophthalmological 
examination, ECG assessment, clinical safety blood tests, ECOG PS, and pregnancy 
testing. 
These safety assessments must be performed at intervals indicated in the schedule of 
assessments (see Table 1). More frequent assessments may be performed at the 
Investigator’s discretion, if medically indicated.
Safety data will also be reviewed by the Sponsor and by the IDMC (see Section 3.5).


 
 
   
 
 
 
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5.3.2.1
Physical examination
The physical examination will include examination of general appearance, skin, nails, neck 
(including thyroid), eyes, nose, throat, cardiovascular system, thorax/lungs, abdomen, 
lymph nodes, extremities, and nervous system. 
Additionally, the patient should undergo assessment of height (Screening visit only), 
weight, and vital signs (temperature [oral, axillary, or tympanic], blood pressure, 
respiration rate, and pulse).
Systolic and diastolic blood pressure must be obtained in the same position throughout a 
given visit, i.e., either sitting, semi-supine, or supine, as appropriate. Recordings are to be 
made after the patient has been in this position for at least 5 min.
Any clinically-significant physical change from baseline that occurs after first study-drug 
administration must be reported as an AE (see Section 7.4.3.1).
5.3.2.2
Eastern Cooperative Oncology Group performance status 
ECOG PS will be assessed at all study visits. 
Table 2 provides the scale to be used for these assessments.
Table 2
ECOG performance status
Grade
ECOG Description 
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Death
Abbreviations: ECOG, Eastern Cooperative Oncology Group.
5.3.2.3
Complete ophthalmological examination
A complete ophthalmological examination, including OCT, should be performed by an 
ophthalmologist at the Screening visit, for the first four cycles (i.e., Day 1 [±7d] of Cycles 
2–5), and at the End of Treatment visit. Thereafter, a complete ophthalmological
examination is to be repeated if clinically indicated (e.g., new ocular symptoms occur or 
vision is impaired).
The complete ophthalmological examination may include the following:

visual acuity

tonometry

anterior segment evaluation

retinal evaluation, including OCT
For the individual patient, the same methods of assessment should be used throughout the 
study. Patients who develop ocular symptoms or changes in visual acuity while on the 


 
 
   
 
 
 
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study should be referred to the ophthalmologist for a complete ophthalmological 
examination.
5.3.2.4 Electrocardiogram (12-lead) triplicates
For all patients, a standard, triplicate, 12-lead ECG must be performed at all study visits 
using the pre-programmed device provided by the Sponsor.
ECGs must always be recorded after at least 5 minutes rest and while the patient is in a 
sitting, semi-supine, or supine position. Measurements should be separated by ~1 minute 
and be taken within a 5-minute time window. The on-treatment ECGs (up to Cycle 4) 
should be performed as close as possible to the corresponding PK blood collection 
timepoint during those visits (see Section 5.3.4.1); if possible, ECG should be measured 
first, and then blood collected for PK within 5–10 minutes. 
ECGs must be assessed by the Investigator or their designee for any abnormalities, 
including prolongation of QTcF. The ECG printouts are to be signed and dated by the 
Investigator or their designee. Further instruction and training on handling the device and 
transmitting data will be provided to the study centers prior to study initiation.
All ECGs are to be transmitted to a central ECG laboratory for evaluation, including QTcF
assessment. Any clinically-significant ECG change from baseline that occurs after first 
study drug administration must be reported as an AE (see Section 7.4.3).
5.3.2.5 Clinical safety laboratory blood tests
Blood samples for clinical safety laboratory testing should be performed locally at all study 
visits. For C1D1, clinical safety laboratory testing must be performed within 72 hours prior 
to study drug administration.
These assessments must be reviewed prior to dosing, and study drug administration should 
only occur if local laboratory test values are acceptable (i.e., CTCAE grade 2 or less), 
unless dose delays or modifications are clinically indicated (as assessed by the Investigator 
and agreed upon by Medical Monitor or designee; see Section 6.1.1.5).
Safety laboratory determinations will include hematology, blood chemistry, liver function 
tests, and coagulation tests. If clinically indicated, some or all of these tests may be repeated 
on other study days.
Clinical safety laboratory tests will comprise the following:

Hematology: complete blood count including hemoglobin, hematocrit, absolute white 
blood cell count with 5-part differential, red blood cell count, and platelet count

Blood chemistry: albumin, calcium, magnesium, chloride, C-reactive protein (CRP), 
creatinine, glucose, phosphate, potassium, amylase, lipase, total protein, sodium, 
thyroid panel (TSH, fT3, fT4), uric acid, and Vitamin D
–
CRP is required at C1D1 only and thereafter if infection is suspected;
–
CLCR, as calculated by the Cockcroft-Gault equation (at the Screening Visit only);
–
TSH, fT3 and fT4 is required at C1D1 and subsequently every 4 cycles;


 
 
   
 
 
 
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–
25-hydroxy vitamin D is required at C1D1, C3D1, C5D1, and the End of Treatment 
visit only. 

Liver function tests: ALT, AST, Alkaline phosphatase (ALP), total and direct bilirubin, 
lactate dehydrogenase

Coagulation tests: prothrombin time, INR, and partial thromboplastin time (at the 
Screening and End of Treatment visits, and if clinically indicated at any time during 
treatment)
Additional testing may be performed whenever clinically indicated at the discretion of the 
Investigator and if applicable in relation to the patient’s medical history. All samples for a 
given study center must be analyzed by the same local laboratory throughout the study, as 
designated by the Investigator. The results are to be printed, signed and dated by the 
Investigator or their designee. 
In the event of unexplained abnormal laboratory test values, the tests must be repeated 
immediately and followed-up until return to the normal range, stabilization, and/or until an 
adequate explanation of the abnormality has been determined. Abnormal laboratory results 
should not be recorded as an AE unless the abnormality is associated with a clinically-
relevant condition (see Section 7.4.3.1.1).
5.3.2.6
Urinalysis
Urinalysis will be performed locally at the Screening visit, at C1D1 (within 72 hours prior 
to study drug administration), at D1 of all subsequent cycles, and at the End of Treatment 
visit.
Urinalysis should consist of specific gravity, pH, glucose, protein, ketones, and blood. If 
clinically indicated, some or all of these tests may be repeated on other study days.
5.3.2.7
Pregnancy testing
Women of child-bearing potential must have a negative hCG at Screening and within 
72 hours prior to dosing at C1D1. Subsequently, serum pregnancy testing will be 
performed prior to study drug dosing on D1 of every cycle, at the End of Treatment visit, 
and serum or urine pregnancy testing will be performed monthly thereafter for 150 days 
following the last administration of study treatment. 
Pregnancy testing after the end of treatment may be performed at the patient`s local 
gynecologist to reduce the burden related to study visits at the site, but must be 
communicated to the study Investigator.
The Investigator may conduct additional pregnancy tests (serum or urine) to confirm the 
absence of pregnancy at any time during the study. If a pregnancy test result is positive, 
study drug must be discontinued, the patient followed for safety, and the outcomes of the 
pregnancy assessed (see Section 7.4.5). Further details regarding the risk of pregnancy are 
provided in Section 7.1.3.


 
 
   
 
 
 
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5.3.2.8
Adverse event monitoring
AEs will be monitored throughout the study and graded in severity according to the 
guidelines outlined in NCI CTCAE 5.0. 
Please refer to Section 7 for details regarding AE collection and management.
5.3.2.9
Concomitant medications
Any medications or significant non-drug therapies (including herbal medicines) that are 
taken by or administered to the patient during the course of the study (until the safety 
follow-up visit at Day 28 for all patients, and Day 90 for patients receiving derazantinib-
atezolizumab in combination) must be recorded in the eCRF including the dosage, 
frequency of administration, route of administration, therapeutic indication, and start/stop 
dates of use.
5.3.3
Efficacy assessments
5.3.3.1
Tumor imaging and assessment of disease
The process for image collection and transmission to the central imaging vendor is 
provided in the Imaging Charter. Tumor disease assessments should comprise the chest, 
abdomen, and pelvis. Tumor imaging should be acquired by computed tomography (CT, 
strongly preferred). Magnetic resonance imaging (MRI) should be used when CT is 
contraindicated, and for imaging in the brain. 
A bone scan (BS) – alternatively, a whole-body MRI (WBMRI) - should also be performed 
at Screening only in patients with new symptoms (e.g., new persistently elevated ALP) to 
assess bone metastasis; screening of asymptomatic patients for clinically unapparent bone 
metastases is not supported by applicable guidelines (Witjes 2018) but may be done at the 
Investigator’s discretion if local routine practice. Patients with positive BS/WBMRI at 
baseline will undergo further radiologic assessments of bone lesions performed at 
protocol-scheduled time points for tumor assessments and as per institutional practice. 
Lytic/mixed lesions with soft tissue component may be included in the evaluation of 
disease burden if it meets measurability criteria while blastic lesions are considered non-
measurable, in accordance with RECIST 1.1.
The same imaging technique regarding modality and use of contrast should be used in a 
patient throughout the study.
Local site Investigator/radiology assessment based on RECIST 1.1 will be used to 
determine patient eligibility. All measurable and evaluable lesions should be assessed and 
documented by the site study team at the Screening visit.
All scheduled images for all study patients must be submitted to the central imaging 
vendor. Additional imaging (including other modalities) obtained at unscheduled time 
points to determine disease progression, as well as imaging obtained for other reasons, but 
which captures radiologic progression, must also be submitted to the central imaging 
vendor.


 
 
   
 
 
 
 
 
 
 
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5.3.3.2
Tumor measurement and response evaluations
Tumor imaging assessments (CT/MRI of the chest, abdomen, and pelvis, plus a 
BS/WBMRI, if applicable) must be done at the time of the Screening visit. However, if an 
assessment has been performed for routine clinical management after administration of the 
last dose of any prior anti-tumor treatment, but prior to obtaining informed consent and 
within 28 days of first dose of study treatment on C1D1, then this may be used for 
Screening purposes; in such situations it is not necessary to repeat tests if the assessments 
are of sufficient diagnostic quality. 
Initial tumor imaging
For initial tumor imaging at Screening, the site study team must review Screening images 
to confirm the patient has measurable disease per RECIST 1.1.
On-treatment tumor imaging
Study imaging assessments consist of CT/MRI of the chest, abdomen, and pelvis (plus a 
BS/WBMRI, if applicable). The first on-study tumor imaging assessments will be 
performed after 9 weeks on study, and will be repeated every 9 weeks from C1D1 (±7 days) 
(approximately every 3 cycles, i.e., at C4, C7, C10) or more frequently if clinically 
indicated. After 27 weeks (9 cycles), the assessment interval is every 12 weeks (±7 days, 
i.e. at C14, C18, etc.) for all patients. Imaging timing should be based on the first dose at 
C1D1, should follow calendar days, and should not be adjusted for delays in cycle starts. 
Results of all on-treatment tumor imaging assessments must be reviewed by the 
Investigator before dosing at the next cycle.
Post-treatment tumor imaging
Patients who discontinue study treatment should have a tumor evaluation visit as soon as 
possible after the event (e.g., clinical deterioration; ± 4-week window). If a previous scan 
was obtained within 4 weeks prior to the End of Treatment Visit, then a scan is not 
mandatory. For patients who discontinue study treatment without documented radiologic 
disease progression, every effort should be made to perform radiologic imaging. For 
patients who discontinue study treatment due to documented PD, this is the final required 
tumor imaging. 
RECIST 1.1 and iRECIST
The efficacy of derazantinib monotherapy treatment and derazantinib-atezolizumab in 
combination will be primarily measured by ORR evaluated by BICR using RECIST 1.1 
(see Appendix 2). 
In addition, an exploratory assessment will be performed using iRECIST criteria 
(Seymour 2017) in patients treated with derazantinib-atezolizumab in combination, 
including those patients undergoing crossover treatment (see Appendix 3 for comparison 
of RECIST 1.1 and iRECIST).
The iRECIST criteria is RECIST 1.1 adapted to account for the tumor response patterns
seen with immunotherapeutic drugs. In patients undergoing combination treatment with 
derazantinib and atezolizumab, iRECIST will be used by the site Investigator / local 


 
 
   
 
 
 
 
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radiology review to assess tumor response and progression, and to make treatment 
decisions. These data will be collected in the clinical database. Treatment efficacy based 
on iRECIST as assessed by central imaging vendor review will be evaluated 
retrospectively.
The Investigator should make every attempt to perform the confirmation scan of CR or PR 
4–5 weeks after the last scan was performed. The confirmation scan of iUPD should be 
performed 4–8 weeks after the last scan was performed, unless criteria for clinical stability 
are not met (see below). 
Management of immunotherapy-treated unconfirmed disease progression
In patients treated with derazantinib-atezolizumab in combination1 who have iUPD 
(i.e., initial evidence of radiological PD by RECIST 1.1 as verified by the central imaging 
vendor), it is at the discretion of the Investigator whether to continue a clinically stable 
patient (as defined below) on study treatment until repeat imaging is obtained. For patients
with iUPD, confirmation is done on the basis of observing any of the following scenarios
in clinically stable patients:
Worsening of existing target lesion(s)
Worsening of existing non-target lesion(s)
Development of new lesions(s)
If progression is confirmed by a CT/MRI after 4–8 weeks, the patient should discontinue 
study treatment. 
If progression is not confirmed and criteria of iCR, iPR, or iSD are met compared with 
baseline (i.e. a reduction in lesion diameter is shown compared to the iUPD assessment), 
then subsequent assessment are to be compared against the tumor diameter nadir values of 
iCR, iPR, or iSD. If iUPD occurs again (compared with nadir values of iCR, iPR, or iSD) 
then iUPD is again to be confirmed (by further growth) at the next assessment for iCPD to 
be assigned. 
If no change in tumor size or extent from iUPD occurs, then the timepoint response would 
again be iUPD. This approach allows atypical responses, such as delayed responses that 
occur after pseudo-progression, to be identified (Seymour 2017). Patient management 
using iRECIST is detailed in Table 3.
This clinical judgment decision by the Investigator should be based on the patient’s overall 
clinical condition, including performance status, clinical symptoms, and laboratory data. 
Patients may continue to receive study treatment and tumor assessment should be repeated 
4–8 weeks later in order to confirm iUPD by iRECIST per site assessment. 
Clinical stability is defined as the following:
                                                
1 Applicable to patients receiving derazantinib-atezolizumab in combination in Substudies 3 and 4, including patients in 
Cohorts 3a and 4a crossing over from derazantinib monotherapy after centrally confirmed radiographic PD per 
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DZB-CS-201 (FIDES-02)
Version 5.0
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Overview of specific PK sampling requirements
All patients, excluding SIA patients in Substudies 3 and 5, will undergo sparse PK 
sampling for measurement of derazantinib plasma concentrations. These samples may also 
be used for exploratory metabolite identification and/or quantification of metabolites. 
All SIA patients in Substudies 3 and 5 will undergo rich PK sampling for measurement 
of plasma concentrations of derazantinib and relevant PK parameters. 
Additionally, in Substudy 3, Cohort 4b and Crossover, PK sampling of atezolizumab 
and ADAs will be performed.
Rich PK profiling
Rich PK profiling will be performed for all SIA patients in Substudies 3 and 5, and will 
be drawn in accordance with the following schedule1:
C1D1, prior to derazantinib dose, and 1 hour (± 5 minutes), 2 hours (± 5 minutes), 
4 hours (± 15 minutes), 8 hours (± 30 minutes), 10 hours (± 30 minutes), 12 hours
(± 30 minutes; prior to the second dose administration), 24 hours after first derazantinib 
administration (i.e., 12-hour post second dose administration but within 1 hour prior to 
the third dose). 
C1D8, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib 
administration.
C1D15, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib 
administration.
C2D1, prior to derazantinib (within 1 hour prior to the next dose), and 1 hour
(± 5 minutes), 2 hours (± 5 minutes), 4 hours (± 15 minutes), 8 hours (± 30 minutes), 
10 hours
(± 30 minutes), 12
hours
(± 30 minutes; prior to the second dose 
administration), 24 hours after derazantinib administration (i.e., 12-hour post previous
dose administration but within 1 hour prior to the next dose). 
C2D8, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib 
administration.
C2D15, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib 
administration.
C3D1, prior to derazantinib (within 1 hour prior to the next dose), and 6–8 hours after 
derazantinib administration.
C4D1, prior to derazantinib administration (within 1 hour prior to the next dose).
28-day Safety Follow-up visit
Sparse PK sampling
Sparse PK profiling will be performed for all patients (excluding SIA patients in 
Substudies 3 and 5), according to the following schedule:
                                                
1 This schedule may be adapted to locally applicable clinical routine with the agreement of the Sponsor.


 
 
   
 
 
 
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
C1D1 and C1D15, prior to derazantinib (within 1 hour prior to the next dose), and 
6–8 hours after the study drug administration.

C2D1, prior to derazantinib (within 1 hour prior to the next dose)

C3D1, prior to derazantinib (within 1 hour prior to the next dose), and 6–8 hours after 
the study drug administration.

C4D1, prior to derazantinib administration (within 1 hour prior to the next dose)

28-day Safety Follow-up visit
5.3.4.2 Assessments for pharmacokinetics and anti-therapeutic antibodies of 
atezolizumab
Blood samples for PK and ADA sampling in all patients in Substudy 3 and Cohort 4b
will be drawn in accordance with the following schedule:

C1D1, prior to atezolizumab administration; and for PK only, 30 minutes after end of 
atezolizumab infusion 

C2D1, C3D1, C4D1, prior to atezolizumab administration

C8D1, C12D1, C16D1, prior to atezolizumab administration

28-day Safety follow-up visit
5.3.5
Biomarker assessments
Archival (or de novo, if collected) tumor tissue and research liquid biopsy samples will be 
collected during this study to analyze a panel of biomarkers, including, but not limited to 
biomarkers representing MAPK (RAS/RAF/MEK/ERK), PI3K/AKT, and JAK/STAT 
pathways; indicating PI3K, PTEN, EGFR, MET and ERB3 signaling; demonstrating the 
phosphorylation status of phospho-S6, phospho-STAT, phospho-AKT, phospho-MEK, 
phospho-ERK. 
In addition to these PD markers of target modulation, more generic markers of proliferation 
could be utilized to help confirm that significant inhibition of tumor proliferation has 
occurred. These include the proliferation index (Ki67), apoptosis levels (caspase 
activation), as measured by immunohistochemistry and also various measures of tumor 
vascularity. Anti-vascular effects may also be measured by immunohistochemistry to 
assess micro-vessel density and the endothelial markers CD34 and CD31. 
Tumor and research liquid biopsy samples for biomarker assessments will be analyzed by 
the Sponsor or in specialized laboratories, as described in Section 5.3.5.2 and Section 
5.3.5.1 below. Exceptions to the schedule of Biomarker assessments can be made 
according to the Sponsor’s discretion.
5.3.5.1
Research liquid biopsy 
Apart from diagnostic liquid biopsies for molecular eligibility, research liquid biopsies may 
comprise, but are not limited to, serum and plasma samples to analyze protein biomarkers, 
and cfDNA. The collection, processing, storage, and shipping of samples for the 
assessment of circulating biomarkers will be performed as described in the Laboratory 
Manual. 


 
 
   
 
 
 
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5.3.5.2
Archival tumor tissue
Archival tumor tissue should be collected from all patients enrolled with an FGFR1–3 GA-
positive test result. An FFPE block; or minimum of two H&E-stained slide plus at least 
10 consecutive, unstained, 4 ± 1 µm thick sections, placed on positively charged slides,
should be sent to the central laboratory for biomarker assessment, including PD-L1, as 
described in the Laboratory Manual.
If archival tumor tissue is not available, de novo biopsy may be performed but only if 
considered by the Investigator as safe and tolerable for the patient. For tumor tissue biopsy 
FFPE preservation, slide preparation and sample submission, see the Laboratory Manual.
5.3.5.3
Pharmacodynamic research (optional)
Patients enrolled into Substudies 3, 4 and 5 have the option to participate in an exploratory 
PDR to investigate the role of CSF1R inhibition by derazantinib, comprising a skin biopsy 
and blood sampling for monocyte subsets prior to the first dose of study drug at the 
Screening visit and on C2D1. Up to 20 patients will be enrolled in this PDR Group.
The samples will be collected, processed and shipped as described in the Laboratory 
Manual.
5.3.5.4
Future biomedical research
The Sponsor will conduct Future Biomedical Research on specimens collected during this 
clinical study. This research may include genetic analyses (DNA), proteomics, 
metabolomics (serum, plasma), and/or the measurement of other analytes. Tissue/blood 
samples, plasma/serum samples, DNA isolates from samples available and processed 
during the study and not fully consumed for the described analyses may be stored and 
subsequently used for Future Biomedical Research.
Such research is for biomarker testing to address emergent questions not described 
elsewhere in the protocol as part of the main study, and will only be conducted on 
specimens from patients who have provided appropriate informed consent. The objective 
of collecting specimens for Future Biomedical Research is to explore and identify 
biomarkers that inform the scientific understanding of diseases and/or their therapeutic 
treatments. The goal is to use such information to develop safer, more effective drugs, 
and/or to ensure that patients receive the correct dose of the correct drug at the correct time. 
The details of this Future Biomedical Research substudy are presented in Appendix 5. 
Additional informational material for IRBs/IECs and investigational site staff is provided 
in Appendix 5.
5.3.6
PRO assessments
Patient-reported outcomes will be measured using the EORTC QLQ C30, FACT-Bl, 
EQ-5D (5L), and Health Transition Index/G-SET instruments. 
The EORTC QLQ-C30 was developed to assess the quality of life of cancer patients and 
is the most widely used cancer-specific HR-QoL instrument. It contains 30 items and 
measures five functional dimensions (physical, role, emotional, cognitive, and social), 


 
 
   
 
 
 
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three symptom scales (fatigue, nausea/vomiting, and pain), six single symptom items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact) and 
global health and quality of life. The global health and quality of life items uses a 7-point
scale scoring with anchors (1=very poor and 7=excellent); the other items are scored on a 
4-point scale (1=not at all, 2=a little, 3= quite a bit, 4=very much). 
The EORTC QLQ-C30 is the most frequently utilized and reported patient reported 
outcome measures in cancer clinical trials. The reliability, validity and practicality of these 
instruments have been reported (Aaronson 1993).
The FACT-Bl is instrument which was developed for patients with bladder cancer. It 
contains 40 items and consists of the five subscales: physical well-being (PWB), functional 
well-being (FWB), emotional well-being (EWB), social well-being (SWB) and an 
additional scale specific to bladder cancer. In addition, the PWB, FWB, EWB, and SWB 
subscales can be summed to form the FACTGeneral (FACT-G) score and the FACT-BL 
total score (FACT-G and the bladder cancer specific scale).  The items are scored on a 
4-point scale (0=not at all, 1=a little bit, 2= somewhat, 3=quite a bit, 4 = very much)
(Karvinen 2007).
The EQ-5D (5L) is a standardized instrument for use as a measure of health outcome. The 
EQ-5D will provide data for use in economic models and analyses including developing 
health utilities or QALYs. The five health state dimensions in this instrument include the 
following: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
Each dimension is rated on a five-point scale from 1 (no problem) to 5 (extreme problem). 
The EQ-5D also includes a graded (0 to 100) vertical VAS on which the patient rates his 
or her general state of health at the time of the assessment.
The Health Transition Index/G-SET is a single item and will be used as an external anchor 
to determine the minimal important difference of the EQ-5D visual analogue scale, EORTC 
QLQ-C30 scales and FACT-Bl scales. It will be administered twice during the study 
following the recent protocol by the EORTC Quality of Life Group (Musoro 2018) for 
evaluating the minimal important difference. The SET will be provided after 6 weeks (at 
C3D1) and 12 weeks (at C5D1). The SET is a patient-rated change in health between two 
time periods using a five point ordinal scale (1=much better now than six weeks ago; 
2=somewhat better now than six weeks ago; 3=about the same as six weeks ago; 
4=somewhat worse now than six weeks ago; 5=much worse now than six weeks ago, the 
recall period was adapted compared to the original item) (Ware 2002, Lloyd 2014). 
The HR-QoL questionnaires will be provided to the patients to complete prior to being 
evaluated by the physician on D1 of every cycle, and at the End of Treatment visit. 
Either a paper instrument or an electronic PRO data collection method may be used. The 
PRO instruments, translated as necessary into the local language, will be distributed by the 
Investigator’s staff and completed by the patient. To ensure instrument validity, and to 
ensure that data standards meet Health Authority requirements, PRO instruments should 
be self-administered at the investigational site before the patient sees the physician (i.e., at 
the start of the visit) and prior to the completion of other study assessments and the 


 
 
   
 
 
 
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administration of study treatment. The questionnaire should be completed by the patient 
without assistance during their scheduled visit(s) at the clinic. Study site staff should 
review all instruments for completeness before the patient leaves the investigational site. 
The EQ-5D will always be completed by patients before completing the EORTC 
QLQ-C30, FACT-Bl, and the Health Transition Index/G-SET (only at visits after 6 and 
12 weeks).


 
 
   
 
 
 
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STUDY TREATMENTS
Derazantinib and atezolizumab are both considered to be IMPs in this study, and will be 
provided by the Sponsor. Detailed information related to IMP handling and storage is 
provided in the Pharmacy Manual.
As this is an open-label study, neither the patient, the Investigator / site staff, nor the 
Sponsor will be blinded to the treatment administered.
6.1
Investigational products
6.1.1
Derazantinib
Derazantinib is an investigational drug supplied as 100 mg powder-filled capsules for oral 
administration.
The Investigator must ensure that derazantinib capsules will be used only in accordance 
with the protocol.
6.1.1.1
Derazantinib administration
Derazantinib capsules will be administered by mouth. The schedules for the administration 
of derazantinib are shown in Section 6.1.3 and Table 6.
Derazantinib capsules should be administered at least 1 hour before, or at least 2 hours 
after, a meal. In the event of nausea or vomiting which is assessed as CTCAE grade ≥ 2, a 
light meal before subsequent derazantinib administration is allowed, to minimize the 
severity of the event.
6.1.1.2
Labeling and packaging
Derazantinib is supplied as capsules in white/opaque high-density polyethylene bottles 
with white/opaque polypropylene caps and labeled in the local languages as investigational 
agent, in accordance with local regulations and the Annex 13 Good Manufacturing Practice 
rules. 
Labels must include the identity of the Sponsor and Investigator, patient number, protocol 
number, drug identification, storage conditions, content of study drug, and expiry date. 
Information on drug shipment including temperature logger and acknowledgement of 
receipt form to be completed by the receiver must also be included in the shipment.
6.1.1.3
Drug accountability
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, drug expiration 
date, and acknowledge receipt in the IWRS system. A Packing Slip will be included with 
the shipment and must be completed upon receipt and returned as instructed on the form. 
In addition, the Investigator or designee shall contact the Sponsor as soon as possible if 
there is a problem with the shipment. 
A Drug Accountability Log will be provided for derazantinib capsules. The log must be 
kept current and should contain the protocol number, the name and clinical site of the 


 
 
   
 
 
 
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Clinical Study Protocol
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Investigator, dates and quantities of drug received, patient’s identification number to whom 
derazantinib capsules were dispensed, the date and quantity dispensed, and balance 
remaining, if from individual patient drug units, as well as the lot number, dose, and the 
initials of the dispenser. Drug accountability is performed to the capsule level. 
To avoid unnecessary waste of derazantinib capsules, in cases where treatment was 
interrupted and/or dose was reduced, the patient can continue dosing from the previously 
dispensed bottle until the next drug dispensing visit where re-supply is needed to maintain 
the protocol dosing regimen. 
At the end of the study or as directed, all study drugs, including unused, partially used, or 
empty containers, will be returned to the designee as instructed by the Sponsor. 
Derazantinib capsules will be returned only after the study monitor has completed a final 
inventory to verify the quantity to be returned. The return of derazantinib capsules must be 
documented and the documentation must be included in the shipment. Unused drug 
supplies may be destroyed by the Investigator when approved in writing by the Sponsor 
and the Sponsor has received copies of the site’s drug handling and disposition Standard 
Operation Procedures (SOPs) or equivalent. 
All derazantinib capsules inventory forms must be made available for inspection by a 
Sponsor authorized representative or designee and regulatory agency inspectors. The 
Investigator is responsible for the accountability of all used and unused study supplies at 
the site.
6.1.1.4
Shipping and storage conditions
The Sponsor will provide derazantinib capsules required for completion of this study. It 
will be shipped to the pharmacist/study personnel at the clinical sites during the study with 
orders being raised via the IWRS.
Drug supplies must be stored in a secure, limited access storage area.
The packaged drug product should be shipped and stored at controlled room temperature 
20°C–25°C (68°F–77°F); allowable excursions are in the range of 15°C–30°C 
(59°F–86°F). Derazantinib capsules are stable when stored at controlled room temperature. 
Refer to the product label for specific storage conditions and handling requirements.
If storage conditions deviate from the above storage requirements, the Investigator will 
document the deviation and inform the study monitor within 24 hours of discovery of the 
deviation. The supplies should be held in quarantine and not dispensed until the deviation 
has been reviewed by the Sponsor’s Quality Assurance or designee. If it is determined that 
the product is no longer suitable for use, the bottles must be reported as damaged in the 
IWRS and a resupply shipment will be made.
6.1.1.5
Dose modifications
In general, once the dose of derazantinib has been modified for a patient (as per Table 4),
all subsequent cycles should be administered to that patient at the modified dose. The 
modified dose will be considered the maximum dose for all subsequent cycles for that 
patient. 




 
 
   
 
 
 
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Table 5
Dose delays/reductions for drug-related toxicity
Hyperphosphatemia
Serum phosphate level
Action
(For serum phosphate ≥7.0 mg/dL, consider adding
an oral phosphate binding/reducing agent until serum
phosphate level returns to < 5.6 mg/dL )
< 7.0 mg/dL (< 2.26 mmol/L)
Continue derazantinib at current dose.
7.0 – 9.0 mg/dL (2.26 – 2.90 mmol/L)
Withhold derazantinib with weekly reassessments until
the level returns to < 5.6 mg/dL; the patient may restart
derazantinib at the dose prior to hyperphosphatemia. If
hyperphosphatemia lasts > 2 weeks, consider restarting at
the next lower dose.
˃ 9.0 – 10.0 mg/dL (˃ 2.90 – 3.23 mmol/L)
Withhold derazantinib with weekly reassessments until
the level returns to < 5.6 mg/dL; the patient may restart
at the next lower dose level.
> 10.0 mg/dL (> 3.23 mmol/L) or
significant alteration from baseline
renal function
or Grade 3 hypercalcemia
Withhold derazantinib with weekly reassessments until
the level returns to < 5.6 mg/dL; the patient may restart
at two dose levels lower, or permanently discontinue
derazantinib (e.g., if considered life threatening event).
Central serious retinopathy / Retinal pigment epithelial detachment
Grade
Action
Asymptomatic clinical or
diagnostic observations only
(Grade 1)
Withhold derazantinib until resolution. If the event resolves
within 4 weeks, restart at the next lower dose level. If stable 
but not resolved for two consecutive eye examinations,
restart at the next lower dose level.
Visual acuity 20/40 or better or
≤3 lines of decreased vision from
baseline (Grade 2)
Withhold derazantinib until resolution. If the event resolves
within 4 weeks, the patient may restart at the next lower
dose level.
Visual acuity worse than 20/40 or
> 3 lines of decreased vision from
baseline (Grade 3)
Withhold derazantinib until resolution. If the event resolves
within 4 weeks, the patient may restart at two dose levels
lower. If the event recurs, consider permanent
discontinuation of derazantinib.
Visual acuity 20/200 or worse in
affected eye (Grade 4)
Permanentlydiscontinue derazantinib.
Other events
CTCAE grade
Action
Grade 1 or 2
Continue derazantinib at current dose, unless dose
delay/modification may be clinically indicated (as
assessed by the Investigator and agreed upon by the
Medical Monitor or designee).
Grade 3
Withhold derazantinib until recovery to Grade 1 or baseline;
administer derazantinib at the next lower dose for
subsequent dosing, unless further dose reduction is required.
Grade 4
Permanently discontinue derazantinib if the event is at least
possibly related to derazantinib.
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events.


 
 
   
 
 
 
 
 
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6.1.1.5.1
Hyperphosphatemia
For all patients, it is recommended to restrict phosphate intake to 600–800 mg daily. 
As hyperphosphatemia is only defined by NCI CTCAE 5.0 with regards to escalating 
interventional measures (without specifications triggering these interventions) and not by 
laboratory values exceeding the upper limits of normal leading to specific interventions, 
Table 5 guides interventions for the management of hyperphosphatemia considered at least 
possibly related to derazantinib. 
In alignment with interventions to ensure patient safety and for the purpose of this protocol,
hyperphosphatemia is defined as:
Grade 1:
> ULN to < 7.0 mg/dL (< 2.26 mmol/L)
Grade 2:
Non-invasive intervention required (e.g., withhold drug or modify dose) or 
between 7.0 – 9.0 mg/dL (2.26 – 2.90 mmol/L)
Grade 3:
Severe or medically significant, but not immediately life threatening 
or > 9.0 – 10.0 mg/dL (˃ 2.90 – 3.23 mmol/L)
Grade 4:
Life-threatening consequences, urgent intervention indicated e.g., dialysis
or > 10.0 mg/dL (> 3.23 mmol/L)
Patients who present with serum phosphate ≥ 7.0 mg/dL, adding an oral phosphate 
binding/reducing agent1 until serum phosphate level returns to < 5.6 mg/dL should be 
considered, and patients should be instructed to adhere to a low-phosphate diet.
Management of retinal adverse events
A complete ophthalmological examination (see Section 5.3.2.3) should be performed by an 
ophthalmologist at the Screening visit, for the first four cycles (i.e., Day 1 of Cycles 2–5), 
and at the End of Treatment visit. Further complete ophthalmological examinations only 
need to be performed if clinically indicated. Table 5 provides specific guidance for the 
management of dose delays/reductions in the case of retinal adverse events possibly related 
to derazantinib.
Management of QTc prolongation or other significant ECG abnormalities
If significant QTc prolongation and/or significant ventricular arrhythmia is observed, 
i.e., a prolonged QTcF interval ≥501 ms on at least two separate ECGs (mean values from 
triplicate ECGs, consistent with a CTCAE grade 3 event), the patient must be monitored 
by the Investigator and hourly (triplicate) 12-lead ECG obtained until the mean QTcF has 
returned to ≤450 msec for males or to ≤ 460 msec for females. The clinical context and 
possible factors contributing to QTc prolongations such as electrolyte abnormalities 
(potassium, calcium or magnesium), concomitant medications, or other clinical factors 
such as cardiac ischemia must be carefully assessed, and any findings documented in the 
eCRF. The decision to continue treatment with derazantinib should be reviewed and 
supported by a cardiologist.
                                                
1 Either calcium-containing (e.g., calcium carbonate and calcium acetate) or non-calcium-containing (e.g., sevelamer) 
phosphate binders, and/or phosphaturic agents, depending on serum calcium levels and in accordance with institutional 
guidelines, recommendations, and schedules.


 
 
   
 
 
 
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Once QTc prolongation has resolved, and if a decision was made to continue treatment 
with derazantinib, patients may continue treatment at a lower dose with an ECG monitoring 
schedule defined by the cardiologist. Patients who experience a mean QTcF interval 
≥501 ms on at least two ECGs at different timepoints after dose reduction will be 
discontinued from study.
All significant QTc prolongations or other relevant ECG abnormalities, will also be 
evaluated centrally.
6.1.1.6
Missed-dose management
A missed or vomited dose should not be replaced. The patient should be instructed to take 
the next scheduled dose at the regularly scheduled time. If the patient vomited the very first 
dose of derazantinib, the patient may be re-challenged at the Investigator’s discretion.
6.1.1.7
Overdose
There is no specific guidance to be given at this time.
In case of overdose, patients should be closely monitored for signs or symptoms of adverse 
reactions, and appropriate symptomatic treatment instituted. Any AE resulting from an 
overdose must be collected (see Section 7.5).
6.1.2
Atezolizumab
Atezolizumab is an approved medication supplied as 1200 mg/20 mL concentrate solution 
for IV infusion. Atezolizumab is an investigational drug for its use in combination with 
derazantinib.
6.1.2.1
Atezolizumab administration
Atezolizumab is for intravenous use. The infusions must not be administered as an 
intravenous push or bolus.
The initial dose of atezolizumab must be administered over 60 minutes. If the first infusion 
is well tolerated, all subsequent infusions may be administered over 30 minutes.
The dosing schedule of atezolizumab in combination with derazantinib is shown in 
Section 6.1.3 and Table 6.
6.1.2.2
Labeling and packaging
Atezolizumab is supplied as 20 mL vials of concentrate for solution for infusion and 
labeled in the local languages as investigational agent, in accordance with local regulations 
and the Annex 13 Good Manufacturing Practice rules. 
Labels must include the identity of the Sponsor and Investigator, patient number, protocol 
number, drug identification, storage conditions, content of study drug, and expiry date. 
Information on drug shipment including temperature logger and acknowledgement of 
receipt form to be completed by the receiver must also be included in the shipment.
6.1.2.3
Drug accountability
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, drug expiration 


 
 
   
 
 
 
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date, and acknowledge receipt in the IWRS system. A Packing Slip will be included with 
the shipment and must be completed upon receipt and returned as instructed on the form. 
In addition, the Investigator or designee shall contact the Sponsor as soon as possible if 
there is a problem with the shipment. 
A Drug Accountability Log will be provided for atezolizumab. The log must be kept 
current and should contain the protocol number, the name and clinical site of the 
Investigator, dates and quantities of drug received, patient’s identification number to whom 
atezolizumab was dispensed, the date dispensed, as well as the lot number, dose, and the 
initials of the dispenser.
At the end of the study or as directed, all study drugs, including unused, partially used, or 
empty containers, will be returned to the designee as instructed by the Sponsor. 
Atezolizumab will be returned only after the study monitor has completed a final inventory 
to verify the quantity to be returned. The return must be documented, and the 
documentation must be included in the shipment. Unused drug supplies may be destroyed 
by the Investigator when approved in writing by the Sponsor and the Sponsor has received 
copies of the site’s drug handling and disposition SOPs or equivalent. 
All atezolizumab inventory forms must be made available for inspection by a Sponsor 
authorized representative or designee and regulatory agency inspectors. The Investigator 
is responsible for the accountability of all used and unused study supplies at the site.
6.1.2.4
Shipping and storage conditions
Ship and store in a refrigerator (2 °C – 8 °C).
Do not freeze.
Store the vial in the outer carton in order to protect from light.
6.1.2.5
Preparation and stability of study drug
Twenty mL of atezolizumab concentrate should be withdrawn from the vial and diluted 
into a 250 mL polyvinyl chloride (PVC), polyethylene (PE) or polyolefin infusion bag 
containing sodium chloride 9 mg/mL (0.9%) solution for injection. After dilution, 1 mL of 
solution should contain approximately 4.4 mg of atezolizumab (1,200 mg/270 mL). The 
bag should be gently inverted to mix the solution in order to avoid foaming. Once the 
infusion is prepared it should be administered immediately (see Section 6.3).
Parenteral medicinal products should be inspected visually for particulates and 
discoloration prior to administration. If particulates or discoloration are observed, the 
solution should not be used.
No incompatibilities have been observed between atezolizumab and intravenous bags with 
product-contacting surfaces of PVC, PE or polyolefin. In addition, no incompatibilities 
have been observed with in-line filter membranes composed of polyethersulfone or 
polysulfone, and infusion sets and other infusion aids composed of PVC, PE, 
polybutadiene, or polyetherurethane. The use of in-line filter membranes is optional.




 
 
   
 
 
 
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6.1.4
Duration of treatment
All patients will be treated until disease progression, patient withdrawal, patient lost to 
follow up, or unacceptable toxicity, or until the Investigator’s decision to remove the 
patient from treatment, or until the cohort, substudy, or the study is terminated by the 
Sponsor, whichever occurs first.
Patients will be permitted to remain on study treatment after RECIST 1.1 criteria for PD 
are met (and are confirmed by BICR; see Section 4.5.1) if, in the opinion of the Investigator 
and with the agreement of the Medical Monitor, they continue to derive benefit from 
derazantinib or derazantinib-atezolizumab in combination.
For patients who continue to derive benefit (per Investigator assessment) from any of the 
study treatment regimens at the time of study closure, the Sponsor will provide continued 
individual access to study drug, either under a rollover study protocol, or in the context of 
compassionate use/named-patient access program, where applicable.
6.2
Treatment compliance
Interruptions from the protocol-specified treatment plan for greater than 6 weeks between 
study drug doses for non-drug-related or administrative reasons (see Section 6.1.1.5 and 
Section 6.1.2.6 for drug-related modifications) require consultation between the 
Investigator and the Sponsor, and written documentation of the collaborative decision on 
patient management.
6.2.1
Treatment compliance for derazantinib 
Derazantinib will be self-administered by the patients outside the patient’s visits. All doses 
given during the patient’s visits with the Investigator will be administered under the 
supervision of clinical study personnel. The patients will be instructed to return all unused 
derazantinib at the next visit. 
Compliance to the derazantinib regimen will be evaluated by counting unused capsules.  
During the treatment period, if compliance is not between 80% and 120%, the patient will 
be counseled about the importance of adherence to the mandated regimen. 
If noncompliance in terms of dosing continues, the patient may have to be discontinued 
from the study treatment. 
Administration of derazantinib capsules will be recorded in the ‘Drug Accountability Log’
and eCRF. Patients must return empty bottles and remaining capsules. Returned capsules 
must be recorded in the ‘Drug Accountability Log’, which is supplied to the site. 
% compliance =
# of capsules dispensed – # of capsules returned
# of capsules prescribed/ daya × # of daysb in the dosing interval × 100
a
Number of capsules prescribed (i.e., 3 or as determined per the dose reduction guidelines for toxicity 
considered related to derazantinib and specified in the eCRF
b
Number of days during that interval that the patient should have dosed (i.e., excluding any days that the patient
was instructed to hold dosing due to an AE)


 
 
   
 
 
 
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At each visit after the study treatment is initiated, the Investigator or designee must record 
the date, interval between visits, dose, and any dose changes/delays of study drug 
dispensed/administered. To avoid unnecessary waste of derazantinib capsules, in cases 
where treatment was interrupted and/or dose was reduced, the patient can continue dosing 
from the previously dispensed bottle until the next drug dispensing visit where re-supply 
is needed to maintain the protocol dosing regimen.
6.2.2
Treatment compliance for atezolizumab
Atezolizumab will be administered by site and/or institution staff in accordance with local 
SOPs and guidelines. The total volume of atezolizumab infused will be compared to the 
total volume prepared to determine compliance for each dose of atezolizumab 
administered. 
6.3
Prior treatment
All non-antineoplastic medications or significant non-drug therapies (including herbal 
medicines) taken within 30 days of the Screening visit must be documented for each patient 
in the eCRF, including accurate start and stop dates of the regimens. 
All surgical procedure history, prior chemotherapy (where allowed), and radiation therapy 
must be recorded on the appropriate eCRF. See Section 4.2, Inclusion criteria, and 
Section 4.3, Exclusion criteria for further details.
In Substudy 3, prior treatment with anti-PD-1 or anti-PD-L1-therapeutic antibody or 
pathway-targeting agents is not allowed. 
Except for Substudy 4, prior treatment with FGFR inhibitor is not allowed. However, prior 
treatment with FGFR inhibitor in combination with anti-PD-1 or anti-PD-L1 therapeutic 
antibody or pathway-targeting agents is not allowed in Substudy 4. Prior treatment with 
either sequential immune-checkpoint blockade and FGFR inhibitor treatment or 
combinations of FGFR inhibitor and chemotherapy are allowed in Substudy 4. Patients 
assessed as having progressed upon prior treatment with FGFR inhibitors must have 
received FGFR inhibitor treatment for at least 12 weeks to be eligible for Substudy 4.
6.4
Concomitant treatments
Any medications or significant non-drug therapies (including herbal medicines) that are 
taken by or administered to the patient during the course of the study (until the safety 
follow-up visit at Day 28 for all patients, and Day 90 for patients receiving derazantinib-
atezolizumab in combination) must be recorded in the eCRF including the dosage, 
frequency of administration, route of administration, therapeutic indication, and start/stop 
dates of use.
6.4.1
Permitted treatment
Palliative and supportive care for disease-related symptoms will be offered to all patients. 
In addition, the following treatments are allowed:

Standard therapies for concurrent medical conditions


 
 
   
 
 
 
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
Erythropoietin Stimulating Agents (in accordance with ASCO, American Society of 
Hematology, or MEDICARE guidelines for the use of epoetin in patients with cancer 
and FDA alerts dated 09 March 2007, 08 November 2007, 12 March 2008, 
31 July 2008, and 02 December 2008)

Hematopoietic growth factors, including filgrastim (Neupogen®), or other granulocyte 
colony stimulating factors (in accordance with ASCO guidelines for the use of white 
blood cell growth factors (see http://jco.ascopubs.org/content/24/19/3187.full)

Antiemetics may be administered according to standard practice 

Megestrol acetate (Megace®)

Use of topical corticosteroids, topical and systemic antibiotics according to standard of 
care or institutional guidelines, and inhaled, intranasal, intraocular, topical, and 
intra-articular joint injections.

Bisphosphonates and denosumab for bone metastases or hypercalcemia of malignancy

Palliative radiotherapy for non-hepatic local pain (e.g., bone) control provided that, in 
the opinion of the Investigator, the patient does not meet the criteria for treatment 
discontinuation (i.e., clear progression of disease) 
6.4.2
Prohibited treatment / Treatment to be avoided or used with caution
The following treatments are not allowed during the study:

Any concurrent anti-cancer therapy including chemotherapy, radiotherapy, hormonal, 
targeted therapy, or immunotherapy
–
Palliative radiotherapy for local pain-control may be allowed, provided the patient 
does not meet criteria of progressive disease and treated lesions will not be 
included in the target/non-target lesion assessment 

Other investigational agents

Immunosuppressive therapies, including systemic corticosteroids (except up to a 
25 mg/day prednisone-equivalent dose or when used intermittently in an antiemetic 
regimen, or as premedication for imaging studies), unless indicated to treat immune-
related AEs and atezolizumab is withheld.

Immunomodulatory agents, including but not limited to interferons or interleukin-2, 
during the entire study; these agents could potentially increase the risk for autoimmune 
conditions when received in combination with atezolizumab.

Immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide; these agents could potentially alter the 
activity and the safety of atezolizumab.

Live, attenuated vaccines within 28 days prior to enrollment.


 
 
   
 
 
 
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The following treatments should be avoided, if possible, or used with caution during the 
study:

Derazantinib may inhibit CYP1A2, CYP2C8, or CYP2D6 metabolism, hence 
co-administration of derazantinib with drugs known to be substrates of CYP1A2, 
CYP2C8, or CYP2D6 should be avoided or used with caution (see Appendix 7).

Derazantinib may be a substrate and inhibitor of human P-glycoprotein (P-gp), 
therefore co-administration of derazantinib with drugs known to be P-gp substrates with 
narrow therapeutic index should be avoided or used with caution (Appendix 8).

Drugs with known liver toxicity, e.g., clotrimazole, should be avoided or used with 
caution; if such drugs need to be administered, liver function tests should be done every 
4–5 days during the drugs’ co-administration.

Drugs with the potential to prolong QT interval (see Appendix 9).

Extended concomitant corticosteroid use at physiological doses (i.e., up to 10 mg/day
prednisone equivalent).

Influenza vaccinations (inactivated forms only) should be given during influenza 
season only (approximately October to March in the Northern hemisphere; April to 
September in the Southern Hemisphere). Patients must agree not to receive live, 
attenuated influenza vaccines (such as FluMist®) 28 days prior to randomization, 
during treatment or within 5 months following the last dose of atezolizumab (for 
patients randomized to atezolizumab).


 
 
   
 
 
 
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SAFETY
7.1
Warnings and precautions
7.1.1
Derazantinib
7.1.1.1
Treatment-emergent adverse events
In a completed Phase 1/2a study 119 patients were treated at doses of 25 mg every other 
day (QOD) to 425 mg QD. The MTD was determined as 400 mg QD, with no DLTs
observed in 12 patients. The RP2D was determined at 300 mg QD with Grade 3 aspartate-
aminotransferase elevations as the DLT at 250 mg and 425 mg QD. The current maximum 
administered dose is 425 mg QD.
Based on the data from all data available from completed and ongoing clinical studies, the 
derazantinib most commonly reported drug-related adverse events (AEs) are transaminases 
increased, fatigue /asthenia, gastrointestinal side effects (nausea, vomiting, diarrhea, 
constipation), xerostomia, hyperphosphatasemia, dysgeusia, decreased appetite, ocular 
side effects (xerophthalmia and blurred vision) and alopecia.
7.1.1.2
Identified and potential risks
In the literature, the most frequently reported AEs related to FGFR inhibitor class effects 
are hyperphosphatemia, fatigue, ocular disorders, gastrointestinal disorders (constipation, 
diarrhea, nausea, vomiting, stomatitis and dry mouth), transaminase elevation, 
hypertension, creatinine increase / renal disorders, hyponatremia, nail toxicity, and 
alopecia (Abou-Alfa 2020, Katoh 2019, Loriot 2019, Mazzaferro 2019, Chae 2017, 
Papadopoulos 2017). 
Increased transaminases are assessed as an important identified risk related to derazantinib, 
requiring monitoring of transaminase levels with management through dose 
delays/reductions, as noted in the Reference Safety Information in Section 6 of the 
Investigator’s Brochure.
Hyperphosphatemia, fatigue, ocular disorders, blood creatinine increased / renal disorders, 
hyponatremia, and nail toxicities are assessed as important potential risks for derazantinib 
based on the clinical toxicity profile of derazantinib (see Section 5.3.2 for safety measures 
to monitor and mitigate these risks during the study). 
The following events are assessed as potential risks for derazantinib: gastrointestinal 
disorders, hypertension, alopecia, and QT prolongation. 
7.1.2
Atezolizumab
The warnings and precautions for atezolizumab are listed in the atezolizumab IB, and in 
the USPI and EU SmPC for Tecentriq®
(atezolizumab) (Tecentriq®
USPI, 
Tecentriq® SmPC).
7.1.3
Contraception and pregnancy
Derazantinib may have adverse effects on a fetus in utero, and may have transient adverse 
effects on the composition of sperm. 


 
 
   
 
 
 
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There are no known reproductive risks to the female partner of a male patient receiving 
atezolizumab.
7.1.3.1
Contraception 
Participants in this study must be informed that taking the study medication may involve 
unknown risks to the fetus if pregnancy were to occur during the study. In order to be 
enrolled in the study, both male and female patients of child-producing potential must agree 
to the contraception requirements in Inclusion criterion 9b) (see Section 4.2), and must 
comply with these requirements from the day of first study medication, or for oral 
contraception from 14 days prior to the first study medication, throughout the study period, 
and until at least 150 days after administration of the last dose of study medication. 
If there is any doubt that a patient of child-producing potential will reliably comply with 
the requirements for contraception, the patient should not be enrolled in the study.
7.1.3.2
Pregnancy testing
See Section 5.3.2.7 for details on pregnancy test requirements for this study. 
See Section 7.4.5 for details of reporting and handling pregnancies. 
7.1.3.3
Nursing mothers
As it is unknown whether derazantinib is excreted in human milk, because of the potential 
for serious adverse reactions in the nursing infant, patients who are breast-feeding are not 
eligible for enrollment in this study (see Section 4.3).
7.2
Definitions
7.2.1
Adverse event 
An AE is defined as any untoward medical occurrence in a patient or clinical 
investigational patient administered a pharmaceutical product that does not necessarily 
have a causal relationship with study-drug treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product.
Complications associated with scheduled procedures are considered AEs.
7.2.2
Serious adverse event 
An SAE is any AE that meets one or more of the following criteria:

results in death

is life-threatening

requires inpatient hospitalization, or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is classified by the Sponsor as an important medical event


 
 
   
 
 
 
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Medical and scientific judgment should be exercised in deciding whether an AE should be 
considered an important medical event (and consequently an SAE). Such events may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient, or may require intervention to prevent one of the outcomes listed in the definitions 
above. These situations should also usually be considered serious.
It should be noted that: 

Death is considered an outcome of an AE. Whenever possible the underlying cause of 
death must be reported as the AE.

A life-threatening SAE is any adverse experience that places the patient at risk of death 
at the time of its occurrence, i.e., it does not include a reaction that, had it occurred in 
a more severe form, might have caused death.

Inpatient hospitalization is defined as any inpatient admission, even if for less than 
24 h. For chronic or long-term inpatients, inpatient admission also includes transfer 
within the hospital to an acute/intensive care inpatient unit.
The following hospitalizations, whether planned before or during the study, can be 
considered AEs but should not be considered SAEs:
–
Routine treatment or monitoring of UC, not associated with any deterioration in 
condition (e.g., hospitalizations related to study procedures, such as study-drug 
administration, PK assessments, etc.).
–
Elective or planned treatment, including surgical interventions, for UC if the plan 
for the respective intervention has been documented prior to first dose of study 
drug.
–
Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
UC and has not worsened.
–
Admission to a hospital or other institution for general care, not associated with any 
deterioration in condition.

Treatment on an outpatient basis for an event which does not meet any of the above 
definitions of ‘serious’, and does not result in hospital admission, should not be 
considered as an SAE.
7.2.3
Unexpected adverse event or serious adverse event
An unexpected AE or SAE is one for which the nature or severity of the event is not 
consistent with the applicable reference safety information.
7.2.4
Suspected adverse event or serious adverse event
A suspected AE or SAE is defined as an AE or SAE that is probably or possibly related to 
the treatment with derazantinib and/or atezolizumab, or when the relationship is unknown.
7.2.5
Suspected unexpected serious adverse reaction 
A suspected unexpected serious adverse reaction (SUSAR) is any SAE considered by the 
Investigator or the Sponsor to be related to the study treatment and for which the nature or 
severity is not consistent with the applicable reference safety information (i.e., regardless 
of whether the nature or severity of an SAE has been previously observed/documented).


 
 
   
 
 
 
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7.2.6
Adverse events of special interest 
The following are considered AEs of special interest (AESIs) for the purposes of this study, 
based on the known safety profiles of derazantinib and atezolizumab:

Hyperphosphatemia/blood phosphorus increased 

Hyponatremia

Stomatitis

Nail disorder

Ocular/eye disorder

Liver function tests abnormal (compared to baseline)

Serum creatinine increase or renal failure

Hypertension / cardiac disorders 

QT prolongation

Immune-related AEs (see Section 4.5.1)
All AESI must be recorded in the eCRF. In addition, immune-related AESIs, which are 
CTCAE grade ≥ 2 or are serious, and all other AESIs which are CTCAE grade > 2 or are 
serious, must be reported to the Sponsor within 24 hours using the SAE/AESI form.
7.2.7
Treatment-emergent adverse events
Treatment-emergent AEs (TEAEs) are AEs not present prior to the start of study treatment, 
or AEs already present prior to the start of study treatment that worsen in either intensity 
or frequency following the treatment. 
7.3
Evaluation of adverse events
7.3.1
Grading of Severity
The severity of AEs will be assessed according to NCI CTCAE 5.0. 
Adverse events not included in NCI CTCAE 5.0 should be reported under “Other” within 
the appropriate category, and graded 1 to 5 according to the general grade definitions:

Grade 1: Mild AE

Grade 2: Moderate AE

Grade 3: Severe AE

Grade 4: Life-threatening or disabling AE

Grade 5: Death
For AEs that can be described by NCI CTCAE 5.0, grade 4 (life-threatening or disabling 
AE) is assessed based on unique clinical descriptions of severity for each AE, and these 
criteria may be different from those used for the assessment of AE seriousness. An AE 
assessed as Grade 4 based on the NCI CTCAE grades may or may not be assessed as 
serious based on the seriousness criteria and annotated accordingly.


 
 
   
 
 
 
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7.3.2
Assessment of causality
The relationship between an AE and derazantinib and/or atezolizumab will be determined 
by the Investigator on the basis of their clinical judgment and following categories 
(see Appendix 10 for definitions):

Not related

Unlikely related

Possibly related

Probably related
7.3.3
Dose-limiting toxicities (applicable to Substudies 3 and 5)
All toxicities will be graded using NCI CTCAE 5.0. Toxicities judged by the Investigator 
to be unrelated to study drug administration (e.g., related to the underlying disease) are not 
considered DLTs. In contrast, the occurrence of any of the following toxicities during 
Cycle 1 (DLT period) will be considered a DLT, if judged by the Investigator to be possibly
or probably related to study drug administration:
1. Grade 4 non-hematologic clinical toxicity (not laboratory).
2. Grade 4 hematologic toxicity lasting ≥14 days with optimal supportive care.
3. Grade 3 non-hematologic toxicity (not laboratory) or non-hepatic major organ AE
lasting > 3 days despite optimal supportive care with the following exceptions:

Grade 3 nausea, vomiting, or diarrhea that resolves to grade <1 with or without 
supportive care prior to the next administration and/or with a light meal prior to 
derazantinib administration.
4. Any laboratory hepatic toxicity meeting Hy’s law criteria for suspected severe drug-
induced liver injury, defined as a rise in serum aminotransferases (AST or ALT) of 
˃ 3 × ULN and total bilirubin ≥2 × ULN, in the absence of any alternative reason 
(e.g., liver metastasis, another liver disease, or a concomitant drug).
5. Any grade 3 or 4 hepatic toxicity with the following exceptions:

For patients with grade 2 AST/ALT abnormality at baseline, an increase in the 
baseline abnormality to > 10 × baseline will be considered a DLT.
6. Any grade 3 non-hematologic or non-hepatic laboratory value if:

Medical intervention is required to treat the patient, or

The abnormality leads to hospitalization, or

The abnormality persists for > 3 days.
7. Febrile neutropenia at CTCAE grade 3 or 4:

CTCAE Grade 3 is defined as ANC <1.0 × 109/L with a single temperature of 
>38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) for more than one 
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
CTCAE Grade 4 is defined as ANC < 1.0 × 109/L with a single temperature of 
>38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) for more than one 
hour, with life-threatening consequences and urgent intervention indicated.
8. Thrombocytopenia < 25 × 109/L if associated with:

A bleeding event which does not result in hemodynamic instability but requires an 
elective platelet transfusion, or

A life-threatening bleeding event which results in urgent intervention and 
admission to an Intensive Care Unit.
9. Grade 5 toxicity (i.e., death).
10. Any immune-related CTCAE grade 2 or higher toxicities that require holding Cycle 2 
of atezolizumab administration (Substudy 3 only, see Section 6.1.2.6). 
Note that there should be a high level of suspicion that new symptoms are treatment related, in particular 
any new and early immune-related toxicity.
As dose modifications and dose titrations are not unusual with other FGFR-inhibitors, any 
ADRs which do not meet DLT criteria but which lead to temporary dose interruptions
and/or dose reductions will contribute to the determination of the benefit-risk profile of the 
dose level, but will not be considered DLTs. Clinical management of ADRs is well 
established, and a dose reduction scheme is already provided in protocol Section 6.1.1.5.
7.4
Handling of safety information and collection periods 
7.4.1
Responsibilities and procedures
The responsibility for the safety of an individual patient lies in all cases with the 
Investigator. This includes the timely review of all safety data obtained during the course 
of the study.
An Investigator must instruct their patients to report any AE and SAE they experience. 
7.4.2
Handling of safety data during the pre-treatment period
Any relevant change in, or worsening of, a patient’s condition occurring after any informed 
consent has been provided but prior to the start of first study-drug administration, is to be 
recorded in the eCRF as pre-dose medical history (see Section 5.3.1.1). However, in this 
period (between ICF and start of study medication), if an AE/SAE is assessed as related to 
the study procedure, the AE/SAE is to be reported accordingly in the eCRF as medical 
history and, in addition, SAE must also be reported to the Sponsor’s safety representative, 
using the same procedures as for an SAE (see Section 7.4.3.2).
7.4.3
Handling of safety data during the treatment period and up to the last 
scheduled follow-up
From the start of first dosing up to and including the Safety Follow-Up visits 28 and – if 
applicable – 90 days after last study drug administration, respectively, any change in, or 
worsening of, a patient’s condition must be collected and reported in the eCRF as an AE 
(see Section 7.4.3.1). Serious adverse events and AESIs must be additionally reported on 
the SAE/AESI report form (see Section 7.4.3.2).


 
 
   
 
 
 
 
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7.4.3.1
Adverse event management
Data collection
All AEs directly observed (physical examination, laboratory test or other assessments), 
mentioned by the patient, or reported by the patient upon non-directive questioning, must 
be recorded on the AE pages of the eCRF.
All AEs must be recorded in the English language in the eCRF and should include the 
following information:

Term. If possible, a diagnosis should be documented rather than signs and symptoms, 
using self-explanatory and concise medical terminology. However, if an observed or 
reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE. Progression of 
disease is considered an efficacy outcome parameter and should not be captured as an 
AE or SAE, unless its outcome is death.

Duration (start and end dates).

Toxicity grade (CTCAE grade; see Section 7.3.1). 

Relationship to the study treatment (causality assessment; see Section 7.3.2).

Action(s) taken with regards to study drugs (derazantinib and atezolizumab), or any 
suspected concomitant medication  

Additional treatments given for the event.

Whether it is an SAE (seriousness assessment; see Section 7.2.2). 

Outcome.
Refer to the eCRF completion guidelines for further details on completing the 
AE/AESI/SAE in the eCRF.
In addition, the concomitant medications (with indication start and stop (if not ongoing) 
and Medical history should be updated as needed.
Abnormal laboratory results should not be recorded as an AE unless the abnormal result
meets one or more of the following criteria: 
induces clinical signs or symptoms which require therapy or additional diagnostic 
evaluation
requires dose modification derazantinib, or discontinuation of study participation
is considered clinically significant
If a laboratory abnormality meets one of the above criteria, the clinical syndrome 
associated with laboratory abnormality is to be recorded, as appropriate (e.g., diabetes 
mellitus instead of hyperglycemia).
AEs must also be reported in the source document with at least the nature of the event, the 
start and end date, the relationship to the study drugs (derazantinib and/or atezolizumab), 
treatment (if applicable), and outcome (in initial or follow up report).




 
 
   
 
 
 
 
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If all information about the SAE or AESI is not yet known, the Investigator will be required 
to report any additional information within 24 hours as it becomes available.
The Investigators must in turn notify their governing IRB/IEC in line with local 
requirements. This activity may be delegated.
Sponsor’s responsibilities
The Sponsor will ensure the reporting of SUSARs and any expeditable SAEs to regulatory 
Authorities, ECs/IRB in accordance with applicable laws.
In the event of a SUSAR, the Sponsor will ensure that Investigators active in 
Basilea-sponsored interventional studies with derazantinib are informed.
Expectedness of SAEs for regulatory expedited reporting will be assessed by the Sponsor 
against the applicable study drug Reference Safety Information (RSI). 
For both derazantinib and atezolizumab the ‘Reference Safety Information’ Section in the 
relevant Investigator’s Brochures (valid at the time of onset of the event) will serve as the 
RSI. 
7.4.4
Handling of post-study safety data
After the Safety Follow-up visit(s), only study drug related SAEs and AESIs
(see Section 7.2.6) should be collected and reported; however, these events should not be 
captured in the eCRF system.
New study drug related SAEs and AESIs that occur after the 28-day Safety Follow-up visit 
(or 90-day Safety Follow-up visit for atezolizumab-treated patients) will be followed until 
they have, in opinion of the Investigator, resolved to baseline, CTCAE grade 1, stabilized, 
or are deemed to be irreversible (including death).and if the patient withdraws their 
consent.
7.4.5
Reporting and handling of pregnancies
Female patients must inform the Investigator within 24 hours if they have experienced a 
ruptured condom, or any other concerns about possible reduction of contraceptive 
effectivity (i.e., forgotten pill or vomiting) during the study. In these cases, the patients 
must return to the study site as soon as possible, but not later than 24 hours after the 
Investigator is informed, for adequate medical measures and follow-up visits.
Female patients must inform the Investigator if they become pregnant during the study, or 
within 150 days after the last dose of study drug.
Study drug(s) must be discontinued immediately if a female patient becomes pregnant. 
The Investigator should counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus. The patient must be monitored until conclusion of the 
pregnancy and infants must be followed-up for at least 8 weeks after delivery. Any SAEs 
associated with the pregnancy (e.g., an event in the fetus, an event in the mother during or 
after the pregnancy, or a congenital anomaly/birth defect in the child) should be reported 
on the AE eCRF and in pregnancy and SAE form.


 
 
   
 
 
 
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The Investigator must immediately notify the Sponsor’s safety representative about 
any pregnancy by submitting a Pregnancy Report Form, in accordance with the 
requirements (timelines and contact details) of an SAE (see Section 7.4.3.2). In addition, 
pregnancy-related adverse outcomes must also be reported as AEs or SAEs 
(see Section 7.4.3.1). Note that an induced abortion which is not due to an AE does not 
constitute an SAE.
Male patients will be instructed through the information provided in the ICF to immediately 
inform the Investigator if their partner becomes pregnant during the study. A Pregnancy 
Report Form should be completed by the Investigator immediately (i.e., no more than 
24 hours after learning of the pregnancy). Attempts should be made to collect and report 
details of the course and outcome of any pregnancy in the partner of a male patient exposed 
to study drug. The pregnant partner will need to sign the appropriate authorization to allow 
for follow-up on her pregnancy. Once the authorization has been signed, the Investigator 
will update the Pregnancy Report Form with additional information on the course and 
outcome of the pregnancy.
An Investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus to support 
an informed decision in cooperation with the treating physician and/or obstetrician.
The Investigator must notify the local IEC/IRB about any pregnancies resulting in an 
adverse outcome, in accordance with applicable laws and regulations.
7.5
Adverse events associated with an overdose or error in drug administration   
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied. 
A medication error is an unintended failure in the drug treatment process that leads to, or 
has the potential to lead to, harm of the patient.
Any overdose or medication error (with or without AE) should be recorded in the eCRF. 
All AEs associated with an overdose or medication error should be recorded on the eCRF
(see Section 7.4.3.1). If the associated AE fulfils seriousness criteria, the event should be 
reported to the Sponsor immediately (see Section 7.4.3.2).


 
 
   
 
 
 
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STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN
Effective Protocol Version 5.0, only statistical considerations applicable to active 
substudies are provided in this section.
Details of the statistical analyses presented below will be provided in the study’s statistical 
analysis plan (SAP). A change to the data analysis methods described in the protocol will 
require a protocol amendment only if it alters a principal feature of the protocol. The SAP 
will be finalized prior to database lock. Any changes to the methods described in the plan 
will be described and justified in the final clinical study report.
8.1
Sample size considerations by substudy
Simon’s two-stage designs (Simon 1989) will be used for Substudies 1 and 4, and
Fleming’s two-stage designs (Fleming 1982) will be used for Substudies 3 and 5. At the 
time point of interim analysis and decision to transition from Stage 1 to 2, all data collected 
in Stage 1 patients will be used to inform the decision. Should the required number of 
events (i.e., responses) be reached prior to full enrollment to Stage 1, the time point for 
decision to transition from Stage 1 to Stage 2 may be taken before the stage is fully enrolled. 
If the required number of events (i.e., responses) is not reached at the time of full 
enrollment to Stage 1, further enrollment may be suspended to allow for all patients to be 
exposed to derazantinib or derazantinib-atezolizumab in combination for at least 3 months 
or until disease progression.
The use of such designs will limit the number of overall exposed patients to a maximum 
of approximately 98, should either derazantinib or derazantinib-atezolizumab in 
combination be ineffective in Stage 1 of all efficacy-estimating substudies, as compared to 
a maximum of 246 patients if derazantinib or derazantinib-atezolizumab are considered to 
be effective in all cohorts. 
Assuming an overall incidence of approximately 20% qualifying FGFR1–3 GAs 
(Helsten 2016), up to approximately 680 patients will be screened for FGFR1–3 GAs, 
depending on the extent of preexisting molecular testing. Assuming that pre-treatment with 
an FGFR inhibitor was based on a known FGFR GA status, no repeated testing is 
anticipated for the approximately 100 patients enrolled in Substudy 4.
8.1.1
Substudy 1
The null hypothesis that the true ORR is p0 ≤ 0.21 will be tested against a one-sided 
alternative. In Stage 1, 35 evaluable patients will be enrolled. If 7 or fewer patients with an
objective response are observed in Stage 1, the cohort will be stopped. If 8 or more patients 
with an objective response (defined as a CR or PR) are observed in these 35 patients, an 
additional 39 patients will be enrolled, for a total of 74 patients. The null hypothesis will 
be rejected if 22 or more responses are observed in these 74 patients. The one-sided Type I 
error rate is 0.0463, and the power is 0.8001 when the true ORR is p1 = 0.34 and higher 
than the ORR of 32.2%, the highest reported value for an FGFR inhibiting treatment in 
mUC patients (Balversa USPI).






 
 
   
 
 
 
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progression (every effort should be made to objectively assess radiographic progression).
Non-evaluable patients will be replaced.
8.2.3
Per-protocol population
The Per-protocol population will include all patients in the mITT population who have no 
major protocol deviations during the study. Protocol deviations will be identified prior to 
final analysis.
This analysis population will be used for secondary analysis of primary and secondary 
endpoints.
8.2.4
Pharmacokinetic analysis population
The PK analysis population consists of all patients who receive at least one dose of 
derazantinib and have at least one PK sample. Three sub-populations are defined, 
according to the analytes and sampling schedule:

The Rich derazantinib PK profiling population (with PK parameter determination) 
consists of the patients enrolled in the rich sampling schedule (see Section 5.3.4.1.2)
who receive at least 1 dose of study drug and have at least one PK sample.

The Sparse derazantinib PK sampling population consists of the patients enrolled in the 
sparse sampling schedule (see Section 5.3.4.1) who receive at least 1 dose of study drug 
and have at least one PK sample.

The atezolizumab PK population (see Section 5.3.4.2) consists of all patients who 
receive at least 1 dose of atezolizumab and have at least one PK sample.
8.3
Statistical and analytical methods
All endpoints will be summarized by substudy and cohort. All analyses will include 
summary statistics, including number and percentage for categorical variables, and number 
of patients, mean, standard deviation, median, minimum, and maximum for continuous 
variables. Two-sided 95% confidence intervals (CIs) will be provided where appropriate, 
except otherwise specified. Time-to-event analysis will be performed using Kaplan-Meier 
(KM) methods. Further detail will be provided in the study SAP.
All analyses will be carried out using SAS® version 9.3 or above (SAS Institute, Cary, 
North Carolina, USA).
8.3.1
Patient demographics, medical history, and other baseline characteristics
Demographics, medical history, and other baseline characteristics will be summarized for 
the safety/ITT, mITT and Per-protocol (PP) populations using descriptive statistics. 
No formal statistical comparisons will be performed.
Demographic, baseline characteristics, and medical history data for each patient will be 
provided in data listings.


 
 
   
 
 
 
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8.3.2
Study treatment exposure and compliance
The dose, duration in days and compliance of study treatment(s) will be listed by patient 
and summarized through descriptive statistics by cohort in the Safety population.
8.3.3
Prior and concomitant treatments
Medications and significant non-drug therapies used prior to and after the start of the study 
drug will be listed by patient and summarized by Anatomical Therapeutic Chemical term
and by cohort.
8.3.4
Efficacy analysis
All efficacy endpoints will be summarized by substudy and cohort.
All analyses will include summary statistics, including number of patients and percentage 
for categorical variables and number of patients, mean, standard deviation, median, 
minimum, and maximum for continuous variables. Two-sided exact 95% CIs based on the 
large sample assumption will be provided where appropriate.
Comparisons between cohorts of Substudy 4 will be performed using descriptive statistics 
and for the purpose of hypothesis generation.
8.3.4.1
Primary endpoint 
The primary endpoint in all substudies will be ORR, defined as the achievement of 
confirmed CR or PR using RECIST 1.1, as assessed by BICR. Point estimates and 2-sided 
95% CIs will be provided. The primary analysis will be performed on the mITT population 
and repeated on the PP population.
Interim analyses for stage transition in the efficacy-estimating substudies will be performed 
when the number of patients specified below have been enrolled, have received at least one 
dose of study drug, and have at least had one post-baseline tumor imaging assessment, but 
no later than after the completion of Cycle 9 (i.e., have received approximately 27 weeks 
of treatment and had up to four post-baseline study imaging assessments). If the required 
number of responses per BICR specified for each cohort has not been observed at the time 
of enrollment of the last patient to Stage 1, enrollment may be suspended, or the cohort 
may be terminated due to apparent futility. 
If the required number of responses per BICR specified for each cohort is reached earlier,
interim analyses may be performed earlier.
The final analysis for ORR will be performed once all patients have been enrolled per 
cohort/substudy and have been followed for approximately up to 27 weeks of treatment
(i.e., each patient had up to four post-baseline study imaging assessments). Patients without 
efficacy assessments are considered non-responders, and included in the analysis.
Hypothesis testing (null hypothesis [H0] versus alternative hypothesis [HA]) will be 
performed at the interim and final analyses as per the below specified decision rules:

Substudy 1
H0: p ≤ 0.21 versus HA: p > 0.21.


 
 
   
 
 
 
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If there are five or fewer patients with a response (defined as a CR or PR) in the first 
35 evaluable patients included in the interim analysis, the substudy will be stopped. If 
not, an additional 39 patients will be enrolled, for a total of 74 evaluable patients. The 
null hypothesis will be rejected if 22 or more responses are observed in these 
74 patients. 

Substudy 3
H0: p ≤ 0.25 versus HA: p > 0.45.
If there are four or fewer patients with a response (defined as a CR or PR) in the first 
18 evaluable patients included in the interim analysis, the cohort will be stopped. If not, 
an additional 18 patients will be enrolled, for a total of 36 evaluable patients. The null 
hypothesis will be rejected if 14 or more responses are observed in these 36 patients 
(or if 10 or more responses are observed in the first 18 patients). Posterior estimates of 
the probability that the response rate exceeds 0.25 will also be calculated assuming a 
non-informative prior distribution.

Substudy 4
H0: p ≤ 0.07 versus HA: p > 0.07.
If there are one or zero patients with a response (defined as a CR or PR) in the 
first 16 evaluable patients included in the interim analysis in each of Cohort 4a and 4b, 
the cohort will be stopped. If not, an additional 34 patients will be enrolled, for a total 
of 50 evaluable patients. The null hypothesis will be rejected if seven or more responses 
are observed in these 50 patients.

Substudy 5
H0: p ≤ 0.10 versus HA: p > 0.30.
If there is one or fewer patient with a response (defined as a CR or PR) in the first 
13 evaluable patients included in the interim analysis, the cohort will be stopped. If not, 
an additional 13 patients will be enrolled, for a total of 26 evaluable patients. The null 
hypothesis will be rejected if six or more responses are observed in these 26 patients 
(or if five or more responses are observed in the first 13 patients). Posterior estimates 
of the probability that the response rate exceeds 0.1 will also be calculated assuming a 
non-informative prior distribution.
8.3.4.2
Secondary efficacy endpoints 
DCR will be summarized in the same way as the primary endpoint.
DOR, PFS and OS analyses will be performed using KM methods. The analysis will be 
performed on the mITT population and repeated on the PP population.
DoR will be calculated from the first date of documented tumor response (CR or PR) to 
the date of disease progression by BICR. If a patient is discontinued or is lost to follow-up 
with no documentation of PD, duration of response is defined as the time from the date of 
the first documentation of objective response to the date of the last tumor assessment as a 
censored value. If the patient dies with no documentation of PD, duration of response is 
defined as the time from the date of the first documentation of objective response to the 


 
 
   
 
 
 
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date of the last tumor assessment as a censored value. Patients who crossover to 
derazantinib-atezolizumab combination will be censored at time of crossover.
PFS will be calculated as the time from cohort assignment by IWRS until disease 
progression per RECIST 1.1, or death from any cause.  Patients who discontinue treatment 
due to reasons other than disease progression by BICR or death will be censored in the PFS 
analyses at the date of their last tumor evaluation. Patients who progress or die after missing 
≥2 consecutive scheduled tumor assessments will be censored at the date of the last tumor 
evaluation prior to progression or death. Patients who either have no baseline tumor 
evaluation or have no post baseline tumor evaluation will be censored at the date of the 
first dose. Patients who crossover to derazantinib-atezolizumab combination will be 
censored for the derazantinib analysis at the time of crossover. For patients crossing over 
from derazantinib to derazantinib-atezolizumab in combination and as an exploratory 
analysis, hazard ratios (HRs) for median OS time will be calculated using an Inverse 
Probability of Censoring Weighted (IPCW) modeling approach (Rimawi 2012).
OS time will be calculated from the date of cohort assignment by IWRS until death from 
any cause. Any patient without a date of death in the database at the time the survival 
analyses are performed will be censored at the time of their last study contact. For patients 
crossing over from derazantinib to derazantinib-atezolizumab in combination and as an 
exploratory analysis, HRs for median OS time will be calculated using an IPCW modeling 
approach (Rimawi 2012). Overall survival analysis may be repeated upon availability of 
long-term survival data.
Sensitivity analyses within Substudy 4 will be performed according to the stratification 
factor composite score and its variables. 
8.3.5
Safety data analysis
Safety will be assessed through summaries of DLTs, AEs, safety laboratory evaluations, 
physical examinations, and vital signs. All safety analyses will be based on the Safety 
population. Analyses will be presented by substudy and cohort. The DLTs will be listed 
and summarized using descriptive statistics.
8.3.5.1
Dose-limiting toxicity (Substudies 3 and 5 only)
Safety interim analyses will be performed once 10 patients have been enrolled and full 
safety data are available to determine if the revised dosing regimen of 200 mg BID 
derazantinib either as monotherapy or in combination with atezolizumab is safe and 
tolerable.
The safety evaluation will comprise updating a three-parameter cumulative BLRM-EWOC
design for the incidence of DLTs with monotherapy and combination therapy to strictly 
manage the risk of excessive toxicity (Neuenschwander 2008). For a derazantib dose , let 
 denote the probability of DLT at dose . If  subjects are evaluated at dose , then the 
number of subjects, , experiencing a DLT is assumed to follow a binomial distribution:
 |  ~ Binomial(, )


 
 
   
 
 
 
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The relationship between monotherapy and combination derazantib doses, and DLT 
probabilities is modelled by the logistic curve;
log( (1 −)
⁄
) = log() +  log( ∗
⁄
) ,
, ,  > 0


 
 
   
 
 
 
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Doses are rescaled as d/d* with reference dose d*= 600mg/day. The model 
parameters ,  and  have the following interpretation:
 equals the odds of toxicity with monotherapy at the reference dose d*.
 equals the odds of toxicity with combination therapy at the reference dose d*.
Doubling the dose results in an increase in odds of toxicity by a factor of 2.
The model parameters log() , log() , log() are given a weakly informative 
multivariate normal prior distribution, following (Neuenschwander 2014), with prior 
means (-1.386, -1.386, -0.781), prior standard deviations (5.472, 5.472, 0.973), and prior 
correlations of 0. This prior distribution ensures wide confidence intervals for toxicity 
probabilities at each dose.
With an acceptable target toxicity range for a dose defined as a probability of toxicity of 
10% to <25% and an overdosing range of ≥25%, the posterior probability of overdosing 
will be updated over time. Data resulting in a posterior probability of overdosing for a dose 
in excess of 25% will be determined as unacceptable. This ensures a safe recommended 
dose is chosen for subsequent testing of anti-tumor efficacy. This process also involves 
regular dose decision meetings to review the updated cumulative model results as well as 
safety in individual patients.
Safety and tolerability of both the monotherapy and the combination dose regimens, and 
restart of enrollment in Substudies 3 and 5 will be concluded by joint decisions taken by 
the IDMC, Investigators, and the Sponsor in reviewing the aggregate of DLT, AE and PK 
data from the first 10 patients each enrolled in Substudies 3 and 5. 
8.3.5.2
Other safety parameters
All AEs occurring during the study will be coded by standard MedDRA and grouped by 
System Organ Class and Preferred Term. Safety endpoints for AEs include the following: 
incidence of all TEAEs1 and all serious AEs, AEs by severity, AEs by relationship to study 
drug, and discontinuation of patients from study therapy due to AEs and deaths. 
Additional safety summaries will be provided for clinical laboratory tests, vital signs, 
ECGs, physical examinations, ophthalmology examinations, ECOG PS, and – if relevant 
– any drug exposure during pregnancy.  
8.3.6
Pharmacokinetic analysis
In the Rich derazantinib PK sampling population, PK parameters will be determined by 
non-compartmental analysis. The following parameters will be determined: Cmax, tmax, 
AUC0-12, AUC0-24, AUClast. PK parameters from rich PK sampling will be summarized by 
Substudy and Cohort using descriptive statistics. Derazantinib plasma concentrations at 
each nominal time-point will be summarized by substudy and cohort using descriptive 
statistics.
                                                
1 Treatment emergent AEs (TEAE) are AEs not present prior to the start of study treatment, or AEs already present prior 
to the start of study treatment that worsen in either intensity or frequency following initiation of study drug treatment.


 
 
   
 
 
 
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In the Sparse derazantinib PK sampling population, derazantinib plasma concentrations at 
each nominal time-point will be summarized by Substudy and Cohort using descriptive 
statistics.
In the atezolizumab PK population, atezolizumab and ADA serum concentrations at each 
nominal time-point will be summarized by Substudy and Cohort using descriptive 
statistics. 
Population PK (PopPK) analyses may be performed with the possibility of pooling PK data 
from other clinical studies. Any PopPK analysis will be reported separately.
8.3.7
Pharmacodynamics analyses
Data from biomarker and other PD analyses will be summarized overall using descriptive 
statistics. Comparisons of clinical activity endpoints between biomarker defined groups 
may be performed.
8.3.8
PRO analysis
PRO scores from the EORTC QLQ-C30, FACT-Bl and EQ-5D instruments will be 
analyzed primarily using descriptive analysis. 
The minimal important difference of the EQ-5D visual analogue scale, EORTC QLQ-C30 
scales and FACT-Bl scales will be determined using the Health Transition Index/G-SET
as an external anchor.
8.3.9
Crossover analysis
In the primary efficacy comparison, patients who crossover to derazantinib-atezolizumab 
combination are censored at time of crossover. Exploratory safety, PK/ADA, PRO and 
efficacy analyses will be conducted for the crossover population including all safety events, 
PK/ADA data, PRO data and RECIST 1.1 responses starting from the date of the first dose 
of derazantinib-atezolizumab combination.
8.3.10
Handling of missing data and discontinuations
Missing data will not be imputed. Patients whose clinical response is unknown or not 
reported will be treated as non-responders.
Reasons for discontinuation and the date of discontinuation from the study will be listed, 
and dates of first and last study drug provided as well as the duration of exposure to study 
drug and date. Summary tables will be provided by substudy and cohort.


 
 
   
 
 
 
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STUDY ADMINISTRATION AND REGULATORY ASPECTS
9.1
Study records
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified.
9.1.1
Investigator Site File
The ISF must contain all essential documents as required by International Council for 
Harmonization (ICH) E6 and applicable regulations, including the Investigators’ Brochure, 
protocol and any subsequent amendments, eCRFs, Query Forms, documented IEC/IRB 
approvals, documented regulatory approvals, sample informed consent forms, drug 
records, staff curriculum vitae, and other appropriate documents/correspondence.
9.1.2
Case report forms
For each patient enrolled in the study via the IWRS, including patients who do not complete 
the study and patients for whom a eCRF is initiated during Screening but are not 
randomized, an eCRF must be completed and signed (manually or electronically) by the 
Investigator or authorized site staff. If a patient withdraws from the study, the reason must 
be noted on the eCRF. If a patient is withdrawn from the study because of an AE, thorough 
efforts should be made to clearly document the outcome. 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the Sponsor in the eCRFs and in all required reports.
If the eCRF is to be the source document for certain data, this must be discussed and agreed 
with the Sponsor in advance, and clearly documented. 
9.1.3
Patient source documents
Patient source documents used to record key efficacy/safety parameters, independent of 
the eCRFs, may include, but are not limited to, patient hospital/clinic records, physicians’ 
and nurses’ notes, appointment books, original laboratory reports, X-ray, pathology and 
special assessment reports, signed ICFs, consultant letters, and patient screening and 
enrollment logs, patient’s diary. Source documents are part of the study documents, and 
must be maintained and made available upon request for clinical monitoring visits, audits 
or inspections.
9.1.4
Document retention and archiving
The Investigator must keep all study documents on file for at least 15 years after completion 
or discontinuation of the study. Subsequently, the Sponsor will inform the Investigator 
when the study documents can be destroyed, subject to applicable regulations. 
These files must be made available for audits and inspection, upon reasonable request, to 
the authorized representative of the Sponsor, or to regulatory authorities.
Should the Investigator wish to assign the study records to another party, or move them to 
another location, the Sponsor must be notified in advance.


 
 
   
 
 
 
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If the Investigator cannot guarantee the archiving requirement at the investigational site for 
any or all of the study documents, arrangements must be made between the Investigator 
and the Sponsor for appropriate storage.
9.2
Sample retention 
All biological samples taken will be stored for up to 5 years after completion or 
discontinuation of the study for future medical and/or scientific research projects related to
derazantinib. All patients will be asked to provide informed consent for this purpose, 
authorizing the Sponsor to use their study information and samples for future research 
projects. If a patient withdraws consent to the use biological samples, the samples will be 
disposed or destroyed, and the action is documented. If samples have already been 
analyzed, the Sponsor is not obliged to destroy the results of this research.
After a maximum of 5 years, all stored samples will be returned to the study center or safely 
destroyed.
9.3
Clinical monitoring
Before study initiation, at a site initiation visit or at an Investigator’s meeting, the Sponsor 
will review the protocol, eCRFs and other study documentation with the Investigators and 
the site staff.
The Monitor must visit the Investigator and the study facilities on a regular basis 
throughout the study to verify adherence to GCP and the protocol and the completeness, 
consistency and accuracy of the data being entered into the eCRFs. The Monitor must also 
ensure that the study drug is being stored, dispensed, and accounted for according to 
specifications. 
The Investigator must ensure that the monitor has direct access to all required study data 
(source documents) during the regular monitoring visits. This includes all patient records 
needed to verify the entries in the eCRFs. 
The Investigator must cooperate with the Monitor to ensure that any protocol deviations or 
other issues detected in the course of monitoring visits are resolved. 
Monitoring reports must be written after each monitoring visit, per site and per visit.  These 
monitoring reports must be reviewed and approved by the respective supervisors of the 
Monitors.
Monitoring instructions are provided in the Monitoring Plan.
9.4
Audits and inspections
The study may be audited at any time, with appropriate notification, by qualified personnel 
from the Sponsor or its designees, to assess compliance with the protocol, GCP, and 
regulatory requirements. These audits may also be conducted for quality assurance 
purposes to ensure that complete and accurate data are submitted, and that all AEs are being 
identified and reported in compliance with the protocol and applicable regulations. The 
study may also be inspected by regulatory authority inspectors, after appropriate 
notification. 


 
 
   
 
 
 
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In the event of an audit or an inspection, the Investigator must ensure that direct access to 
all study documentation, including source documents, is granted to the auditors or 
inspectors.
9.5
Protocol amendments
Protocol amendments must be prepared by a representative of the Sponsor, and be reviewed 
and approved in accordance with the Sponsor’s SOPs.
All protocol amendments must be submitted to the appropriate IEC/IRB for information 
and approval, in accordance with applicable laws and regulations, and to regulatory 
agencies if required. 
Approval of a protocol amendment must be awaited before changes are implemented, with 
the exception of for changes necessary to eliminate an immediate hazard to study 
participants, or changes involving only logistical or administrative aspects of the study
(e.g., changes to monitors, changes to telephone numbers).
9.6
Premature termination of the study
The Sponsor reserves the right to terminate the study at any time (see Section 4.5.4). An 
Investigator has the right to terminate his or her participation to the study at any time. 
Should either of these events occur, both parties will arrange the necessary procedures after 
review and consultation.
If the study is to be terminated early, the Sponsor and the Investigator must ensure that 
adequate consideration is given to the protection of the interests of all patients enrolled in 
the study.
9.7
Publication policy
The Sponsor is committed to registering this study in a publicly accessible clinical trial 
registry (e.g., www.clinicaltrials.gov), and will ensure that results of this study will be 
made available to the medical community consistent with the ICH GCP guidelines, the 
Sponsor’s SOPs, applicable laws and regulations, and the Good Publication Practice 
(GPP3) guidelines (Battisti 2015).
This study is intended for publication, even if terminated prematurely. Publication may 
include any or all of the following: posting of a synopsis online, submission of an abstract 
and/or presentation at a scientific conference, or publication of a full manuscript. The 
Sponsor will work with the authors to submit a manuscript describing study results within 
12 months after the last data become available, which may take up to several months after 
the last patient visit. The Sponsor will post a synopsis of study results for approved products 
on www.clinicaltrials.gov within 12 months after the last patient’s last visit for the primary 
outcome, or within 12 months after the decision to discontinue development of 
derazantinib, or within 12 months of product marketing (dispensed, administered, 
delivered or promoted), whichever is later.


 
 
   
 
 
 
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These timelines may be extended if derazantinib is not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties. Authors of the primary results manuscript will be provided 
the complete results from the clinical study report, subject to applicable confidentiality 
agreements.
When a manuscript is submitted to a biomedical journal, the Sponsor’s policy is to also 
include the protocol a Statistical Analysis Plan to facilitate peer and editorial review of the 
manuscript. If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so wishes, to post on its website the key sections of the protocol that 
are relevant to evaluating the study, specifically including those sections describing the 
study objectives and hypotheses, the inclusion and exclusion criteria, the study design and 
procedures, the efficacy and safety measures, the Statistical Analysis Plan, and any 
protocol amendments relating to those sections. The Sponsor reserves the right to redact 
proprietary information from these documents.
As this is a multicenter study, subsequent to the multicenter publication (or after public 
disclosure of the results online at www.clinicaltrials.gov if a multicenter manuscript is not 
planned), an Investigator and his or her colleagues may publish their data independently. 
The limitations of single study site observations in a multicenter trial should always be 
described in such a manuscript. 
Authorship credit and related decisions in regard to publication of the results of this study 
will comply with the GPP3 guidelines (Battisti 2015).
The Sponsor retains the right to review all proposed abstracts, manuscripts, or presentations 
regarding this study 45 days prior to submission for publication/ presentation. Any 
information identified by the Sponsor as confidential must be deleted prior to submission; 
this confidentiality does not include efficacy and safety results. Sponsor review can be 
expedited to meet publication timelines.


 
 
   
 
 
 
 
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ETHICS AND GOOD CLINICAL PRACTICE
10.1
Good Clinical Practice
The study must be conducted in compliance with this protocol, ICH Guideline E6 and any 
relevant supplementary guidance on GCP and applicable laws and regulations.
This study will be conducted in accordance with the ethical principles having their origin 
in the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human 
Subjects. 
All definitive non-clinical safety studies were conducted in accordance with Good 
Laboratory Practices regulations: OECD Principles of Good Laboratory Practice 
ENV/MC/CHEM (98)17 (revised in 1997).
10.2
Informed consent
Eligible patients may only be included in the study after providing written 
IEC/IRB-approved informed consent. Written informed consent must be obtained by the 
Investigator or designee from each patient prior to initiation of any study procedures. 
It is the responsibility of the Investigator, or a person designated by the Investigator if 
acceptable by local regulations, to obtain prior written informed consent from each 
individual participating in this study, after adequate explanation of the aims, methods, 
objectives and potential and identified risks of the study. It must also be explained to 
patients that they are completely free to refuse to enter the study, or to withdraw from the 
study at any time for any reason. 
Written consent must be witnessed and countersigned by the Investigator or a qualified 
designee, as appropriate. In obtaining and documenting informed consent, the Investigator 
must comply with applicable regulatory requirements and GCP as outlined in ICH 
Guideline E6 and other relevant guidelines, and the ethical principles having their origin 
in the Declaration of Helsinki. 
Copies of signed consent forms must be given to the patient and the originals filed at the 
study site. 
In the event that the patient is unable to read the consent document; an impartial witness 
must be present during the entire informed consent discussion. After the patient has 
verbally consented to participation in the study, the witness’ signature must be obtained on 
the form to attest that the information in the consent form was accurately explained and 
understood. 
The eCRFs for this study contain a section for documenting informed patient consent, and 
this must be completed appropriately. If new safety information results in significant 
changes in the benefit/risk assessment for derazantinib or atezolizumab, the consent form 
must be reviewed and updated. All patients currently enrolled in the study who have not 
yet completed the treatment or post-treatment phases must be given the new information 
and a copy of the revised form, and asked to give their consent to continuing in the study.


 
 
   
 
 
 
 
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10.3
Patient confidentiality and data protection
The Investigator must ensure that patient anonymity is maintained, and that patients’ 
identities are protected from unauthorized parties. This includes any electronic data 
generated during the study. In the eCRF, or other documents submitted to the Sponsor, 
patients must be identified only by an identification code, and not by name. The 
Investigator must keep a confidential patient identification code list, as described in Section 
8.3.21 of ICH Guideline E6. 
The Sponsor is responsible for ensuring compliance with all applicable data protection 
laws.
10.4
Independent Ethics Committees / Institutional Review Boards
This protocol and any accompanying material provided to the patient, including patient 
information sheets or descriptions of the study used to obtain informed consent, as well as 
any advertising material and information about any compensation provided to the patient, 
must be submitted to an IEC/IRB operating in compliance with ICH Guideline E6 and any 
relevant supplementary guidance on GCP, and with applicable laws and regulations. 
Approval from the IEC/IRB must be obtained and documented before starting the study.
Amendments made to the protocol after receipt of IEC/IRB approval must also be 
submitted to the IEC/IRB in accordance with local procedures and applicable laws and 
regulations.
PROTOCOL VERSION HISTORY
Date
Version
Summary of changes
27 March 2019
1.0
Submitted to the US FDA for review. 
10 May 2019
2.0
Implemented FDA comments.
4 October 2019
3.0
Two changes initiated by the Sponsor, and changes in response to 
Health Authority requests made in the course of Clinical Trial 
Applications.
20 August 2020
4.0
Changes made to ensure consistency with the updated 
Investigator’s Brochure, and changes pursuant to Investigator 
feedback. 
8 March 2021
5.0
Changes made to adapt the design of substudies following the 
completion of Substudy 2 and interim results of Substudy 1. The 
design of Substudy 3 was modified, and a new substudy 
(Substudy 5) was added. 


 
 
   
 
 
 
 
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APPENDICES
Appendix 1
Eligible FGFR genetic aberrations
Small variants in FGFR1–3 (FGFR1–3mt)
Missense point mutations (substitutions), in-frame deletions and insertions, excluding 
inactivating variants in FGFR2 (H213Y, V248D, D530N, R759X, I642V, A648T).
Excluding small variants introducing a premature stop codon or reading frame shift 
upstream of the kinase domain.

FGFR1–3 small variants (insertions, deletions, substitutions) introducing a premature 
stop codon or a frame-shift downstream of the kinase domain are eligible.
FGFR1–3 gene fusions and other rearrangements (‘FGFR1–3fus’)

FGFR1–3 gene fusions with breakpoints upstream or downstream of the kinase domain 
which are in-strand and in-frame with the partner gene

FGFR1–3 gene fusions with breakpoints upstream or downstream of the kinase domain 
likely to be a functional event but with insufficient data for stringency criteria and/or 
canonical orientation  

FGFR1–3 gene rearrangements of any type (translocations, truncations, deletions, 
splice site variants) with breakpoints in introns and/or exons upstream or downstream 
of the kinase domain 
Concurrent assumed activating and inactivating genetic aberrations
In the event that assumed activating (i.e., eligible) and inactivating genetic aberrations are 
detected in a patient sample and considering heterogeneity of tumor cell clonality, which 
cannot be resolved with cfDNA analysis from plasma, the resulting FGFR1–3 GA status 
will be, for the purpose of this clinical study protocol, defined as molecularly eligible for 
considering conduct of clinical study screening procedures.


 
 
   
 
 
 
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Appendix 2
Assessment of anti-tumor activity per RECIST v. 1.1
Assessment of tumor responses may be performed following the revised RECIST 
guidelines, version 1.1. Some of these definitions and criteria are highlighted below.
Measurability of tumor baseline

CT with IV contrast and MRI are the best currently available and reproducible 
methods to measure target lesions selected for response assessment. Conventional 
CT and MRI should be performed with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.

Standard imaging studies should be performed according to the imaging manual 
provided by the central imaging laboratory designated by the Sponsor.
Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable 
as follows:
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm).

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).

20 mm by chest X-ray.
Measurable malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed. See also notes below on 
‘Baseline documentation of target and non-target lesions’ for information on lymph node 
measurement.
Non-measurable
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin (nevi) 
or lung, and abdominal masses/abdominal organomegaly identified by physical exam that 
is not measurable by reproducible imaging techniques.


 
 
   
 
 
 
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Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment:
Bone lesions
Bone scan, positron emission tomography scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.
Blastic bone lesions are non-measurable.
Cystic lesions
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions.
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are not considered measurable unless there has been demonstrated 
progression in the lesion. 
Specifications by methods of measurements
Measurement of lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the treatment 
start and NEVER more than 4 weeks before the beginning of the treatment.
Method of assessment
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (e.g., skin (nevi) nodules). For 
the case of skin (nevi) lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. As noted above, when lesions can be evaluated 
by both clinical exam and imaging, imaging evaluation should be undertaken since it is 
more objective and may also be reviewed at the end of the study.


 
 
   
 
 
 
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Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans 
have a slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body 
scans). 
Tumor response evaluation
Assessment of overall tumor burden and measurable disease
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. In this 
study, only patients with measurable disease at baseline should be included in the study. 
Baseline documentation of ‘target’ and ‘non-target’ lesions
When more than one measurable lesion is present at baseline, all lesions up to a maximum 
of five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where patients have only one or two organ sites involved, a 
maximum of two and four lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumor. As noted above, pathological nodes 
which are defined as measurable and may be identified as target lesions must meet the 
criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will 
contribute to the baseline sum. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported 
as two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or coronal). 
The smaller of these measures is the short axis. For example, an abdominal node which is 
reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant, 
measurable node. In this example, 20 mm should be recorded as the node measurement. 
All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be 
considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed.


 
 
   
 
 
 
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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of the diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into 
the sum. The baseline sum of the diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. Measurements are 
not required and these lesions should be followed as ‘present’, ‘absent’, or in rare cases 
‘unequivocal progression’ (more details to follow). In addition, it is possible to record 
multiple non-target lesions involving the same organ as a single item on the case record 
form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response criteria
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.
Evaluation of target lesions

Complete Response: Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.

Partial Response: At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.

Progressive Disease: At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression).

Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. In this 
study, the minimum duration for SD is defined as 6 weeks.
Special notes on the assessment of target lesions
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of < 10 
mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to be included 
in the sum of target lesions.


 
 
   
 
 
 
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Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
Response Criteria subsequent evaluation, even when very small (e.g., 2 mm). However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline become 
so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs, it is 
important that a value be recorded on the case report form. If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 
0 mm. If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a 
definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this circumstance as 
well). This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness). The measurement of these lesions is potentially 
non-reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error. To reiterate, however, if the radiologist is able 
to provide an actual measure, that should be recorded, even if it is below 5 mm.
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would 
aid in obtaining maximal diameter measurements of each individual lesion. If the lesions 
have truly coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximal longest diameter for the ‘coalesced lesion’.
Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only qualitatively 
at the time points specified in the protocol. 

Complete Response: Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm 
short axis).

Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.

Progressive Disease: Unequivocal progression (see comments below) of existing 
non-target lesions. (Note: the appearance of one or more new lesions is also 
considered progression).


 
 
   
 
 
 
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Special notes on the assessment of progression of non-target disease
The concept of progression of non-target disease requires additional explanation as 
follows:
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy (see further details below). A modest ‘increase’ in the size of one or more non-
target lesions is usually not sufficient to quality for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in the 
face of SD or PR of target disease will therefore be extremely rare. 
Evaluation of new lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the patient’s baseline lesions show PR or CR. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, 
which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of 
this is the patient who has visceral disease at baseline and while on study has a CT or MRI 
of the brain ordered which reveals metastases. The patient’s brain metastases are 
considered to be evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it truly represents a new disease. If repeat scans confirm 
there is definitely a new lesion, then progression is to be declared using the date of the 
initial scan. 
Evaluation of best overall response
The best overall response is the best response recorded from the start of the study treatment 
until the End of Treatment. 
The patient’s best overall response assignment will depend on the findings of both target 
and non-target disease and will also take into consideration the appearance of new lesions. 




 
 
   
 
 
 
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For patients with PR or CR, the Investigator should make every attempt to perform the 
confirmation scan 4 to 5 weeks after the last scan was performed. Radiographic disease 
progression must be confirmed by central radiology prior to treatment discontinuation if 
progression is seen on first or second post-treatment scan.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy. The objective 
response status of such patients is to be determined by evaluation of target and non-target 
disease.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Frequency of tumor re-evaluation
In this study, tumor measurement will be conducted at baseline, and once every 9 weeks 
(every three cycles) for the first 27 weeks, and every 12 weeks (every four cycles) thereafter 
while the patient is on treatment or as clinically indicated until progression of disease, 
withdrawal of consent, or death. Tumor measurement will also be performed during the 
End of Treatment visit if it is not done within 28 days of the End of Treatment visit date or 
if prior scan did not show radiographic disease progression.
Baseline tumor assessments must be performed within 4 weeks (28 days) of the first dose 
of treatment. 
All efforts must be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning methods, equipment, 
technique (including slice thickness and field of view), and the radiographic interpreter.
The radiological evaluation must include CT or MRI scanning of the chest, abdomen, and 
pelvis. Any additional suspected sites of disease should also be imaged. All evaluations 
must meet the SoC for imaging of lesions in the respective organ(s). 
All target and non-target sites are evaluated at each time point of tumor assessment. 


 
 
   
 
 
 
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Confirmatory measurement/duration of response
Confirmation
Confirmation of PR and CR is required approximately 4–5 weeks after the initial scan 
showing PR or CR. 
Duration of overall response
The duration of overall response is measured from the time measurement criteria are first 
met for CR/PR (whichever is first recorded) until the first date that recurrent or PD is 
objectively documented (taking as reference for PD the smallest measurements recorded 
on study).
The duration of overall complete response is measured from the time measurement criteria 
that are first met for CR until the first date that recurrent disease is objectively documented.
Duration of stable disease
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest sum on study (if the baseline sum is the smallest, 
this is the reference for calculation of PD). In this study, the minimum duration for SD is 
defined as 6 weeks.


 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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Appendix 3
Comparison of RECIST 1.1 and iRECIST criteria
























 
 
   
 
 
 
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Appendix 5
Collection and Management of Specimens for Future Biomedical 
Research
Definitions
Biomarker:
A biological molecule found in blood, other body fluids, or tissues 
that is a sign of a normal or abnormal process or of a condition or 
disease. A biomarker may be used to see how well the body responds 
to a treatment for a disease or condition.
Pharmacogenomics: The investigation of variations of DNA characteristics as related to 
drug/vaccine response. 
Pharmacogenetics:
A subset of pharmacogenomics; pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.
DNA:
Deoxyribonucleic acid.
Future Biomedical Research Sample Collection
For the purposes of this appendix, the specimens collected in this study as outlined in 
Section 5.3.5.4 are considered to be the ‘Future Biomedical Research Sample Collection’, 
and will be used to study various causes for how patients may respond to a drug.
Scope of future biomedical research
Future biomedical research specimens will be stored to provide a resource for future studies 
conducted by the Sponsor focused on the study of biomarkers responsible for how a drug 
enters and is removed by the human body, how a drug works, other pathways a drug may 
interact with, or other aspects of disease. The specimens may be used for future assay 
development and/or drug development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance the understanding of how individuals 
respond to drugs and the understanding of human disease, and ultimately to improve public 
health through development of novel treatments targeted to populations with the greatest 
need. All specimens will be used by the Sponsor, or those working in partnership with, or 
at the direction of, the Sponsor.
Summary of procedures for future biomedical research
1. Patients for enrollment
All patients enrolled in Substudies 1, 3, 4 and 5 in clinical study DZB-CS-201 will be 
considered for enrollment in the Future Biomedical Research study.
2. Informed consent
Informed consent for specimens (i.e., DNA, protein, etc.) will be obtained during screening 
for protocol enrollment from all patients, at a study visit by the investigator or his or her 
designate. Informed consent for future biomedical research is part of the study ICF and 
must be obtained before samples not fully consumed for the study analyses are 
subsequently used for Future Biomedical Research. 
Informed consent for future biomedical research is to be handled in the same manner as 
other consents provided for the purposes of this study (see Section 10.2). 


 
 
   
 
 
 
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3. eCRF documentation for future biomedical research specimens
Documentation of patient consent for future biomedical research will be captured in the 
eCRF. Any specimens for which such an informed consent cannot be verified must be 
destroyed.
4. Future Biomedical Research Specimen Collections
Collection of specimens for future biomedical research will be performed as part of sample 
collection in accordance with study procedures. 
Confidential subject information for future biomedical research
To optimize the research that can be conducted with future biomedical research specimens, 
it is critical to link patient clinical information with future test results, so that specific 
analyses can be conducted. Knowing patient characteristics like sex, age, medical history 
and treatment outcomes are critical to understanding the clinical context of analytical 
results.
All patient personal data collected for future biomedical research will be handled in 
accordance with the Sponsor’s confidentiality and personal data standard operating 
procedures (SOPs), and in compliance with the EU General Data Protection Regulation 
(GDPR).
Biorepository specimen usage
Analyses utilizing the future biomedical research specimens may be performed by the 
Sponsor, or a third party (e.g., a university investigator) designated by the Sponsor. The 
investigator conducting the analysis will be contractually bound to comply with the 
Sponsor’s personal data protection and confidentiality requirements, and with the GDPR. 
Any contracted third-party analyses will conform to the specific scope of analysis outlined 
in the Future Biomedical Research study. Future biomedical research specimens remaining 
with the third party after specific analysis is performed will continue to be protected by the 
contractual provisions and the requirement to comply with the GDPR.
Withdrawal from future biomedical research
Patients may withdraw their consent for future biomedical research at any time by 
contacting either the investigator or the Sponsor, and may have their specimens and all 
derivatives removed from the biorepository and destroyed. While any analyses in progress 
at the time of a request for destruction or already performed prior to the request being 
received by the Sponsor will continue to be used as part of the overall research, no new 
analyses of a patient’s specimens will be generated after a request for destruction is 
received.
Retention of specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 5 years from the end of the main study. 


 
 
   
 
 
 
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Data security
Databases containing specimen information and test results must be accessible only to the 
authorized Sponsor representatives and the designated study personnel and/or authorized 
collaborators. The Sponsor must ensure that database user authentication is highly secure, 
and is accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
Reporting of future biomedical research data to patients 
Information obtained from exploratory laboratory studies will not usually be reported to 
the patient, family, or physicians. 
If any exploratory results are definitively associated with clinical significance for patients 
while the clinical study is ongoing, investigators will be contacted with information. After 
the clinical study has been completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available through 
appropriate mechanisms (e.g., scientific publications and/or presentations). Patients will 
not be identified in any published reports about this study or in any other scientific 
publication or presentation.
Risks versus benefits of future biomedical research
No additional risks to the patient from future biomedical research have been identified, as 
no additional specimens will be collected for future biomedical research after completion 
of this study (i.e., only leftover samples are being retained). 
Questions
Any questions related to the future biomedical research should be emailed directly to 
medical.information@basilea.com.


 
 
   
 
 
 
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Appendix 6
Understanding the intent, scope and public health benefits of 
exploratory biomarker research
Education Task Force, Industry Pharmacogenomics Working Group. Understanding the 
Intent, Scope and Public Health Benefits of Exploratory Biomarker Research, a Guide for 
IRBs/IECs & Investigational Site Staff. Published on I-PWG web site (www.i-pwg.org). 
December 2009. 
Available at:
https://i-pwg.org/document-manager/publications/18-i-pwg-pharmacogenomics-
informational-brochure/file


  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 7
Examples of in vivo substrates, inhibitors, and inducers for specific 
CYP enzymes
Inhibitors can be classified by their potency, such as:

Strong inhibitor being one that causes at least a 5-fold increase in the plasma area 
under the curve (AUC) values, or more than 80% decrease in clearance.

Moderate inhibitor being one that causes at least a 2-fold increase in the plasma 
AUC values, or 50-80% decrease in clearance.

Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase 
in the plasma AUC values, or 20-50% decrease in clearance.
Selected inducers, inhibitors, and substrates of CYP2C8
Substrates
Inhibitors
Inducers

Amodiaquine (anti-malarial)

Cerivastatin (statin)

Paclitaxel (anti-tumoral)

Repaglinide (anti-diabetic)

Sorafenib (anti-tumoral)

Torsemide (diuretic)
Strong: 

Gemfibrozil (lipid lowering)
Moderate

trimethoprim (antibiotic)
Unspecified potency:

glitazones (anti-diabetic)

montelukast (anti-asthmatic)

quercetin (antioxidant, 
supplement)

rifampin  (antibiotic)
Selected inducers, inhibitors, and substrates of CYP1A2
Substrates
Inhibitors
Inducers

many antidepressants 
o
amitriptyline (tricyclic 
antidepressant) 
o
clomipramine (tricyclic 
antidepressant) 
o
imipramine (tricyclic 
antidepressant) 
o
agomelatine 

some atypical antipsychotics 
o
clozapine 
o
olanzapine 

haloperidol (typical 
antipsychotic) 

caffeine (stimulant) 

ropivacaine (local anaesthetic) 

theophylline (xanthine, in 
respiratory diseases) 

zolmitriptan (serotonin 
receptor agonist) 
Strong: 

ciprofloxacin (fluoroquinolone 
bactericidal) 

many other fluoroquinolones 
(broad-spectrum antibiotics) 

fluvoxamine (SSRI antidepressant) 

verapamil (calcium channel 
blocker) 
Weak

cimetidine (H2-receptor 
antagonist) 
Unspecified potency:

amiodarone (antiarrhythmic agent) 

interferon (antiviral, antiseptic, 
antioncogenic) 

methoxsalen (in psoriasis) 

mibefradil (calcium channel 
blocker) 

Some foods

tobacco 

Some foods
o
broccoli 
o
brussels sprouts 
o
chargrilled meat 
o
cauliflower 

insulin (in diabetes) 

methylcholanthrene 
(carcinogen) 

modafinil (eugeroic) 

nafcillin (beta-lactam 
antibiotic) 

beta-Naphthoflavone 
(chemopreventive) 

omeprazole (proton 
pump inhibitor) 


 
 
   
 
 
 
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Selected inducers, inhibitors, and substrates of CYP1A2
Substrates
Inhibitors
Inducers

melatonin (antioxidant, sleep-
inducer) 

tamoxifen (SERM) 

erlotinib (Tarceva, a tyrosine 
kinase inhibitor) 

cyclobenzaprine (muscle 
relaxant, depressant) 

estradiol (in hypoestrogenism) 

fluvoxamine (SSRI 
antidepressant) 

mexiletine (antiarrhythmic) 

naproxen (NSAID) 

ondansetron (5-HT3 
antagonist) 

phenacetin (analgesic) 

paracetamol (analgesic, 
antipyretic) 

propranolol (beta blocker) 

riluzole (in amyotrophic 
lateral sclerosis) 

tacrine 
(parasympathomimetic) 

tizanidine (α-2 adrenergic 
agonist) 

verapamil (calcium channel 
blocker) 

warfarin (anticoagulant) 

zileuton (in asthma) 
o
grapefruit juice (its bitter 
flavanone naringenin) 
o
cumin 
o
turmeric 


 
 
   
 
 
 
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Selected inducers, inhibitors, and substrates of CYP2D6
Substrates
↑ = bioactivation by CYP2D6
Inhibitors
Inducers

All tricyclic antidepressants, 
e.g. 
o
imipramine 
o
amitriptyline 
o
etc. 

Most SSRIs (antidepressant), 
e.g. 
o
fluoxetine 
o
paroxetine 
o
fluvoxamine 

venlafaxine (SNRI 
antidepressant) 

mianserin (tetracyclic 
antidepressant) 

opioids 
o
codeine↑ into morphine 
o
tramadol↑ 
o
oxycodone 

antipsychotics, e.g. 
o
haloperidol 
o
risperidone 
o
perphenazine 
o
thioridazine 
o
zuclopenthixol 
o
iloperidone 
o
aripiprazole 
o
chlorpromazine 
o
levomepromazine 
o
remoxipride 

minaprine (RIMA 
antidepressant) 

tamoxifen↑ (SERM) 

beta-blockers 
o
metoprolol 
o
timolol 
o
alprenolol 
o
carvedilol 
o
bufuralol 
o
nebivolol 
o
propranolol 

debrisoquine (antihypertensive) 

Class I antiarrhythmics 
o
flecainide 
o
propafenone 
o
encainide 
o
mexiletine 
o
lidocaine 
o
sparteine 
Strong:

SSRIs 
o
fluoxetine 
o
paroxetine 

bupropion (non-SSRI 
antidepressant) 

quinidine (class I antiarrhythmic 
agent) 

cinacalcet (calcimimetic) 

ritonavir (antiretroviral) 
Moderate

sertraline (SSRI) 

duloxetine (SNRI)

terbinafine (antifungal) 
Weak:

buprenorphine (in opioid 
addiction) 

amiodarone (antiarrhythmic) 

cimetidine (H2-receptor 
antagonist) 
Unspecified potency:

antipsychotics 
o
haloperidol 
o
perphenazine 
o
thioridazine 
o
zuclopenthixol 
o
risperidone 
o
chlorpromazine 

bicalutamide 

hyperforin (St. John’s Wort) 

antihistamines (H1-receptor 
antagonists) 
o
Promethazine 
o
chlorphenamine 
o
diphenhydramine 
o
hydroxyzine 
o
tripelennamine 

some SSRI antidepressants 
o
citalopram 
o
escitalopram 

clemastine (antihistamine and 
anticholinergic) 

celecoxib (NSAID) 

clomipramine (tricyclic 
antidepressant) 

cocaine (stimulant) 

doxorubicin (chemotherapeutic) 

dexamethasone
(glucocorticoid) 

rifampicin (bactericidal) 
Strong:

glutethimid


 
 
   
 
 
 
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Selected inducers, inhibitors, and substrates of CYP2D6
Substrates
↑ = bioactivation by CYP2D6
Inhibitors
Inducers

ondansetron (antiemetic) 

donepezil (acetylcholinesterase 
inhibitor) 

phenformin (antidiabetic) 

tropisetron (5-HT3 receptor 
antagonist) 

amphetamine (in ADHD, 
narcolepsy) 

atomoxetine (in ADHD) 

chlorphenamine (antihistamine) 

dexfenfluramine (serotoninergic 
anorectic) 

dextromethorphan (antitussive) 
into psychoactive dextrorphan 

duloxetine (SNRI) 

metoclopramide (dopamine 
antagonist) 

Methoxyamphetamine 

perhexiline (antianginal agent) 

phenacetin (analgesic) 

promethazine (antihistamine 
antiemetic) 

metoclopramide (antiemetic, 
prokinetic) 

methadone (analgesic and anti-
addictive) 

moclobemide (antidepressant) 

ranitidine (H2-receptor 
antagonist) 

doxepin (tricyclic antidepressant, 
anxiolytic) 

halofantrine (in malaria) 

levomepromazine (antipsychotic) 

mibefradil (calcium channel 
blocker) 

midodrine (α1 agonist) 

ticlopidine (antiplatelet) 
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx 


 
 
   
 
 
 
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Appendix 8
Examples of in vivo
substrates, inhibitors, and inducers of 
P-glycoprotein
Examples of In Vivo Substrates, Inhibitors, and Inducers of P-glycoprotein1
Transporter
Substrates
Inhibitors1
Inducers2
P-gp
(Gene ABCB1)
Aliskiren 
ambrisentan 
colchicine 
dabigatran etexilate
digoxin 
everolimus 
fexofenadine 
imatinib 
lapatinib 
maraviroc, 
nilotinib 
posaconazole 
ranolazine 
saxagliptin 
sirolimus 
sitagliptin 
talinolol 
tolvaptan 
topotecan 
Amiodarone
azithromycin3
captopril
carvedilol
clarithromycin
conivaptan
cyclosporine
diltiazem
dronedarone
erythromycin4
felodipine
itraconazole
ketoconazole3
lopinavir and ritonavir
quercetin3
quinidine
ranolazine
ticagrelor 
verapamil
Avasimibe5
carbamazepine6
phenytoin
rifampin
St John’s wort7
tipranavir/ritonavir
Source: Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and 
Labeling Recommendations 
(http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf)
1
Not an exhaustive list. For an updated list, see the following link: 
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
80499 htm
1
Inhibitors listed for P-gp are those that showed >25% increase in digoxin AUC or otherwise indicated if substrate 
is other than digoxin
2
Inducers listed for P-gp are those that showed >20% decrease in digoxin AUC or otherwise indicated if substrate 
is other than digoxin
3
Inhibitors listed are those that showed >25% increase in fexofenadine AUC
4
Inhibitors listed are those that showed >25% increase in talinolol AUC
5
Not a marketed drug
6
Inducers listed are those that showed >20% decrease in fexofenadine AUC
7
Herbal product


 
 
   
 
 
 
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Appendix 9
Drugs with the potential to prolong QT and/or cause Torsades de 
Pointes
Known risk of Torsades de Pointes24
Generic name
Brand name
Generic name
Brand name
Aclarubicin
Aclacin and others
Ibogaine
None
Amiodarone
Cordarone and others
Ibutilide
Corvert
Anagrelide
Agrylin and others
Levofloxacin
Levaquin and others
Arsenic trioxide
Trisenox
Levomepromazine 
(methotrimeprazine)
Nosinan and others
Astemizole
Hismanal
Levomethadyl acetate
Orlaam
Azithromycin
Zithromax and others
Levosulpiride
Lesuride and others
Bepridil
Vascor
Mesoridazine
Serentil
Chloroquine
Aralen
Methadone
Dolophine and others
Chlorpromazine
Thorazine and others
Moxifloxacin
Avelox and others
Cilostazol
Pletal
Ondansetron
Zofran and others
Ciprofloxacin
Cipro and others
Oxaliplatin
Eloxatin
Cisapride
Propulsid
Papaverine 
HCl 
(Intra-coronary)
None
Citalopram
Celexa and others
Pentamidine
Pentam
Clarithromycin
Biaxin and others
Pimozide
Orap
Cocaine
Cocaine
Probucol
Lorelco
Disopyramide
Norpace
Procainamide
Pronestyl and others
Dofetilide
Tikosyn
Propofol
Diprivan and others
Domperidone
Motilium and others
Quinidine
Quinaglute and others
Donepezil
Aricept
Roxithromycin
Rulide and others
Dronedarone
Multaq
Sevoflurane
Ultane and others
Droperidol
Inapsine and others
Sotalol
Betapace and others
Erythromycin
E.E.S. and others
Sparfloxacin
Zagam
Escitalopram
Cipralex and others
Sulpiride
Dogmatil and others
Flecainide
Tambocor and others
Sultopride
Barnetil and others
Fluconazole
Diflucan and others
Terfenadine
Seldane
Gatifloxacin
Tequin
Terlipressin
Teripress and others
Grepafloxacin
Raxar
Terodiline
Micturin and others
Halofantrine
Halfan
Thioridazine
Mellaril and others
Haloperidol
Haldol and others
Vandetanib
Caprelsa
                                                
24
Source: CredibleMeds® (https://www.crediblemeds.org).


 
 
   
 
 
 
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Possible risk of  Torsades de Pointes25
Generic name
Brand name
Generic name
Brand name
Abarelix
Plenaxis
Dexmedetomidine
Precedex and others
Alfuzosin
Uroxatral
Dextromethorphan/
Quinidine
Nuedexta
Apalutamide
Erleada
Dolasetron
Anzemet
Apomorphine
Apokyn and others
Efavirenz
Sustiva and others
Aripiprazole
Abilify and others
Eliglustat
Cerdelga
Artemether + Lumefantrine Coartem
Encorafenib
Braftovi
Artenimol+piperaquine
Eurartesim
Epirubicin
Ellence and others
Asenapine
Saphris and others
Eribulin mesylate
Halaven
Atomoxetine
Strattera
Ezogabine (Retigabine)
Potiga and others
Bedaquiline
Sirturo
Felbamate
Felbatol
Bendamustine
Treanda and others
Fingolimod
Gilenya
Benperidol
Anquil and others
Fluorouracil (5-FU)
Adrucil and others
Betrixaban
Bevyxxa
Flupentixol
Depixol and others
Bortezomib
Velcade and others
Gemifloxacin
Factive
Bosutinib
Bosulif
Glasdegib
Daurismo
Buprenorphine
Butrans and others
Granisetron
Kytril and others
Cabozantinib
Cometriq
Hydrocodone - ER
Hysingla ER and others
Capecitabine
Xeloda
Iloperidone
Fanapt and others
Ceritinib
Zykadia
Imipramine 
(melipramine)
Tofranil
Clofazimine
Lamprene
Inotuzumab ozogamicin
Besponsa
Clomipramine
Anafranil
Isradipine
Dynacirc
Clotiapine
Entumine
Ketanserin
Sufrexal
Clozapine
Clozaril and others
Lacidipine
Lacipil and others
Crizotinib
Xalkori
Lapatinib
Tykerb and others
Cyamemazine 
(cyamepromazine)
Tercian
Lenvatinib
Lenvima
Dabrafenib
Tafinlar
Leuprolide
Lupron and others
Dasatinib
Sprycel
Lithium
Eskalith and others
Degarelix
Firmagon and others
Lopinavir and ritonavir
Kaletra and others
Delamanid
Deltyba
Maprotiline
Ludiomil and others
Desipramine
Pertofrane and others
Melperone
Bunil and others
Deutetrabenazine
Austedo
Memantine
Namenda XR and others
(Continued)
                                                
25
Source: CredibleMeds® (https://www.crediblemeds.org).


 
 
   
 
 
 
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Clinical Study Protocol
DZB-CS-201 (FIDES-02)
Version 5.0
8 March 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 176 of 180
Possible risk of Torsades de Pointes (continued)26
Generic name
Brand name
Generic name
Brand name
Midostaurin
Rydapt
Rilpivirine
Edurant and others
Mifepristone
Korlym and others
Risperidone
Risperdal
Mirabegron
Myrbetriq
Romidepsin
Istodax
Mirtazapine
Remeron
Saquinavir
Invirase(combo)
Moexipril/HCTZ
Uniretic and others
Sertindole
Serdolect and others
Necitumumab
Portrazza
Sorafenib
Nexavar
Nicardipine
Cardene
Sunitinib
Sutent
Nilotinib
Tasigna
Tacrolimus
Prograf and others
Norfloxacin
Noroxin and others
Tamoxifen
Nolvadex and others
Nortriptyline
Pamelor and others
Telavancin
Vibativ
Nusinersen
Spinraza
Telithromycin
Ketek
Ofloxacin
Floxin
Tetrabenazine
Nitoman and others
Osimertinib
Tagrisso
Tiapride
Tiapridal and others
Oxytocin
Pitocin and others
Tipiracil and Trifluridine Lonsurf
Paliperidone
Invega and others
Tizanidine
Zanaflex and others
Palonosetron
Aloxi
Tolterodine
Detrol and others
Panobinostat
Farydak
Toremifene
Fareston
Pasireotide
Signifor
Tramadol
Crispin and others
Pazopanib
Votrient
Trimipramine
Surmontil and others
Perflutren lipid 
microspheres
Definity and others
Tropisetron
Navoban and others
Perphenazine
Trilafon and others
Valbenazine
Ingrezza
Pilsicainide
Sunrythm
Vardenafil
Levitra
Pimavanserin
Nuplazid
Vemurafenib
Zelboraf
Pipamperone
Dipiperon and others
Venlafaxine
Effexor and others
Primaquine phosphate
None
Vorinostat
Zolinza
Promethazine
Phenergan
Zotepine
Losizopilon and others
Prothipendyl
Dominal and others
Zuclopent(h)ixol
Cisordinol and others
Ribociclib
Kisqali
                                                
26 Source: CredibleMeds® (https://www.crediblemeds.org).


 
 
   
 
 
 
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Clinical Study Protocol
DZB-CS-201 (FIDES-02)
Version 5.0
8 March 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 177 of 180
Conditional risk of  Torsades de Pointes27
Generic name
Brand name
Generic name
Brand name
Amantadine
Symmetrel and others
Ketoconazole
Nizoral and others
Amisulpride
Solian and others
Lansoprazole
Prevacid
Amitriptyline
Elavil and others
Loperamide
Imodium and many other 
OTC and Rx brands
Amphotericin B
Fungilin and others
Metoclopramide
Reglan and others
Amsacrine (acridinyl 
anisidide)
Amsidine
Metolazone
Zytanix and others
Atazanavir
Reyataz and others
Metronidazole
Flagyl and many others
Bendroflumethiazide or 
bendrofluazide
Aprinox and others
Nelfinavir
Viracept
Chloral hydrate
Aquachloral and others
Olanzapine
Zyprexa and others
Cimetidine
Tagamet and others
Omeprazole
Losec and others
Diphenhydramine
Benadryl and others
Pantoprazole
Protonix and others
Doxepin
Sinequan and others
Paroxetine
Paxil and others
Eperisone
Myonal and others
Piperacillin/Tazobactam
Tazosyn and Zosyn
Esomeprazole
Nexium and others
Posaconazole
Noxafil and others
Famotidine
Pepcid and others
Propafenone
Rythmol SR and others
Fluoxetine
Prozac and others
Quetiapine
Seroquel
Fluvoxamine
Faverin and others
Quinine sulfate
Qualaquin
Furosemide (frusemide)
Lasix and others
Ranolazine
Ranexa and others
Galantamine
Reminyl and others
Sertraline
Zoloft and others
Garenoxacin
Geninax
Solifenacin
Vesicare
Hydrochlorothiazide
Apo-Hydro and others
Telaprevir
Incivo and others
Hydroxychloroquine
Plaquenil and others
Torsemide (torasemide)
Demadex and others
Hydroxyzine
Atarax and others
Trazodone
Desyrel and others
Indapamide
Lozol and others
Voriconazole
VFend
Itraconazole
Sporanox and others
Ziprasidone
Geodon and others
Ivabradine
Procoralan and others
                                                
27
Source: CredibleMeds® (https://www.crediblemeds.org).


 
 
   
 
 
 
Derazantinib
Clinical Study Protocol
DZB-CS-201 (FIDES-02)
Version 5.0
8 March 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 178 of 180
Appendix 10
Criteria for evaluating relationship between adverse events and 
study treatment
The relationship between an AE/SAE and derazantinib and/or atezolizumab will be 
determined by the Investigator on the basis of their clinical judgment and following 
definitions.
To align with the binary causality assessment required for clinical studies, based on the 
Investigator’s evaluations, the cases will be categorized as:

Unrelated: when evaluated as not related or unlikely related to derazantinib and/or 
atezolizumab.
The AE does not follow a reasonable temporal sequence from study product 
administration, or can be reasonably explained by the patient’s clinical state or other 
factors (e.g., disease under study, concurrent diseases, and concomitant medications).

Related: when evaluated as possibly or probably related to derazantinib and/or 
atezolizumab.
The AE follows a reasonable temporal sequence from study drug administration and 
cannot be reasonably explained by the patient’s clinical state or other factors 
(e.g., disease under study, concomitant diseases, concomitant medications).
The AE follows a reasonable temporal sequence from study drug administration, and 
is a known reaction to the drug under study or its chemical group, or is predicted by 
known pharmacology, a known reaction to agent, or chemical group.
NOT RELATED
This category is applicable to an AE that meets the following three criteria:
1. It does not follow a reasonable temporal sequence from administration of the drug, 
i.e., the time between the administration of study drug and occurrence of the event is 
not plausible. If the drug was interrupted or stopped the event did not improve or 
disappear. (There are important exceptions when an AE does not disappear upon 
discontinuation of the drug, yet drug-relatedness clearly exists; e.g., [i] bone marrow 
depression, [ii] tardive dyskinesias). If the drug was re-administered, it did not 
reappear.
2. It does not follow a known pattern of the response to the suspected drug or drugs of the 
same substance class.
3. It is judged to be clearly and incontrovertibly due only to extraneous causes such as the 
patient’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
UNLIKELY 
This category is applicable to an AE that meets the following three criteria:
1. It does not follow a reasonable temporal sequence from administration of the drug, 
i.e., the time between the administration of study drug and occurrence of the event is 
not plausible. If the drug was interrupted or stopped the event did not improve or 
disappear. If the drug was re-administered, it did not re-appear.


 
 
   
 
 
 
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Clinical Study Protocol
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Version 5.0
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Page 179 of 180
2. It does not follow a known pattern of the response to the suspected drug or drugs of the 
same substance class.
3. It may readily have been produced by the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient.
POSSIBLE 
This category is applicable to an AE that does not meet the criteria for ‘not related’ 
or ‘unlikely’, nor the criteria for ‘probable’. An AE would be considered possible if, or 
when e.g.:
1. It follows a reasonable temporal sequence from administration of the drug (see also 
additional explanations above) or it follows a known pattern of the response to the 
suspected drug or drugs of the same substance class. 
2. It may or may not have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient.
Note: If an event neither follows a plausible temporal relationship nor a known pattern of 
response but there is no alternative explanation for the event, this will usually be judged a 
possibly related event. 
PROBABLE 
This category is applicable to an AE that is considered, with a high degree of certainty, to 
be related to the test drug. An AE event may be considered probable if it meets the 
following three criteria:
1. It follows a reasonable temporal sequence from administration of the drug, i.e., the time 
between the administration of study drug and occurrence of the event is plausible. If 
the drug was interrupted or stopped the event did improve or disappear. (There are 
important exceptions when an AE does not disappear upon discontinuation of the drug, 
yet drug-relatedness clearly exists; e.g., [i] bone marrow depression, [ii] tardive 
dyskinesias.) If the drug was re-administered it did re-appear.
2. It follows a known pattern of the response to the suspected drug or drugs of the same 
substance class.
3. It cannot be reasonably explained by the known characteristics of the patient’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the 
patient.
Regardless of the criteria mentioned above, reappearance of an event upon re-challenge 
must be regarded as strong evidence of probable relationship to test drug.


 
 
   
 
 
 
Derazantinib
Clinical Study Protocol
DZB-CS-201 (FIDES-02)
Version 5.0
8 March 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 180 of 180
Appendix 11 Investigator’s protocol signature page
BASILEA 
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE
Protocol / Version
DZB-CS-201 / 5.0
Basilea Product No:
Derazantinib
Protocol Title:
An open-label multi-cohort Phase 1b/2 study of derazantinib and 
atezolizumab in patients with urothelial cancer expressing activating 
molecular FGFR aberrations (FIDES-02)
Basilea Pharmaceutica International Ltd
Protocol date:
8 March 2021
Project Physician:
Name of Principal Investigator: 
Study site: 
I agree to the conditions relating to this study as set out in the above named Protocol and Study 
Procedures. I fully understand that any changes instituted by the Investigator(s) without previous 
discussion with the Sponsor’s Project Clinician, Clinical Pharmacologist and Biostatistician (only 
if required) would constitute a protocol deviation, including any ancillary studies or procedures 
performed on study patients (other than those procedures necessary for the well-being of the 
patients).
I agree to follow International Conference on Harmonisation (ICH) guidelines for good clinical 
practice (GCP), including the EU Clinical Trial Directive 2001/20/EC and specifically, obtain 
approval from the Independent Ethics Committee / Institutional Review Board prior to study start, 
allow direct access to source documents and agree to inspection by auditors from Basilea and 
regulatory authorities, as required by ICH GCP. I will ensure that the investigational product(s) 
supplied by the Sponsor will be used only as described in the above named protocol; if any other 
use is desired, written permission must be obtained from the Sponsor.
I acknowledge that I have read the protocol for this study, and I agree to carry out all of its 
terms in accordance with applicable laws and regulations.
To be signed by Principal Investigator (at minimum):
Please print names and dates next to the corresponding signatures
Signature
Name
Date
Principal Investigator

SAP_001.pdf: 




Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 3 of 50 
Filing requirement: TMF 
 
 
Table Of Contents 
Revision History .......................................................................................................................... 2 
Table Of Contents ....................................................................................................................... 3 
List of Abbreviations and Definition of Terms .............................................................................. 6 
1. 
Introduction ........................................................................................................................ 8 
1.1. 
Background on Urothelial Cancer ........................................................................... 8 
1.2. 
Immune-checkpoint Inhibiting Agents in Urothelial Cancer...................................... 8 
1.3. 
FGFR Inhibition in Urothelial Carcinoma ................................................................. 8 
2. 
Study Objectives .............................................................................................................. 10 
2.1. 
Primary Objectives ................................................................................................ 10 
2.1.1. 
Primary efficacy objectives .................................................................................. 10 
2.1.2. 
Primary safety objective for Substudy 3 .............................................................. 10 
2.1.3. 
Primary safety objective for Substudy 5 .............................................................. 10 
2.2. 
Secondary Objectives ........................................................................................... 10 
2.3. 
Exploratory objectives ........................................................................................... 10 
2.3.1. 
Exploratory objectives specific to efficacy-estimating substudies ....................... 10 
2.3.2. 
Exploratory PK objectives .................................................................................... 11 
3. 
Study Design .................................................................................................................... 12 
3.1. 
Substudy 1 ............................................................................................................ 12 
3.2. 
Substudy 3 ............................................................................................................ 13 
3.3. 
Substudy 4 ............................................................................................................ 13 
3.4. 
Substudy 5 ............................................................................................................ 14 
3.5. 
Subject crossover ................................................................................................. 14 
4. 
Schedule of Assessments ................................................................................................ 15 
5. 
Analysis Populations ........................................................................................................ 19 
5.1. 
Safety Population/ Intent-to-treat Population ......................................................... 19 
5.2. 
Modified Intent-to-treat (mITT) Population ............................................................. 19 
5.3. 
Per-protocol (PP) Population ................................................................................ 19 
5.4. 
Maximum-tolerated Dose (MTD) Population (Substudy 2 only) ............................. 19 
5.5. 
Pharmacokinetic (PK) analysis population ............................................................ 20 
6. 
Statistical Methodology..................................................................................................... 21 
6.1. 
Statistical and Analytical Issues ............................................................................ 21 


Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 4 of 50 
Filing requirement: TMF 
 
 
6.1.1. 
Statistical Methods ............................................................................................... 21 
6.1.2. 
Dose Level, Substudy, and Cohort Assignment .................................................. 21 
6.1.3. 
Visit Windows ....................................................................................................... 21 
6.1.4. 
Handling of Dropouts and Missing Data .............................................................. 21 
6.1.5. 
Pooling of Investigative Sites ............................................................................... 21 
6.1.6. 
Determination of Sample Size ............................................................................. 22 
6.2. 
Patient Characteristics .......................................................................................... 24 
6.2.1. 
Patient Disposition ............................................................................................... 24 
6.2.2. 
Protocol Deviations .............................................................................................. 24 
6.2.3. 
Background and Demographic Characteristics ................................................... 25 
6.2.4. 
Smoking History ................................................................................................... 25 
6.2.5. 
Tumor Molecular Status ....................................................................................... 25 
6.2.6. 
Prior and Concomitant Medications and Procedures .......................................... 26 
6.2.7. 
Medical History (Non-Cancer Related) ................................................................ 27 
6.2.8. 
Cancer-Related Medical History .......................................................................... 27 
6.2.9. 
Treatment Exposure and Compliance ................................................................. 27 
6.3. 
Efficacy Analysis ................................................................................................... 28 
6.3.1. 
Primary Efficacy Analysis ..................................................................................... 29 
6.3.2. 
Secondary Efficacy Variable(s) ............................................................................ 31 
6.3.3. 
Exploratory Analysis ............................................................................................ 34 
6.4. 
Safety Analysis (All substudies) ............................................................................ 35 
6.4.1. 
Adverse Events .................................................................................................... 35 
6.4.2. 
BLRM analyses for Dose-limiting toxicity (Substudies 3 and 5 only)................... 37 
6.4.3. 
Physical and Ophthalmological Examinations ..................................................... 38 
6.4.4. 
Vital Signs ............................................................................................................ 38 
6.4.5. 
Electrocardiogram ................................................................................................ 38 
6.4.6. 
Laboratory Parameters ........................................................................................ 39 
6.4.7. 
Evaluation of Performance Status ....................................................................... 39 
6.5. 
PK/PD Analysis ..................................................................................................... 39 
6.6. 
PRO Assessments (Substudies 1, 3, 4 and 5) ...................................................... 40 
6.6.1. 
Establishing the Minimally Important Clinical Difference ..................................... 40 
6.6.2. 
EQ-5D (5L) ........................................................................................................... 40 
6.6.3. 
EORTC QLQ-C30 ................................................................................................ 41 
6.6.4. 
FACT-Bl ............................................................................................................... 42 


Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 5 of 50 
Filing requirement: TMF 
 
 
6.6.5. 
G-SET .................................................................................................................. 44 
6.7. 
Independent Data Monitoring Committee .............................................................. 44 
6.8. 
Changes to Methods Planned in the Protocol ....................................................... 44 
7. 
Tables, Listings, And Figures ........................................................................................... 45 
7.1. 
Programming Guidelines ...................................................................................... 45 
7.1.1. 
Format of Output .................................................................................................. 45 
7.1.2. 
Format of Data ..................................................................................................... 45 
7.2. 
Table of Contents for Tables, Listings and Figures ............................................... 46 
8. 
References ....................................................................................................................... 47 
 


Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 6 of 50 
Filing requirement: TMF 
 
 
List of Abbreviations and Definition of Terms 
Abbreviation or specialist term
Explanation
(i)CPD1 
Confirmed progressive disease 
(i)CR1 
Complete response 
(i)PR1 
Partial response 
(i)RECIST1 
Response Evaluation Criteria In Solid Tumors 
(i)SD1 
Stable disease 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
AE of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
ATC 
Anatomic therapeutic class 
AZB 
Atezolizumab 
BLRM 
Bayesian Logistic Regression Model  
BICR 
Blinded independent central review  
CCG 
Clinical change groups 
CI 
Confidence interval 
CLCR 
Creatinine clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events  
CxDx 
Cycle (cycle number), Day (day number), e.g. C4D1 = Cycle 4, Day 1 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
DOR 
Duration of response  
DZB 
Derazantinib 
ECG 
Electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EWB 
Emotional well-being 
EWOC 
Escalation with Overdose Control 
FACT-G 
FACT General 
FDA 
Food and Drug Administration 
FGFR 
Fibroblast growth factor receptor  
ft3 
Tri-iodothyronine 
ft4 
Thyroxine 
FWB 
Functional well-being 
GA 
Genetic aberration 
H0 
Null hypothesis  
HA 
Alternative hypothesis  
HR 
Hazard ratios 
HR-QoL 
Health-related quality of life  
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee  
 
 
1 Where predicated by the letter ‘i´, abbreviation refers to the equivalent acronym under RECIST adapted to account for the unique 
tumor response seen with immunotherapeutic drugs. 


Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 7 of 50 
Filing requirement: TMF 
 
 
IEC 
Independent Ethics Committee 
IPCW 
Inverse Probability of Censoring Weighted 
IRB 
Institutional Review Board 
IRT 
Interactive response technology  
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities  
MID 
Minimally important difference 
mITT 
Modified intent-to-treat  
MRI 
Magnetic resonance imaging  
MTD 
Maximum tolerated dose 
mUC 
Locally advanced or metastatic and recurrent or progressing urothelial cancer   
n 
Number 
NCI 
National Cancer Institute  
NE 
Not evaluable 
NGS 
Next-generation sequencing 
OCT 
Optical coherence tomography 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
PRO 
Patient-reported outcome 
PSV 
Pre-screening visit 
PT 
Preferred term 
PWB 
Physical well-being 
Q1 
First quartile 
Q3 
Third quartile 
Q3W 
Every 3 weeks 
QoL 
Quality of life 
QTc 
Corrected QT interval 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan  
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SV 
Screening visit 
SWB 
Social well-being 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
USA 
United States of America 
VAS 
Visual analog scale  
WHO 
World Health Organization 


Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 8 of 50 
Filing requirement: TMF 
 
 
1. Introduction 
1.1. 
Background on Urothelial Cancer 
Urothelial cancer (UC) is the most common cancer of the urinary system worldwide, with UC of the bladder 
being the predominant histologic type and location. Although less common, UC may also originate in the 
renal pelvic, ureter or urethra. It has been estimated that in 2019, there would be 80,470 new cases of 
bladder cancer and 17,670 deaths in the USA. Similar worldwide data estimate that there were 549,000 
new cases and 199,922 deaths in 2018 (Bray 2018). The gender-specific estimates were 424,082 new 
cases and 148,270 deaths in men, and 125,311 new cases and 51,652 deaths in women (Bray 2018). 
Current choices for standard treatment of patients with locally-advanced or metastatic and recurrent or 
progressing UC (hereafter identified by the acronym mUC) are cisplatin-based chemotherapy, immune-
checkpoint blockade, and combinations thereof. Specifically identified subgroups of mUC patients 
represent the indications investigated in this study. At the time of protocol set up, no targeted agents 
directed against oncogenic driver mutations have yet been fully approved in these indications. 
1.2. 
Immune-checkpoint Inhibiting Agents in Urothelial Cancer 
UC is a highly immunogenic tumor, partly as a result of the relatively high level of nonsynonymous 
mutations, which represents at least one mechanism for the generation of tumor neoantigens for the host 
immune system to recognize (Alexandrov 2013). PD-L1 overexpression in the tumor microenvironment and 
its binding to PD-1 on tumor antigen-specific T-cells is a mechanism for immune escape in UC. After 
decades of slow progress in drug development in UC, the advent of immune-checkpoint blockade has 
rapidly become an indispensable tool for its treatment. To date, atezolizumab, durvalumab, and avelumab 
(PD-L1 inhibitors), and pembrolizumab and nivolumab (PD-1 inhibitors), have been approved by the Food 
and Drug Administration (FDA) for mUC. In the post-platinum refractory setting, these five checkpoint 
blocking agents generated response rates between 15–21% (Balar 2017a, Balar 2017b, Suzman 2018, 
O’Donnell 2017, Sharma 2017, Powles 2017, Apolo 2017, Balar 2017c), while ORR in the cisplatin-ineligible 
frontline setting was approximately 24% and 29% for atezolizumab and pembrolizumab, respectively. 
In the two ongoing clinical studies, of atezolizumab (IMvigor130) and pembrolizumab (KEYNOTE-361), the 
Data Monitoring Committee (DMC) for each study performed an early review and found that patients in the 
monotherapy arms of both studies with PD-L1-low status had higher mortality compared with patients who 
received cisplatin- or carboplatin-based chemotherapy. The sponsors of both studies stopped enrolling 
patients whose tumors have PD-L1-low status to the atezolizumab or pembrolizumab monotherapy arms, 
in accordance with the DMCs’ recommendations (Suzman 2018). 
As a consequence, patients with mUC and PD-L1-low expression are without a standard and well-tolerated 
first-line treatment option beyond cytotoxic regimens which are often poorly tolerated in this indication (De 
Santis 2011). 
1.3. 
FGFR Inhibition in Urothelial Carcinoma 
Activation of the fibroblast growth factor receptor (FGFR) is a common oncogenic mechanism, occurring in 
a subset of nearly all common cancers (Babina 2017, Turner 2010). Genetic aberrations (GAs) in the FGFR 
genes in carcinoma result in receptor amplification, mutation, and generation of aberrant receptor fusions 
through translocation (Babina 2017, Turner 2010). 


Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 9 of 50 
Filing requirement: TMF 
 
 
It is estimated that approximately 15–20% of patients with advanced/metastatic urothelial cancer have 
genomic FGFR aberrations (Necchi 2018, di Martino 2016, Helsten 2016). FGFR3 mutations, and FGFR1, 
FGFR2, or FGFR3 gene rearrangements and fusions (for the purposes of this protocol hereafter referred 
to as FGFR1–3 GAs) are the most frequent FGFR GA among patients with UC and are found predominantly 
among patients whose tumors are allocated to the luminal subgroup (Choi 2014). 
FGFR inhibitors have therefore been proposed for the treatment of patients whose tumors harbor FGFR 
GAs, and a number of FGFR inhibitors are currently under development in Phase 1–3 studies. Patients 
with mUC and FGFR GAs treated with FGFR inhibitors achieved an ORR ranging from 21–40% in 
uncontrolled clinical Phase 1/2 studies. The current evidence for FGFR-inhibiting treatment in mUC patients 
was generated with the following compounds:  
 
Erdafitinib (Balversa®) was granted an accelerated approval from the U.S. FDA in 2019 for the 
treatment of adult patients with locally advanced or metastatic urothelial carcinoma that have 
susceptible FGFR3 or FGFR2 genetic alterations and who progressed during or following at least one 
line of prior platinum-containing chemotherapy including within 12 months of neoadjuvant or adjuvant 
platinum-containing chemotherapy (Balversa USPI) based on a Phase 2 study, reporting an ORR of 
32% (N=87); of note, erdafitinib achieved an ORR of 59% (13 responses) in 22 UC patients 
unresponsive to immune-checkpoint blockade and an ORR of 35% (27 responses) in 77 UC patients 
without prior immune-checkpoint blockade (Loriot 2019). 
 
Infigratinib (BGJ398) achieved an ORR of 25% (N=67) in patients with NGS confirmed FGFR3 GAs 
(Pal 2018). 
 
Pemigatinib (INCB054828) is being investigated in an ongoing Phase 2 study of UC patients with 
fibroblast growth factor (FGF)/FGFR GAs (NCT02872714). Interim results from 61 patients with FGFR3 
mutations/fusions have demonstrated an ORR of 21% (Necchi 2018). 
 
Rogaratinib achieved an ORR of 24% (N=51) in patients with mRNA-ISH/NanoString confirmed 
FGFR1/3 mRNA overexpression (Phase 1 expansion cohort) (Joerger 2018).  
 
For derazantinib, preclinical data from a number of patient-derived xenograft mouse models in UC 
expressing FGFR mutations suggested a similar or superior efficacy with derazantinib in a direct 
comparison to erdafitinib using previously described equivalent dosing schedules (Perera 2017, Basilea 
data on file). In these experiments, similar or less body weight loss was observed with derazantinib. 
 


Statistical Analysis Plan for Phase I/II Oncology 
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2. Study Objectives 
2.1. 
Primary Objectives 
2.1.1. Primary efficacy objectives 
 
To evaluate the objective response rate (ORR) of derazantinib monotherapy (in Substudies 1 and 5, 
and Cohort 4a) and of derazantinib-atezolizumab in combination (in Substudy 3and Cohort 4b) in 
patients with mUC expressing FGFR1–3 GAs. 
 
2.1.2. Primary safety objective for Substudy 3 
 
To confirm derazantinib 200mg BID in combination with atezolizumab 1200mg Q3W as a safe a 
tolerable dose regimen. 
 
2.1.3. Primary safety objective for Substudy 5 
 
To confirm derazantinib 200mg BID as a safe and tolerable dose regimen of derazantinib 
 
monotherapy.  
 
2.2. 
Secondary Objectives 
 
To evaluate the efficacy of the study drugs as measured by ORR (Substudy 2), disease control rate 
(DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS) 
 
To assess the safety and tolerability of the study drugs 
 
To characterise the PK profile of derazantinib 200 mg BID (and, if applicable, derazantinib metabolites) 
as monotherapy (Substudy 5) and in combination with atezolizumab (Substudy 3). 
 
To evaluate changes, and assess the minimally important difference, in health-related quality of life 
(HR-QoL) and symptom response from baseline using the EORTC QLQ C30, FACT-Bl, and EQ-5D 
(5L) visual analogue scale (VAS), and Health Transition Index/G-SET. 
 
2.3. 
Exploratory objectives 
2.3.1. Exploratory objectives specific to efficacy-estimating substudies 
 
To describe the type of FGFR1–3 GAs in responders and non-responders 
 
To explore the concordance  between molecular FGFR assessments from plasma-based and tissue-
based NGS testing 
 
To explore the efficacy of derazantinib-atezolizumab in combination following documented disease 
progression in patients who previously received derazantinib monotherapy and crossed over to 
combination treatment (Substudy 4) 
 
To explore the efficacy of derazantinib-atezolizumab in combination by iRECIST as measured by ORR, 
DCR, DOR and PFS 
 
To compare the efficacy of derazantinib with that of derazantinib-atezolizumab in combination to 
generate potential hypotheses for future comparative studies (Substudy 4) 


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 
To explore the efficacy of derazantinib and of derazantinib-atezolizumab in combination by response-
indicating molecular biomarkers, as measured by ORR, DCR, DOR, PFS and OS 
 
To explore the effect of derazantinib on CSF1R expressing cells in blood samples and skin biopsies 
 
To characterize utilities in patients treated with derazantinib or derazantinib-atezolizumab in 
combination using the EQ-5D (5L) for health economic modeling. 
 
2.3.2. Exploratory PK objectives 
 
To explore the exposure of 300mg QD derazantinib monotherapy (and, if applicable, derazantinib 
metabolites) and in combination with atezolizumab 
 
To explore the exposure of atezolizumab and anti-drug antibodies (ADA) directed against atezolizumab, 
in the context of atezolizumab combination with derazantinib 
 


Statistical Analysis Plan for Phase I/II Oncology 
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3. Study Design 
This study is a multiple cohort, multi-center Phase 1b/2 study. An overview of the overall study design is 
provided in Figure 1. The efficacy of derazantinib or derazantinib-atezolizumab in combination is evaluated 
in cohorts addressing various clinical stages of disease progression and prior treatments.  
Effective from Protocol Version 5.0, Substudy 3 has been modified and Substudy 5 has been added. 
Substudy 2 has been completed.  
In all efficacy-estimating cohorts, sample-size minimizing statistical designs with interim analyses for futility 
and efficacy will be used. 
Figure 1: Overview of study design 
 
Abbreviations: 1L, first-line treatment; 2+L: second-line or post-second line; ∆: decision for transition to Part 2 / Stage 2; FGFR: 
fibroblast growth factor receptor; GA: genetic aberration; mUC: locally advanced or metastatic and recurrent or progressing urothelial 
cancer; R, randomization. 
* Derazantinib 300mg QD 
† Derazantinib 200 mg BID 
‡ Safety interim analysis after 10 patients 
§ If derazantinib 200 mg BID is not assessed as safe and tolerable, the RP2D in Substudy 2 will be used. 
 
Only patients with mUC expressing FGFR1–3 GAs will be enrolled. 
As of Protocol Version 5.0, this study comprises five open-label substudies (of which four are ongoing: see 
Figure 1): 
 
3.1. 
Substudy 1 
This substudy will enroll patients with mUC expressing FGFR1–3 GAs who have progressed on at least 
one standard chemotherapy and/or immune-checkpoint blockade and have not received prior FGFR 


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inhibiting treatment. Patients in this substudy are to receive  derazantinib 300mg QC monotherapy, with the 
primary objective of assessing efficacy of this treatment regimen in this patient population. Randomization 
is not required. 
Substudy 1 uses a Simon’s two-stage design. In Stage 1, 35 evaluable patients will be enrolled. The 
decision to transition from Stage 1 to 2 will use all data collected in stage 1 to inform the decision and the 
decision will be taken according to the principles laid out in the IDMC charter. If 7 or fewer patients with an 
objective response (defined as a CR or PR) are observed in Stage 1, the cohort will be stopped. If 8 or 
more patients with an objective response  are observed in these 35 patients, an additional 39 patients will 
be enrolled, for a total of 74 patients. The null hypothesis will be rejected if 22 or more responses are 
observed in these 74 patients. 
Substudy 2 
This substudy will enroll patients with any advanced solid tumor and any prior treatment (including FGFR 
inhibitor treatment), who have no standard treatment alternative. Patients in this substudy are to receive 
derazantinib-atezolizumab in combination, with the primary objective of identifying the appropriate 
recommended Phase 2 dose (RP2D) of the derazantinib-atezolizumab combination to be used in Cohort 
3b and Cohort 4b. Assignment to a specific dose level and cohort will be controlled by the IWRS system. 
This substudy is a safety run-in using a modified rolling-six design including up to 24 patients in two dose 
cohorts. If none or 1 of six patients in the dose-level 1 cohort (200 mg derazantinib QD plus 1,200 mg 
atezolizumab Q3W) experiences a DLT in Cycle 1, dose level 1 will be considered tolerable. The dose-level 
1 will then be expanded by additional 6 patients (expansion cohort for dose level 1) to further characterize 
the safety and tolerability profile. In addition, the dose-level 2 cohort (300 mg derazantinib QD plus 1,200 
mg atezolizumab Q3W) will start enrollment with an initial target sample size of 6 patients. If dose level 2 is 
considered tolerable, then dose level 2 will be expanded by additional 6 patients to further characterize the 
safety and tolerability profile of this dose level. The sample size may increase if there is a need to explore 
further intermediate dose levels. 
The RP2D will be declared based on observed AEs by a joint decision taken by the IDMC, Investigators, 
and the Sponsor. 
3.2. 
Substudy 3 
As of Protocol Version 5.0, this substudy has been modified. First-line cisplatin-ineligible patients with mUC 
expressing FGFR1–3 GAs are to be treated with derazantinib 200 mg BID and atezolizumab 1200 mg Q3W 
in combination, with the co-primary objectives of assessing the safety and efficacy of this regimen in this 
patient population. If derazantinib 200 mg BID at the SIA is not assessed as safe and tolerable, patients 
are to be treated with the RP2D determined in Substudy 2.Substudy 3 uses a Fleming’s two-stage design. 
A total sample size of 36 is required to test a null hypothesis of H₀: π ≤ 0.25 versus an alternative hypothesis 
of Hₐ: π ≥ 0.45, where π is the true proportion of successes. See Section 6.1.6.3 for details regarding the 
required sample size and required responses to either accept or reject H0.  
3.3. 
Substudy 4 
This substudy will enroll FGFR inhibitor-resistant patients with mUC expressing FGFR1–3 GAs. Patients in 
this substudy are to be randomized (1:1) into two non-comparative groups: Cohort 4a patients will receive 
derazantinib 300mg QC monotherapy, and Cohort 4b patients will receive derazantinib 300mg QC and 
atezolizumab 1200 mg Q3W in combination. The primary objective of this substudy is to assess the efficacy 


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of derazantinib monotherapy and derazantinib-atezolizumab in combination in this patient population. 
Randomization will be based on a computer-generated randomization schedule via IWRS and will be 
stratified for key prognostic factors. The presence of visceral metastasis, an ECOG PS of 2, or a preceding 
FGFR inhibitor treatment interval of less than 6 months (i.e., less than 24 full weeks) will be credited with 
one point, and patients will be stratified according to their composite score values of 0–1 versus 2–3 points. 
Substudy 4 uses a Simon’s two-stage design. In Stage 1, 16 evaluable patients will be enrolled for both 
cohorts. If 1 or fewer patients with an objective response are observed in these 16 patients, the cohort will 
be stopped. If 2 or more patients with an objective response are observed, an additional 34 patients will be 
enrolled for a total of 50 patients. The null hypothesis will be rejected if 7 or more responses are seen in 
these 50 patients. 
3.4. 
Substudy 5 
Patients with mUC expressing FGFR1–3 GAs who have progressed on at least one standard chemotherapy 
and/or immune-checkpoint blockade, and have not received prior FGFR inhibiting treatment. Patients in 
this substudy are to be treated with derazantinib 200 mg BID monotherapy. 
 
Substudy 5 uses a Fleming’s two-stage design. A total sample size of 26 is required to test a null hypothesis 
of H₀: π ≤ 0.1 versus an alternative hypothesis of Hₐ: π ≥ 0.3, where π is the true proportion of successes. 
See Section 6.1.6.5 for details regarding the required sample size and required responses to either accept 
or reject H0. 
 
3.5. 
Subject crossover 
Upon disease progression and at the Investigator’s discretion, patients randomized to  derazantinib 
monotherapy Cohort 4a may be offered to crossover to treatment with derazantinib-atezolizumab in 
combination. 
Patients from Cohorts 4a with PD (as assessed by BICR) will have the opportunity to receive treatment with 
derazantinib-atezolizumab in combination in a Crossover Phase. Crossover patients may initiate treatment 
with derazantinib-atezolizumab within 2 months of their last dose of derazantinib, regardless of the time of 
progression.  
Crossover is optional and is at the discretion of the Investigator (with the Sponsor’s and patient agreement). 
The precise eligibility criteria for study treatment crossover are outlined in the associated study protocol. 
 






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after the end of treatment may be performed by the patient’s local gynecologist to reduce the burden related to study visits at the site, but must be 
communicated to the study Investigator. 
11. Research liquid biopsies are requested from all patients enrolled in Substudies 1, 3, 4 and 5 at Screening and End of Treatment visits, and at the time point 
of the confirmatory CT scan (for complete response/partial response).  
12. Archival tumor tissue (FFPE block; or a minimum of two H&E-stained slides plus at least 10 consecutive, unstained, 4 ± 1 µm thick sections, placed on 
positively charged slides) should be collected at the SV from all enrolled patients for biomarker assessment (including PD-L1 testing). If archival tumor 
tissue is not available, de novo biopsy may be performed but only if considered by the Investigator as safe and tolerable for the patient. 
13. Tumor assessments performed as SoC prior to obtaining informed consent and within 28 days of the first dose of study treatment on C1D1 may be used 
rather than repeating tests. The first on-study tumor imaging assessments will be performed after 9 weeks on study, and will be repeated every 9 weeks (±7) 
from C1D1 (i.e., at C4D1, C7D1, C10D1) and every 12 weeks (±7) from C10D1 (i.e., at C14D1, C18D1, etc.) thereafter (with additional scans as clinically 
indicated and as per RECIST 1.1 criteria) until disease progression, death, or loss of follow-up. A tumor assessment should be performed at the End-of-
Treatment visit only if the prior scan was not done within 4 weeks (28 days) prior to this visit, or if the prior scan did not show radiographic disease 
progression. The same radiographic procedure as used at the SV must be used throughout the study for each patient to follow target lesions, and results 
must be reviewed by the Investigator before dosing at the next cycle. Imaging timing should be based on the first dose at C1D1, should follow calendar days, 
and should not be adjusted for delays in cycle starts. 
14. For pre-dose PK blood sampling at C1D15 (all substudies), and C1D8, C2D8 and C2D15 (safety interim analysis patients in Substudies 3 and 5), 
administer derazantinib at the study site.  
15. Derazantinib PK blood (plasma) sampling will be performed according to the following schedule:  
a. 
Rich PK profiling - Applicable to safety interim analysis patients in Substudy 3 and 5 only: 
 C1D1, prior to derazantinib dose, and 1 hour (± 5 minutes), 2hours (± 5 minutes), 4 hours (± 15 minutes), 8 hours (± 30 minutes), 10 hours 
(± 30 minutes), 12 hours (± 30 minutes; prior to the second dose administration), 24 hours after first derazantinib administration (i.e., 12 hours post 
second dose administration but within 1 hour prior to the third dose).  
 C1D8, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib administration. 
 C1D15, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib administration. 
 C2D1, prior to derazantinib (within 1 hour prior to the next dose), and 1 hour (± 5 minutes), 2 hours (± 5 minutes), 4 hours (± 15 minutes), 8 hours 
(± 30 minutes), 10 hours (± 30 minutes), 12 hours (± 30 minutes; prior to the second dose administration), 24 hours after derazantinib administration 
(i.e., 12-hour post previous dose administration but within 1 hour prior to the next dose).  
 C2D8, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib administration. 
 C2D15, pre-dose (within 1 hour prior to the next dose), and 6–8 hours after derazantinib administration 
 C3D1, prior to derazantinib (within 1 hour prior to the next dose), and 6–8 hours after derazantinib administration. 
 C4D1, prior to derazantinib administration (within 1 hour prior to the next dose). 
 28-day Safety Follow-up visit 
b. 
Sparse PK – Applicable to all patients (except safety interim analysis patients in Substudy 3 and 5; see rich PK sampling): 
 C1D1 and C1D15, prior to derazantinib (within 1 hour prior to next dose), and 6–8 hours after the study drug administration. 
 C2D1, prior to derazantinib (within 1 hour prior to next dose) 


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 C3D1, prior to derazantinib (within 1 hour prior to next dose), and 6–8 hours after the study drug administration. 
 C4D1, prior to derazantinib administration (within 1 hour prior to next dose) 
 28-day Safety Follow-up visit 
16. For all patients in Substudy 3 and Cohort 4b and Crossover, atezolizumab PK and ADA (serum) blood sampling will be performed according to the 
following schedule: 
 C1D1, prior to atezolizumab administration; and for PK only, 30 minutes after end of atezolizumab infusion  
 C2D1, C3D1, C4D1, prior to atezolizumab administration 
 C8D1, C12D1, C16D1, prior to atezolizumab administration 
 28-day Safety follow-up visit 
17. Non-serious and serious changes in or worsening of a patient’s condition that occur between any informed consent and first study-drug administration, as 
well as any AEs in conjunction with tumor/liquid biopsies or imaging studies, will be captured in the eCRF.  
18. AEs occurring between C1D1 and C1D21 in patients during the DLT observation period of Substudy 3 and 5 will be assessed against the DLT definitions 
prior to study drug administration on C2D1. DLTs are also to be recorded in the eCRF.  
19. PRO instruments should be self-administered at the study site before the patient sees the physician (i.e., at the start of the visit) and prior to the completion of 
other study assessments and the administration of study treatment.  
20. (Optional) PD assessments in Substudy 3, 4 or 5 (i.e., blood sampling and skin biopsy) to be performed at screening, and on C2D1. 
21. Survival contact can be in person, via phone, or, where applicable, by checking regional/national death registries.  
 


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5. Analysis Populations 
The following patient populations (i.e., analysis sets) will be evaluated and used for presentation of the 
data: 
5.1. 
Safety Population/ Intent-to-treat Population 
The safety/intent-to-treat (ITT) population consists of all patients with an eligible FGFR1–3 GA who received 
at least one dose of derazantinib or atezolizumab. Safety data will be summarized according to the 
treatment actually received. 
In the primary safety comparison, patients who crossover to derazantinib-atezolizumab combination are 
censored at time of crossover (i.e., AEs occurring during treatment with derazantinib-atezolizumab 
combination are excluded for Cohort 4a patients).  
5.2. 
Modified Intent-to-treat (mITT) Population 
For all efficacy endpoint analyses, a mITT population will be used, comprising all patients who received at 
least one dose of derazantinib or atezolizumab, and have at least one post-baseline imaging assessment 
in accordance with RECIST 1.1, or documented clinical progression (every effort should be made to 
objectively assess radiographic progression) or death. Non-evaluable patients will be replaced. 
5.3. 
Per-protocol (PP) Population 
The PP population will include all patients in the mITT population who have no major protocol deviations 
which are determined to potentially impact efficacy analyses during the study. Protocol deviations will be 
identified prior to final analysis. 
This analysis population will be used for secondary analysis of primary and secondary endpoints. 
5.4. 
Maximum-tolerated Dose (MTD) Population (Substudy 2 only) 
The MTD-determining population includes all patients enrolled in the MTD Part of each dose level who 
meet the following minimum criteria during the DLT period: 
 
received at least one dose of derazantinib and atezolizumab and has experienced a DLT;  
 
received ≥ 90% of the derazantinib and atezolizumab dose, respectively, in Cycle 1 and did not 
experience a DLT, have been observed for ≥ 21 days following the first dose, and have been evaluated 
for safety.  
In the event that Cycle 1 exceeds 21 days, the period for patient’s evaluability and DLT assessment will 
remain at 21 days. 
Patients who do not meet these minimum evaluation requirements will be regarded as ineligible for the 
MTD-determining population. These patients will be included in the safety/ITT population but will be 
excluded from the calculation of DLT incidence and will be replaced by recruitment of additional patients. 
Interim analyses for DLTs may be performed once at least five patients have been enrolled to a particular 
dose level, full DLT/safety data are available and a patient has not experienced a DLT, or when two DLTs 
have been observed in any number of patients enrolled in MTD Part of a particular dose level, whichever 
occurs first. Interim analyses are performed to determine if dose escalation is justified (or dose de-
escalation is required) and if derazantinib in combination with atezolizumab is safe and tolerable. 


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5.5. 
Pharmacokinetic (PK) analysis population 
The PK analysis population consists of all patients in the ITT population who have at least one PK sample 
result. Three sub-populations are defined, according to the analytes and sampling schedule: 
 
The Rich derazantinib PK profiling population (with PK parameter determination) consists of the patients 
enrolled in the rich sampling schedule (see Section 5.3.4.1.2 of the protocol) who receive at least 1 
dose of study drug and have at least one PK sample result. 
 
The Sparse derazantinib PK sampling population consists of the patients enrolled in the sparse 
sampling schedule (see Section 5.3.4.1.3 of the protocol) who receive at least 1 dose of study drug and 
have at least one PK sample result. 
 
The atezolizumab PK population (see Section 5.3.4.2 of the protocol) consists of all patients who 
receive at least 1 dose of atezolizumab and have at least one PK sample result. 


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6. Statistical Methodology 
6.1. 
Statistical and Analytical Issues 
6.1.1. Statistical Methods 
Tabulations will be produced for appropriate demographic, baseline, safety and efficacy parameters.  
Continuous variables will be summarized by reporting the number of observations, mean, standard 
deviation, median, first quartile (Q1), third quartile (Q3), minimum, and maximum. Categorical variables will 
be summarized using frequency tables showing the number and percentage of patients within a particular 
category, where the denominator is the number of patients within the category at applicable time point 
(unless otherwise specified). Time-to-event data will be summarized using the Kaplan-Meier method.  
By-patient data listings will be produced for data collected through the study (e.g., CRF, lab).  All data 
listings that contain an evaluation date will contain a relative study day (Study Day).  Pre-treatment and on-
treatment study days are numbered relative to the day of the first dose of study medication, which is 
designated as Day 1.  The preceding day is Day -1, the day before that is Day -2, etc. Baseline will be 
defined as the last evaluable/non-missing observation/assessment prior to the first dose of study drug on 
Cycle 1, Day 1. 
Statistical analyses will be carried out by using SAS Version 9.4 or higher. Any deviations from the planned 
analysis as described in the SAP will be justified and recorded in the clinical study report.  
Adverse events will be graded by the Investigator based on the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 5.0, and will be coded for summarization using 
the Medical Dictionary for Regulatory Activities (MedDRA® Version 22.0 or later). Concomitant medications 
will be coded using the World Health Organization (WHO) Drug Dictionary (March 2019 version or later). 
6.1.2. Dose Level, Substudy, and Cohort Assignment 
The definition of cohort and substudy in this study are detailed in Section 3. All analyses will be summarized 
by substudy and cohort (Substudies 1, 3, 4 and 5) or by dose level (Substudy 2) 
6.1.3. Visit Windows 
All data will be tabulated per the evaluation visit as recorded on the eCRF, even if the assessment is outside 
of the visit window. Unless otherwise stated in the analysis sections below, unscheduled visits will be 
included in data listings only.  
6.1.4. Handling of Dropouts and Missing Data 
Unless indicated otherwise, summary statistics will be reported for observed data only and missing data 
will not be imputed. Patients whose clinical response is unknown or not reported will be treated as non-
responders. 
6.1.5. Pooling of Investigative Sites 
As this is a Phase 1b/2 study, no by-site analyses are planned. 


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6.1.6. Determination of Sample Size 
Simon’s two-stage designs (Simon 1989) will be used for Substudies 1 and 4 and Fleming’s two-stage 
designs will be used for Substudies 3 and 5. At the time point of interim analysis and decision to transition 
from Stage 1 to 2, all data collected in Stage 1 patients will be used to inform the decision.  
Should the required number of events (i.e., responses) be reached prior to full enrollment to Stage 1, the 
time point for decision to transition from Stage 1 to Stage 2 may be taken before the stage is fully enrolled.  
If the required number of events (i.e., responses) is not reached at the time of full enrollment to Stage 1, 
further enrollment may be suspended to allow for all patients to be exposed to derazantinib or derazantinib-
atezolizumab in combination for at least 3 months or until disease progression. 
The use of such designs will limit the number of overall exposed patients to a maximum of approximately 
98, should either derazantinib or derazantinib-atezolizumab in combination be ineffective in Stage 1 of all 
efficacy-estimating substudies, as compared to a maximum of approximately 246 patients if derazantinib 
or derazantinib-atezolizumab are considered to be effective in all cohorts.  
Assuming an overall incidence of approximately 20% qualifying FGFR1–3 GAs (Helsten 2016), up to 
approximately 680 patients will be screened for FGFR1–3 GAs, depending on the extent of preexisting 
molecular testing. Assuming that pre-treatment with an FGFR inhibitor was based on a known FGFR GA 
status, no repeated testing is anticipated for the approximately 100 patients enrolled in Substudy 4. 
6.1.6.1. 
Substudy 1 
The null hypothesis that the true ORR is p0 ≤ 0.21 will be tested against a one-sided alternative. In Stage 
1, 35 evaluable patients will be enrolled. If 7 or fewer patients with an objective response are observed in 
Stage 1, the cohort will be stopped. If 8 or more patients with an objective response (defined as a CR or 
PR) are observed in these 35 patients, an additional 39 patients will be enrolled, for a total of 74 patients. 
The null hypothesis will be rejected if 22 or more responses are observed in these 74 patients. The one-
sided Type I error rate is 0.0463, and the power is 0.8001 when the true ORR is p1 = 0.34 and higher than 
the ORR of 32.2%, the highest reported value for an FGFR inhibiting treatment in mUC patients (Balversa 
USPI).  
The ORR of 21% for the null hypothesis reflects the lower range of ORR seen in recent clinical studies of 
UC patients with FGFR Gas inhibitors (Loriot 2019, Necchi 2018, Pal 2018). 
6.1.6.2. 
Substudy 2 
This is a safety run-in using a modified rolling-six design including up to 24 patients in two dose cohorts. If 
none or 1 of six patients in the dose-level 1 cohort (200 mg derazantinib QD plus 1,200 mg atezolizumab 
Q3W) experiences a DLT in Cycle 1, dose level 1 will be considered tolerable. The dose-level 1 will then 
be expanded by additional 6 patients (expansion cohort for dose level 1) to further characterize the safety 
and tolerability profile. In addition, the dose-level 2 cohort (300 mg derazantinib QD plus 1,200 mg 
atezolizumab Q3W) will start enrollment with an initial target sample size of 6 patients. If dose level 2 is 
considered tolerable, then dose level 2 will be expanded by additional 6 patients to further characterize the 
safety and tolerability profile of this dose level. The sample size may increase if there is a need to explore 
further intermediate dose levels. 
The RP2D will be determined by a joint decision taken by the IDMC, Investigators, and the Sponsor in 
reviewing the aggregate of DLT and AE data, and considering efficacy data. 


Statistical Analysis Plan for Phase I/II Oncology 
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6.1.6.3. 
Substudy 3 
The Fleming’s two-stage design sample size calculation is based on the assumption that first-line cisplatin-
ineligible patients with advanced or metastatic mUC expressing FGFR1–3 GAs treated with 200 mg BID 
derazantinib in combination with 1200 mg atezolizumab Q3W will attain a clinically meaningful ORR of 
approximately 45%, which is similar to that obtained with erdafitinib and cetrelimab (Moreno 2020), or 
rogaratinib and atezolizumab (Rosenberg 2020), in combination for this patient population, and is 
considered the benchmark by oncology experts. An ORR of 25% (estimated mean ORR with immune 
checkpoint-inhibiting monotherapy available for cisplatin-ineligible patients) is not considered sufficiently 
effective to warrant further clinical investigation. Using a Fleming’s two-stage design, a total sample size of 
36 is required to test a null hypothesis of H₀: π ≤ 0.25 versus an alternative hypothesis of Hₐ: π ≥ 0.45 with 
a one-sided target significance level of 0.05 and target power of 80%, where π is the true proportion of 
successes. This design results in an exact type 1 error rate of 0.046, an exact level of power of 81%, and 
an average sample size of 27 patients under H₀ and 31 under H₁. 
Table 2 summarizes the required samples sizes and required responses to either accept or reject H0. 
Table 2: Sample size and required responses of proposed two-stage Fleming design (Substudy 3) 
 
Sample size
Responders to accept H0
Responders to reject H0
 
N 
n 
% 
n 
% 
Stage 1 
18 
4 
22.2 
10 
55.6 
Stage 2 
36 
13 
36.1 
14 
38.9 
 
6.1.6.4. 
Substudy 4, Cohorts 4a and 4b 
For both cohorts within Substudy 4, the null hypothesis that the true ORR is p0 ≤ 0.07 will be tested against 
a one-sided alternative. In Stage 1 of each cohort, 16 evaluable patients will be enrolled. If 1 or fewer 
patients with an objective response are observed in these 16 patients, the cohort will be stopped. If 2 or 
more patients with an objective response are observed, an additional 34 patients will be enrolled for a total 
of 50. The null hypothesis will be rejected if seven or more responses are seen in these 50 patients. Type I 
error rate is 0.0448 and power is 0.8027 when true ORR is p1 = 0.20. 
The ORR of 7% for the null hypothesis reflects the ORR reported based on literature of retrospective data 
and/or small cohorts of uncontrolled studies (Di Lorenzo 2015, Soga 2010) for FGFR1–3 GA expressing 
UC patients treated with third or fourth-line single-agent chemotherapy with prior progression following 
platinum-containing chemotherapy, immune-checkpoint blockade and/or FGFR inhibitor treatment. 
 
6.1.6.5. 
Substudy 5 
The Fleming’s two-stage design sample size calculation is based on the assumption that patients with mUC 
expressing FGFR1–3 GAs, after failure of prior platinum- or immune checkpoint- inhibitor-containing 
treatment, treated with 200 mg BID derazantinib will attain a clinically meaningful ORR of approximately 
30%. This is similar to that obtained with erdafitinib for this patient population, and considered the 
benchmark by oncology experts. An ORR of 10% is not considered sufficiently effective to warrant further 
clinical investigation. 
Using a two-stage Fleming design, a total sample size of 26 is required to test a null hypothesis of H₀: π ≤ 
0.1 versus an alternative hypothesis of Hₐ: π ≥ 0.3 with a one-sided target significance level of 0.05 and 


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target power of 80%, where π is the true proportion of successes. This design results in an exact type 1 
error rate of 0.039, an exact level of power of 81.9%, an average sample number of 18 patients under H₀ 
and of 21 under H₁. Table 3 summarizes the required samples sizes and required responses to either 
accept or reject H0. 
Table 3: Sample size and required responses of proposed two-stage Fleming design (Substudy 5) 
 
Sample size
Responders to accept H0
Responders to reject H0
 
N 
n 
% 
n 
% 
Stage 1 
13 
1 
7.7 
5 
38.5 
Stage 2 
26 
5 
19.2 
6 
23.1 
 
6.2. 
Patient Characteristics 
6.2.1. Patient Disposition 
Patient disposition will be presented by substudy and cohort. In substudy 2 disposition will be presented by 
dose level. Tabulation will include the following: 
 
Number of patients screened 
 
Number (%) of patients dosed 
 
Number (%) in each patient population for analysis (including frequency of reasons excluded from PP 
population; distribution of major protocol deviations) 
 
Number (%) of patients who discontinued and reason(s) for discontinuation  
 
Number (%) of patients who completed the safety follow-up period (28 day and 90 day) and reasons 
for discontinuation 
 
Number (%) of patients who completed the survival follow-up period and reasons for discontinuation 
 
Treatment Phase and Study Duration 
 
Patients excluded from the various analysis populations will be listed by substudy, cohort and dose level.  
Patients who discontinue will be listed by substudy, cohort and dose level with reason for discontinuation. 
The number of patients by geographical region, country and site will be tabulated. 
6.2.2. Protocol Deviations 
Protocol deviations will be identified and categorized using the process outlined in the protocol deviation 
and non-compliance management plan. Review of protocol deviations for potential exclusion from analysis 
populations occurs at the monthly internal review meeting. The final decision will be made at the data review 
meeting with Basilea providing the final review and approval. 
Major protocol deviations which are determined to potentially impact efficacy analyses will result in the 
removal of a patient from the PP population. For DZB-CS-201, the classification and categorization of 
protocol deviations per sponsor’s definition are outlined in the Protocol Deviations Grading and 
Categorization Guidelines (Appendix 2 of the Protocol Deviation and Non-Compliance Management Plan) 
which is maintained in the collaborative workspace. The decision on which major protocol deviations 
warrant exclusion from the PP population will be determined prior to final analysis. Other 
deviations/scenarios may arise during the pre-lock data review that will be documented and reported.  


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Protocol deviations will be summarized for the safety/ITT population. The number and percentage of 
patients with a major deviation by type of deviation category will be presented by substudy and cohort 
(Substudies 1, 3,4 and 5) or by dose level (Substudy 2). In addition, all protocol deviations will be provided 
in a by-patient listing.  
6.2.3. Background and Demographic Characteristics 
Background and demographic characteristics will be summarized for the safety/ITT, mITT and PP 
populations. The following variables will be listed and summarized using both continuous and categorical 
descriptive statistics: 
 
Age 
 
Sex 
 
Ethnicity 
 
Race 
 
Height (cm) 
 
Weight (kg) 
 
BMI (kg/m2) – calculated as weight (kg)/height (m)2 
 
Child bearing potential 
 
Surgically Sterilized Status 
 
Menopausal Status 
 
ECOG at baseline 
 
6.2.4. Smoking History 
Smoking history data will be listed.  
 
6.2.5. Tumor Molecular Status 
For substudies 1, 3, 4 and 5, liquid and tissue tumor molecular status will be presented by substudy and 
cohort. For substudy 2, liquid and tissue tumor molecular status will be presented overall and by dose level. 
Tumor molecular status will be summarized for the safety/ITT population. The following variables will be 
summarized as categorical variables: 
 
Sample type (liquid/tissue) 
 
FGFR1 Status 
 
FGFR1 Gene Aberration Type 
 
FGFR2 Status 
 
FGFR2 Gene Aberration Type 
 
FGFR3 Status 
 
FGFR3 Gene Aberration Type 
 
Other FGFR 
 
Tissue PD-L1 Result 
 
Tissue PD-L1 Positive Result Category 


Statistical Analysis Plan for Phase I/II Oncology 
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 
Expression results/range 
 
Score/cell type 
 
6.2.6. Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and concomitant procedures will be summarized for the safety/ITT 
population.  
Study drug will be considered as any dose of either derazantinib or atezolizumab. The first dose date will 
be the first dose either derazantinib or atezolizumab was received and the last dose date will be last dose 
either derazantinib or atezolizumab was administered.  
Prior medication will be defined as any medication taken and stopped prior to the first dose of study drug. 
Concomitant medication is defined as any medication ongoing at time of first dose of study drug or taken 
after the first dose of study drug. A concomitant procedure is defined as any procedure ongoing at time of 
first dose of study drug or occurring after the first dose of study drug.  
Medications or procedures missing both start and stop dates, or having a start date prior to the first dose 
of study drug and missing the stop date, or having a stop date on or after the last dose of study drug and 
missing start date will be counted as concomitant. 
For partial dates, the following approach will be taken: 
 
If the start day is missing but the start month and year are complete, a medication or procedure will be 
excluded as being concomitant only if the start month/year is before the month/year of study drug 
administration and if the stop date (either full date, month and year if missing day, or year if missing 
month and day) is before study drug administration. 
 
If the start day and month are missing but the start year is complete, a medication or procedure will be 
excluded as concomitant only if the start year is before the year of study drug administration and if the 
stop date (either: full date, month and year if missing day, or year if missing month and day) is before 
study drug administration.  
 
Prior and concomitant medications will be coded using the WHO Drug Dictionary (WHODRUG Global B3 
Mar2019), and patient incidence will be tabulated by Anatomic Therapeutic Class (ATC) level 4 and 
preferred term (PT). Patients will be counted only once for each ATC or PT in the event that they have 
multiple records of the same ATC or PT in the database.  
Concomitant procedures will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 
22.0 or above and will be summarized by system organ class (SOC) and PT. Patients will be counted only 
once for each SOC or PT in the event that they have multiple records of the same SOC or PT in the 
database. 
All prior and concomitant medications and procedures will be included in by-patient data listings. 


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6.2.7. Medical History (Non-Cancer Related) 
Medical history will be summarized for the safety/ITT population. Medical history data will be summarized 
by SOC and PT per Medical Dictionary for Regulatory Activities (MedDRA) version 22.0 or above. Patients 
will be counted only once for each SOC or PT in the event that they have multiple records of the same SOC 
or PT in the database. All medical history data will be listed. 
6.2.8. Cancer-Related Medical History 
Cancer-related medical history will be summarized for the safety/ITT population. Descriptive statistics on 
cancer-related medical history characteristics will be presented for the following: 
 
Number of prior regimens of anti-cancer therapies related to study indication, and time since last anti-
cancer related therapy calculated as date of first dose of study treatment – stop date of last anti-cancer 
related therapy. For each prior regimen of anti-cancer therapies (as well as last regimen), the following 
will be summarized: treatment setting, medication received, best treatment response, duration of 
response, time to progression, type of progression and reason therapy ended.  
 
Prior anti-cancer surgeries related to study indication. Anatomical location, Type of procedure, reason 
for procedure, presence of residual disease and time since last surgery will be summarized. 
 
Prior anti-cancer radiotherapy related to study indication. Anatomical location, total dose and time since 
last radiotherapy will be summarized. 
 
Time since first cancer diagnosis and time since most recent progression, calculated as the date of first 
dose of study treatment minus date of first diagnosis. If only month and year are provided, the day=15 
will be assumed.  If only year is provided, month=6 and day=30 will be assumed. 
 
Presence of Primary Tumor at Screening 
 
Tumor histology/Cytology at diagnosis/screening  
 
Anatomical location at diagnosis/screening 
 
Stage Classification at diagnosis/screening 
 
Histopathological Grade at diagnosis/screening 
 
TNM Staging at diagnosis/screening 
 
Metastatic location at diagnosis/screening 
 
Distant Metastasis at diagnosis/screening 
 
The above will also be presented in data listings by substudy and patient. 
6.2.9. Treatment Exposure and Compliance 
Treatment exposure and compliance will be presented using the safety/ITT population. 
Exposure to derazantinib and atezolizumab will be presented cumulatively. The number of cycles received 
and duration of treatment will be summarized using continuous statistics. The number of subjects with a 
dose reduction/interruption will be summarized as a categorical variable, including a summary of the 
reduced dose level achieved and the reasons for dose reduction/interruption. In addition, the total 
cumulative dose (mg) received will be summarized.  


Statistical Analysis Plan for Phase I/II Oncology 
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Dose intensity (%) will be summarised, defined as the percentage of the study drug a patient has taken 
compared to the amount of study drug the patient was originally planned to take at the time of their treatment 
allocation.  
 
% 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦=
௧௢௧௔௟ ௖௨௠௨௟௔௧௜௩௘ ௗ௢௦௘ ௥௘௖௘௜௩௘ௗ (௠௚)
௧௢௧௔௟ ௖௨௠௨௟௔௧௜௩௘ ௗ௢௦௘ ௣௟௔௡௡௘ௗ (௠௚) × 100 
 
Derazantinib treatment compliance will be presented for each cycle and overall.  Compliance will be 
calculated by counting unused capsules: 
 
% 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒=
# ௢௙ ௖௔௣௦௨௟௘௦ ௗ௜௦௣௘௡௦௘ௗ ି # ௢௙ ௖௔௣௦௨௟௘௦ ௥௘௧௨௥௡௘ௗ
# ௢௙ ௖௔௣௦௨௟௘௦ ௣௥௘௦௖௥௜௕௘ௗ / ௗ௔௬ × # ௢௙ ௗ௔௬௦ ௜௡ ௧௛௘ ௗ௢௦௜௡௚ ௜௡௧௘௥௩௔௟× 100 
 
Compliance will also be summarized categorically, considering cut-offs of 80% and 120% for compliance. 
Day 1 for each cycle will be identified using the Visit eCRF.  The number of capsules prescribed per day 
will be 3 (except for substudy 2 dose level 1 where 2 capsules are planned) or as determined per the dose 
reduction guidelines for toxicity considered related to derazantinib and specified in the eCRF. Number of 
days during a dosing interval will be the number of dosing days in a cycle excluding any days that the 
patient was instructed to hold dosing due to an AE. The periods with missed dose for any other reason are 
not excluded when calculating compliance. Patients with discontinuation dates that fall within cycles will 
have their expected days adjusted in the compliance calculation for that cycle.  For example, if a patient 
discontinues within Week 2 of Cycle 1, the number of days in the dosing interval will be calculated based 
of the date of the last dose within Week 2. 
The total volume and total dose of atezolizumab administered will be presented cumulatively. The number 
of doses where atezolizumab is administered will be summarized using continuous descriptive statistics.  
Treatment compliance will be presented for each dose administered. Compliance will be determined by the 
total dose of atezolizumab received divided by the total planned dose. 
6.3. 
Efficacy Analysis 
All efficacy endpoints will be summarized by substudy and cohort. P-values and 95% CIs will be provided 
where appropriate. Comparisons between cohorts of substudy 4 will be performed using descriptive 
statistics and for the purposes of hypothesis generation only. 
All efficacy analyses will be conducted using the mITT population. To evaluate sensitivity, the primary 
efficacy analyses (i.e. Section 6.3.1), will also be conducted using the PP population.   
Assessments by Blinded Independent Central Review (BICR) consider two readers. Should there be 
disagreement between these two readers, an adjudicator decides which reader is correct. As such, all 
analyses which consider BICR assessments will be based upon the first reader by default, unless the 
second reader is selected following adjudication.  
Per protocol inclusion criteria, only patients with measurable disease by RECIST version 1.1 criteria should 
be enrolled. If a patient without measurable disease is enrolled, the ITT principle requires including these 
patients in the analyses. Hence, analyses will be based on patients with either measurable or non-


Statistical Analysis Plan for Phase I/II Oncology 
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measurable disease. For this purpose, non-CR/non-PD in patients with non-measurable disease will be 
considered equivalent to SD in patients with measurable disease, and the same rules will be applied. 
Waterfall plots, spider plots and swimmer plots will be produced to accompany efficacy analyses. 
6.3.1. Primary Efficacy Analysis 
6.3.1.1. 
Objective Response Rate 
The primary efficacy endpoint in all substudies will be objective response rate (ORR), defined as the 
achievement of confirmed CR or PR using RECIST 1.1 (Eisenhauer 2009) as assessed by BICR. Point 
estimates and exact 2-sided 95% CIs will be provided. 
Classification of best confirmed response is done according to the following hierarchy and rules: 
1. Complete Response (CR): requires two consecutive CR response assessments a minimum of four 
weeks apart 
2. Partial Response (PR): requires two consecutive PR response assessments OR a PR response 
immediately followed by a CR response assessment (a minimum of four weeks apart) 
3. Stable Disease (SD): requires only one SD response assessment (provided minimum criteria for SD 
duration met) 
4. Non-CR/Non-PD (non-measurable disease patients only): requires only one Non-CR/Non-PD response 
assessment (provided minimum criteria for Non-CR/Non-PD duration met) 
5. Progressive Disease (PD): requires only one PD response assessment 
 
The minimum duration for SD and Non-CR/Non-PD is defined as 6 weeks, where the duration is calculated 
from the start of treatment until the criteria of SD is met. 
The classification as per RECIST 1.1 (Eisenhauer 2009) is summarized in Table 4. 




Statistical Analysis Plan for Phase I/II Oncology 
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the first 18 patients). Posterior estimates of the probability that the response rate exceeds 0.25 will also be 
calculated assuming a non-informative prior distribution. A prior distribution Beta(1,1) will be used as a 
vague, non-informative prior, giving a uniform distribution with mean of 0.5 response rate with wide 
uncertainty. This will be multiplied by a likelihood with distribution Beta(a,b) where a is the number of 
responses and b is the number of non-responses, to obtain the posterior distribution from which the 
probability that the response rate exceeds 0.25 will be estimated. This analysis will only consider BICR 
assessed response within the mITT population. 
Substudy 4 
H0: p ≤ 0.07 versus HA: p≥0.20 
If there are one or zero patients with an objective response (defined as a confirmed CR or PR) in the first 
16 evaluable patients included in the interim analysis in each of Cohort 4a and 4b, the cohort will be 
stopped. If not, an additional 34 patients will be enrolled, for a total of 50 evaluable patients. The null 
hypothesis will be rejected if 7 or more objective responses are observed in these 50 patients. 
Comparisons between cohorts will be descriptively summarized by reporting the difference in point 
estimates between cohorts, with a 2-sided exact 95% CI for the difference and a p-value from a Fisher 
exact test. 
Substudy 5 
H0: p ≤ 0.10 versus HA: p≥0.30 
If there is one or fewer patient with a response (defined as a CR or PR) in the first 13 evaluable patients 
included in the interim analysis, the cohort will be stopped. If not, an additional 13 patients will be enrolled, 
for a total of 26 evaluable patients. The null hypothesis will be rejected if six or more responses are observed 
in these 26 patients (or if five or more responses are observed in the first 13 patients). Posterior estimates 
of the probability that the response rate exceeds 0.1 will also be calculated assuming a non-informative 
prior distribution. This analysis will only consider BICR assessed response within the mITT population. 
6.3.2. Secondary Efficacy Variable(s) 
6.3.2.1. 
Disease Control Rate (All Substudies) 
Disease Control Rate (DCR) is defined as the proportion of patients achieving a confirmed CR or PR or 
stable disease (SD) (or Non-CR/Non-PD for patients with non-measurable disease) using RECIST 1.1 as 
assessed by BICR. Point estimates and exact 2-sided 95% CIs will be provided. Comparisons between 
cohorts of substudy 4 will be descriptively summarized by reporting the difference in point estimates 
between cohorts, with a 2-sided exact 95% CI for the difference and a p-value from a Fisher exact test. 
6.3.2.2. 
Duration of Response (All Substudies) 
Duration of Response (DOR) will be calculated from the first date of documented objective tumor response 
(confirmed CR or PR) to the date of disease progression as assessed by BICR or death. If a patient is 
discontinued or lost to follow-up with no documentation of PD, DOR is defined as the time from the date of 
first documented objective tumor response to the date of last tumor assessment as a censored value. PD 
or death post end of treatment will be censored at date of last tumor assessment as a censored value. 


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DoR will be derived only for patients who have the best overall response of CR or PR. 
DOR will be analyzed using Kaplan-Meier methodology (Kaplan & Meier 1958). The median DOR will be 
presented along with the standard error and 2-sided 95% CI. If they are calculable, the 25th and 75th 
percentiles and the 2-sided 95% CIs around the percentiles will be presented. Kaplan-Meier estimates at 
3, 6, 9 and 12 months will also be presented. The Kaplan-Meier survival curves will also be presented. For 
substudy 4 only comparisons between cohorts will be made by considering a hazard ratio, with associated 
2-sided 95% confidence interval and p-value, from an unadjusted Cox proportional hazards model. 
These analyses will be performed per cohort in substudies 1, 3, 4 and 5 and by dose level in substudy 2. 
The date of first dose, documented objective tumor response, disease progression, death, last tumor 
assessment, last contact and DOR days will be reported in a by-patient listing. 
6.3.2.3. 
Progression-Free Survival (All Substudies) 
Progression-Free Survival (PFS) will be calculated as the time from cohort assignment by IWRS until 
disease progression as assessed by BICR, or death from any cause, whichever comes first. Patients who 
either have no baseline tumor evaluation or have no post- baseline tumor evaluation will be censored at 
date of cohort assignment by IWRS. Patients without disease progression will be censored at the date of 
their last tumor evaluation. Patients who discontinue treatment due to reasons other than disease 
progression by BICR or death will be censored in the PFS analyses as the date of their last tumor evaluation 
prior to EOT. Patients who progress or die after missing ≥2 consecutive scheduled tumor assessments will 
be censored at the date of the last tumor evaluation prior to progression or death. Any deaths occurring 
after end of treatment are not taken into account as a PFS event. Patients who stopped treatment without 
PD will be censored at their last scan prior to end of treatment. For patients with missing end of treatment 
visit date, a +7 day window compared to the maximum of last dose date, last on treatment visit date will be 
applied to create a tentative end of treatment visit date and a cut-off for death occurring after this date. The 
rules for censoring PFS are summarized in the table below: 
Table 5: Censoring scheme for PFS 
Situation
Date of progression or censoring
Outcome
No baseline or post-baseline tumor 
assessments  
Randomization / Cohort assignment 
Censored 
Progression documented between 
scheduled visits 
Date of radiological assessment of 
measured lesions  
Progressed 
No progression 
Date of last radiological assessment 
of measured lesions  
Censored 
Treatment discontinuation for 
reasons other than disease 
progression by BICR or death 
Date of last radiological assessment 
of measured lesions  
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate 
assessment visits  
Date of death 
Progressed 
Death or progression after more 
than one missed tumor assessment 
or after end of treatment  
 
Date of last radiological assessment 
of measured lesions prior to 
progression or death 
Censored 
 


Statistical Analysis Plan for Phase I/II Oncology 
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Additional sensitivity analyses will be conducted which consider alternative censoring methods as outlined 
in FDA guidelines (FDA 2018, FDA 2015).  
A first sensitivity analysis will consider the same analysis as outlined in Table 5, but also considering clinical 
progression as an event (either clinical or radiographic progression will be considered as an event, rather 
than just radiographic).  
A second sensitivity analysis will include all post end of treatment assessments, such that subjects who die 
or progress after end of treatment will be considered as an event, with censoring at the earliest of last scan 
performed / new anti-cancer treatment. The censoring scheme for this analysis is outlined in Table 6. 
Table 6: Censoring scheme for PFS - sensitivity analysis 2 
Situation
Date of progression or censoring
Outcome
No baseline or post-baseline tumor 
assessments  
Randomization / Cohort assignment 
Censored 
Progression documented between 
scheduled visits 
Date of radiological assessment of 
measured lesions  
Progressed 
No progression 
Date of last scan performed / new 
anti-cancer treatment  
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate 
assessment visits  
Date of death 
Progressed 
Death or progression after more 
than one missed tumor assessment 
or after end of treatment  
 
Date of death or progression 
Progressed 
A third sensitivity analysis (Table 7) uses a conservative approach by assigning the date of 
discontinuation, or missed visit as an event date. 
Table 7: Censoring scheme for PFS - sensitivity analysis 3 
Situation
Date of progression or censoring
Outcome
No baseline or post-baseline tumor 
assessments  
Randomization / Cohort assignment 
Censored 
Progression documented between 
scheduled visits 
Date of radiological assessment of 
measured lesions  
Progressed 
No progression, treatment ongoing 
Date of last radiological assessment 
of measured lesions  
Censored 
Treatment discontinuation for 
reasons other than disease 
progression by BICR or death 
Date of discontinuation  
Progressed 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate 
assessment visits  
Date of death 
Progressed 
Death or progression after more 
than one missed tumor assessment 
or after end of treatment  
 
Date of first missed visit 
Progressed 
 
PFS will be analyzed using Kaplan-Meier methodology (Kaplan & Meier 1958). The median duration of PFS 
will be presented along with the 2-sided 95% CI.  If they are calculable, the 25th and 75th percentiles and 


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the 2-sided 95% CIs around the percentiles will be presented. Kaplan-Meier estimates at 3, 6, 9 and 12 
months will also be presented. The Kaplan-Meier survival curves will also be presented. For substudy 4 
comparison between cohorts will be made by considering a hazard ratio, with associated 2-sided 95% 
confidence interval and p-value, from an unadjusted Cox proportional hazards model.  
The date of cohort assignment by IWRS, first dose, disease progression, death, last tumor assessment and 
PFS days will be reported in a by-patient listing. 
6.3.2.4. 
Overall Survival (All Substudies) 
Overall Survival (OS) will be calculated from the date of cohort assignment by IWRS until death from any 
cause. Any patient without a date of death in the database at the time the survival analyses are performed 
will be censored at the time of their last study contact. Crossover patients (Cohort 4a) will be censored at 
the time of crossover in the primary analysis of OS.  
OS will be analyzed using Kaplan-Meier methodology (Kaplan & Meier 1958). The median duration of OS 
will be presented along with the standard error and 2-sided 95% CI.  If they are calculable, the 25th and 
75th percentiles and the 2-sided 95% CIs around the percentiles will be presented. Kaplan-Meier estimates 
at 3, 6, 9 and 12 months will also be presented. The Kaplan-Meier survival curves will also be presented. 
For substudy 4 comparisons between cohorts will be made by considering a hazard ratio, with associated 
2-sided 95% confidence interval and p-value, from an unadjusted Cox proportional hazards model. 
These analyses will be performed per cohort in substudies 1, 3, 4 and 5 and by dose level in substudy 2. 
The date of cohort assignment by IWRS, first dose, death, last study contact and OS days will be reported 
in a by-patient listing. 
6.3.3. Exploratory Analysis 
6.3.3.1. 
Time to progression 
TTP will be calculated based on BICR assessment review from the first date of receiving study drug until 
radiographic disease progression.  
The rules for censoring TTP are similar to PFS censoring. These are summarized in the table below: 
Table 8: Censoring Scheme for TTP 
Situation
Date of progression or censoring
Outcome
No baseline or post-baseline tumor 
assessments  
Randomization / Cohort assignment 
Censored 
Progression documented between 
scheduled visits 
Date of radiological assessment of measured 
lesions  
Progressed 
No progression 
Date of last radiological assessment of measured 
lesions  
Censored 
Treatment discontinuation for reasons 
other than disease progression by 
BICR  
Date of last radiological assessment of measured 
lesions  
Censored 
 
TTP will be analyzed using Kaplan-Meier methodology (Kaplan & Meier 1958). The median duration of TTP 
will be presented along with 2-sided 95% CI.  If they are calculable, the 25th and 75th percentiles and the 2-
sided 95% CIs around the percentiles will be presented. Kaplan-Meier estimates at 3, 6, 9 and 12 months 
will also be presented. The Kaplan-Meier survival curves will also be presented. For substudy 4 comparison 


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between cohorts will be made by considering a hazard ratio, with associated 2-sided 95% confidence 
interval and p-value, from an unadjusted Cox proportional hazards model.  
6.3.3.2. 
Subgroup Analyses 
Subgroup analyses (consisting of separate analyses within each subgroup) will be undertaken for all 
efficacy endpoints considering the following subgroups: 
 
FGFR1-3 mutation 
 
Other gene aberration types 
 
Upper tract urothelial cancer 
 
Lower tract urothelial cancer 
 
Stratification factor composite score (0-1 points) – substudy 4 only  
 
Stratification factor composite score (2-3 points) – substudy 4 only 
 
Stratification factor: Visceral metastasis – substudy 4 only 
 
Stratification factor: ECOG PS ≥2 – substudy 4 only 
 
Stratification factor: FGFR inhibitor internal of less than 6 months – substudy 4 only 
 
6.3.3.3. 
iRECIST (Substudies 3 and 4) 
Analyses of ORR, DCR, DOR and PFS will be repeated as outlined above evaluated by BICR using 
iRECIST criteria (Seymour 2017).  
6.3.3.4. 
Crossover patients (Substudy 4) 
There will be no specific analysis for crossover patients, due to low sample size. Crossover patients will not 
be included in summary tables/figures and their data will be listed only. 
6.3.3.5. 
Investigator assessed response 
In the primary analysis, tumor response will be based upon measurements evaluation by the BICR. 
However, an initial assessment of tumor response will be made by investigators at site. As an exploratory 
measure, analyses of BOR, DCR, DOR, PFS will be conducted considering investigator assessment  only. 
6.4. 
Safety Analysis (All substudies) 
All safety analyses will be performed using the safety/ITT population, apart from in the analysis of DLTs in 
substudy 2 which will be performed using the MTD population (see Section 5.4). Analyses will be presented 
by substudy and cohort. 
6.4.1. Adverse Events 
Adverse events will be graded according to the NCI CTCAE Version 5.0, coded using the MedDRA coding 
system (version 22.0 or later), and displayed in tables and data listings by system organ class (SOC) and 
preferred term (PT). Dose-limiting toxicities (DLTs) are applicable to substudy 2, substudy 3 and substudy 
5 only and are classified as the occurrence of any toxicity during Cycle 1 if judged by the investigator to be 
possibly or probably related to study drug administration from a pre-specified list in the protocol version 5 
for substudies 3 and 5, and protocol version 4 for substudy 2. 


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Analyses of AEs will be performed for those events that are considered treatment-emergent, where 
treatment-emergent is defined as any condition that was not present prior to treatment with study 
medication but appeared following treatment, was present at treatment initiation but worsened during 
treatment, or was present at treatment initiation but resolved and then reappeared while the individual was 
on treatment (regardless of the intensity of the AE when the treatment was initiated). A condition present 
at baseline that worsens after initiation of study treatment will be captured as an AE with the onset date as 
the date the event worsened. AEs will be reported (considered treatment-emergent) up to the end of the 
safety follow-up period. 
Adverse events are summarized by patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given SOC or PT (i.e., the most related occurrence or the most 
intense occurrence). Missing relationship will be considered related to study drug. 
An overall AE incidence summary table will be produced and will include: 
 
The number and percentage of patients reporting at least 1 treatment-emergent AE (TEAE) 
 
The number and percentage of patients reporting at least 1 serious TEAE (SAE) 
 
The number and percentage of patients reporting at least 1 related TEAE 
 
The number and percentage of patients reporting at least 1 related serious TEAE (SAE) 
 
The number and percentage of patients reporting at least 1 AE of Special Interest (AESI) 
 
The number and percentage of patients reporting at least 1 serious AESI 
 
The number and percentage of patients reporting at least 1 TEAE with toxicity grade of 3 or higher 
 
The number and percentage of patients reporting at least 1 related TEAE with toxicity grade of 3 or 
higher 
 
The number and percentage of patients reporting at least 1 TEAE classified as a DLT (Substudy 2, 3 
and 5) 
 
The number and percentage of patients reporting a TEAE leading to a dose modification/interruption 
 
The number and percentage of patients reporting a TEAE leading to permanent discontinuation of study 
drug 
 
The number and percentage of patients with a TEAE leading to death 
 
The overall AE incidence summary table described above will also include the number of events reported. 
For all event types listed above in the overall AE incidence summary table, tabulations by SOC and PT will 
also be produced. Related TEAEs with toxicity grade of 3 or higher will also be summarised. These will be 
presented by SOC and PT, sorted by decreasing frequency. 
No formal hypothesis-testing analysis of AE incidence rates will be performed.  All AEs occurring on-study 
will be provided in data listings. By-patient listings also will be provided for the following: SAEs, DLTs 
(Substudy 2, 3 and 5), AEs leading to permanent discontinuation of study drug, and AEs leading to death. 


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6.4.2. BLRM analyses for Dose-limiting toxicity (Substudies 3 and 5 only) 
Safety interim analyses will be performed once 10 patients have been enrolled and full safety data are 
available to determine if the revised dosing regimen of 200 mg BID derazantinib either as monotherapy or 
in combination with atezolizumab is safe and tolerable. 
The safety evaluation will comprise updating a three-parameter cumulative BLRM-EWOC design for the 
incidence of DLTs with monotherapy and combination therapy to strictly manage the risk of excessive 
toxicity (Neuenschwander 2008). For a derazantinib dose 𝑑, let 𝜋𝑑 denote the probability of DLT at dose 𝑑. 
If 𝑛 subjects are evaluated at dose 𝑑, then the number of subjects, 𝑦, experiencing a DLT is assumed to 
follow a binomial distribution: 
𝑦 | 𝜋𝑑 ~ Binomial(𝑛, 𝜋𝑑) 
The relationship between monotherapy and combination derazantinib doses, and DLT probabilities is 
modelled by the logistic curve; 
log(𝜋𝑑⁄(1 − 𝜋𝑑)) = log(𝛼𝑖) + 𝛽 log(𝑑⁄𝑑∗) , 𝛼1, 𝛼2, 𝛽 > 0 
Doses are rescaled as d/d* with reference dose d*= 600mg/day. The model parameters 𝛼1, 𝛼2 and 𝛽 have 
the following interpretation: 
 
𝛼1 equals the odds of toxicity with monotherapy at the reference dose d*. 
 
𝛼2 equals the odds of toxicity with combination therapy at the reference dose d*. 
 
Doubling the dose results in an increase in odds of toxicity by a factor of 2𝛽. 
 
The model parameters log(𝛼1) , log(𝛼2), log(𝛽) are given a weakly informative multivariate normal prior 
distribution, following (Neuenschwander 2014), with prior means (-1.386, -1.386, -0.781), prior standard 
deviations (5.472, 5.472, 0.973), and prior correlations of 0. This prior distribution ensures wide confidence 
intervals for toxicity probabilities at each dose. 
With an acceptable target toxicity range for a dose defined as a probability of toxicity of 10% to <25% and 
an overdosing range of ≥25%, the posterior probability of overdosing will be updated over time. Data 
resulting in a posterior probability of overdosing for a dose in excess of 25% will be determined as 
unacceptable. This ensures a safe recommended dose is chosen for subsequent testing of anti-tumor 
efficacy. This process also involves regular dose decision meetings to review the updated cumulative model 
results as well as safety in individual patients. 
Safety and tolerability of both the monotherapy and the combination dose regimens, and restart of 
enrollment in Substudies 3 and 5 will be concluded by joint decisions taken by the IDMC, Investigators, and 
the Sponsor in reviewing the aggregate of DLT, AE and PK data from the first 10 patients each enrolled in 
Substudies 3 and 5. 
Safety interim analyses of dose-limiting toxicities in substudies 3 and 5 will be undertaken entirely by 
Basilea Pharmaceutica International Ltd.  


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6.4.3. Physical and Ophthalmological Examinations 
Physical examinations will be performed at pre-screening, screening, at each cycle, end of treatment and 
safety follow-up visits (28 days and 90 days after last dose, as applicable), and symptom-driven 
examinations will be done as needed. Ophthalmological examinations will be performed during screening, 
the first four cycles (i.e. Day 1 of Cycles 2–5) and the End of Treatment visit. Physical examination and 
ophthalmological results will be listed. 
6.4.4. Vital Signs 
The actual value and change from baseline to each visit and at end of study will be descriptively summarized 
by visit/assessment  for vital signs (i.e., systolic and diastolic blood pressure, heart rate, respiratory rate, 
temperature and body weight).  
Height is measured at screening only. All vital sign data will be reported in a by-patient listing. 
6.4.5. Electrocardiogram 
The actual value and change from baseline to each visit and at end of study will be descriptively summarized 
by visit for ECG parameters (e.g., heart rate, RR interval, PR interval, QRS duration, QT interval,  QTcF 
interval and QTcB interval).  For all patients, a standard, triplicate, 12-lead ECG must be performed at all 
study visits using the pre-programmed device provided by the Sponsor. Summary tables will consider the 
mean of the triplicate measurements at each visit as the single reported value.  
A categorical analysis of QTcF interval and QTcB interval correction will also be presented, based on the 
number and percentage of patients meeting or exceeding specific thresholds for absolute QTcF/QTcB 
interval prolongation and change from baseline in QTcF/QTcB interval. In this analysis, the mean of the 
triplicate measurements will not be used; instead, the maximum at each timepoint will be considered.  
For absolute QTcF/QTCB interval prolongation, the number and percentage of patients within the following 
thresholds will be summarized at each visit. The worst (largest) value will also be summarized. 
 
Interval ≤450 ms 
 
Interval >450 ms and ≤480 ms 
 
Interval >480 ms and ≤500 ms 
 
Interval >500 ms 
 
The change from baseline in QTcF/QTcB interval to the worst (largest) post-baseline observation and at 
each study visit will also be summarized, considering the following thresholds: 
 
Interval increased from baseline ≤30 ms 
 
Interval increased from baseline >30ms and ≤60 ms 
 
Interval increased from baseline >60 ms  
 
For the analysis of change from baseline, the mean of the triplicate measurements will be used for all visits.  
In the categorical analyses, the maximum of triplicate measurements will be used for post-baseline values. 


Statistical Analysis Plan for Phase I/II Oncology 
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These summary tables will be presented by timepoint, and for the maximum post baseline value.  
All summary outputs for ECG will consider central ECG data.  
All ECG data will be provided in a by-patient listing. Local ECG data will be listed only. 
6.4.6. Laboratory Parameters 
Baseline values and values at each visit for each laboratory parameter collected will be descriptively 
summarized.  
Laboratory data will also be summarized using shift tables where appropriate. Each patient’s continuous 
laboratory safety parameter values will be flagged as “low”, “normal”, “high” or “missing” relative to the 
normal ranges. Each patient’s categorical laboratory safety parameter values will be flagged as “abnormal” 
or “normal”. This categorical data will be summarized in shift tables comparing the minimum post-baseline 
value, maximum post-baseline value and all other relevant post-baseline visits with those at the baseline 
visit. Note that minimum post-baseline will only be displayed in the instances where there is a range with 
LLN>0.  
In addition, CTCAE grade and hyperphosphatemia grade will be summarized. Shift tables of grade from 
baseline to maximum or minimum on-treatment as applicable will be produced. This analysis will also be 
produced considering cycle 1 only. 
Laboratory results will be included in by-patient listings and will include CTCAE grade and 
hyperphosphatemia grade at each visit, as well as change from baseline at each visit. 
Hy’s law  
 
Subjects who have elevated ALT, AST, and total bilirubin post baseline will be summarized descriptively as 
follows and  Hy’s law cases identified.  
 
 
ALT and AST: > 3x Upper Limit of Normal (ULN), > 5x ULN, > 10x ULN, > 20x ULN  
 
Total bilirubin >2x ULN  
 
ALT or AST: > 3x ULN and Total bilirubin >2x ULN 
 
Plots of ALT and AST vs. Total bilirubin by module will also be produced with reference lines at 3×ULN for 
ALT, AST, and 2×ULN for total bilirubin. In each plot, peak total bilirubin x ULN will be on the vertical axis 
and peak ALT or AST x ULN will be on the horizontal axis. 
 
6.4.7. Evaluation of Performance Status 
ECOG performance status will be summarized in a shift table, which will summarise values at baseline, 
each visit and the maximum values during the study.  
All ECOG performance assessments will be provided in a by-patient listing. 
6.5. 
PK/PD Analysis 
PK analyses are not the responsibility of 
 and details of planned analyses will be covered in 
a separate statistical analysis plan. 


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6.6. 
PRO Assessments (Substudies 1, 3, 4 and 5) 
All PRO assessments analyses will be performed using the safety/ITT population and presented per 
substudy and cohort. 
6.6.1. Establishing the Minimally Important Clinical Difference 
For each assessment the minimally important difference (MID) in a score at C3D1 and C5D1 will be 
determined following the recent protocol by the EORTC Quality of Life Group (Musoro 2018). The Global 
Self Evaluated Transition (G-SET™) is a single item questionnaire administered twice during the study after 
6 weeks (at C3D1) and 12 weeks (at C5D1). The questionnaire is a patient-rated change in health between 
two time periods using a five point ordinal scale (1 = much better now than 6 weeks ago; 2 = somewhat 
better now than 6 weeks ago, 3 = about the same as 6 weeks ago; 4 = somewhat worse now than 6 weeks 
ago; 5 = much worse now than 6 weeks ago). 
Patients with complete data will be categorized into five mutually exclusive clinical change groups (CCG) 
reflecting the five possible levels of change. For each pair of timepoints (Change in summary score from 
baseline at C3D1 and Change in summary score from C3D1 at C5D1), a patient can thus belong to only 
one CCG category. Two methods for determining the MID will be explored: 
1. Mean Change Method 
For a given mean absolute change in PRO assessment scale summary score: the MID for improvement 
is equal to the mean summary score of the ‘small positive change’ CCG (somewhat better now than 6 
weeks ago) and the MID for deterioration is equal to the mean summary score of the ‘small negative 
change’ CCG (somewhat worse now than 6 weeks ago). The mean summary score of the ‘small 
change’ CCGs and that of the ‘no change’ CCG will be compared and reported. If the mean summary 
score for ‘no change’ CCG is similar to any of the two ‘small change’ CCGs, the estimated MID may be 
considered doubtful. No a priori rule will be established to determine if mean summary scores are 
sufficiently similar to determine MID to be doubtful. 
 
2. Linear Regression 
For a given absolute change in PRO assessment scale summary score: the estimate of the numerical 
change in summary score that is associated with the transition between adjacent CCG categories will 
be determined using linear regression. Separate models will be fitted for improving and deteriorating 
scores based on the anchor. The outcome variable is the PRO assessment summary score, and the 
covariate is a binary anchor variable; coded as ‘no change’=0 and ‘small positive change’=1 for model 
on improvement (Other CCG categories are excluded from the linear regression model), and ‘no 
change’=0 and ‘small negative change’=1 for model on deterioration (Other CCG categories are 
excluded from the linear regression model. The resulting β’s (i.e. slope parameters) correspond to the 
MIDs for improvement and deterioration respectively. No other covariates will be included in these 
models. 
6.6.2. EQ-5D (5L) 
The EQ-5D (5L) is a standardized instrument for use as a measure of health outcome. The five health state 
dimensions in this instrument include the following: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension is rated on a five-point scale from 1 (no problem) to 5 (extreme 


Statistical Analysis Plan for Phase I/II Oncology 
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Sponsor: Basilea Pharmaceutica International Ltd; 
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problem). The EQ-5D (5L) also includes a graded (0 to 100) vertical visual analog scale (VAS) on which 
the patient rates his or her general state of health at the time of the assessment. 
The 5 questions will be summarized descriptively as categorical variables per substudy and cohort for all 
visits where the EQ-5D (5L) is collected. Each dimension and the VAS will be summarized as a continuous 
variable using descriptive statistics for the scores, change from baseline and percent change from baseline 
for all visits where the EQ-5D (5L) is collected. In addition, at C5D1, the change from C3D1 at C5D1 and 
the percentage change at C5D1 from C3D1 will also be reported. The minimally important change from 
baseline at C3D1 and change from C3D1 at C5D1 will be determined using the two methods detailed in 
Section 6.6.1. Missing scores will not be included in summary statistics and only subjects with both an 
observation at the specified visit and at baseline will be included in change from baseline summaries. 
6.6.3. EORTC QLQ-C30 
The EORTC QLQ-C30 was developed to assess the quality of life of cancer patients and is the most widely 
used cancer-specific HR-QoL instrument. It contains 30 items and measures five functional dimensions 
(physical (PF), role (RF), emotional (EF), cognitive (CF) and social (SF)), three symptom scales (fatigue, 
nausea/vomiting, and pain), six single symptom items (dyspnea, sleep disturbance, appetite loss, 
constipation, diarrhea and financial impact) and global health and quality of life. The global health and 
quality of life items uses a 7-point scale scoring from 1 (very poor) to 7 (excellent). The other items are 
scored on a 4-point scale from 1 (not at all) to 4 (very much). A high score for a functional scale represents 
a high/healthy level of functioning. A high score for the global health status represents a high QoL. However, 
a high score for a symptom scale/item represents a high level of symptomatology/problems. The scoring 
method is outlined in Table 9 and the following paragraphs. 


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Table 9: Scoring the QLQ-C30 version 3.0 
 
Scale 
Number of 
items 
Item 
range 
Version 3.0 
Item 
numbers  
Function 
scales 
Global health Status /QoL 
QL 
2 
6 
29, 30 
 
Functional Scales 
Physical functioning 
PF 
5 
3 
1 to 5 
F 
Role functioning 
RF 
2 
3 
6,7 
F 
Emotional functioning 
EF 
4 
3 
21 to 24 
F 
Cognitive functioning 
CF 
2 
3 
20, 25 
F 
Social function 
SF 
2 
3 
26, 27 
F 
Symptom scales/items 
Fatigue 
FA 
3 
3 
10, 12, 18 
 
Nausea and vomiting 
NV 
2 
3 
14,15 
 
Pain 
PA 
2 
3 
9, 19 
 
Dyspnea 
DY 
1 
3 
8 
 
Insomnia 
SL 
1 
3 
11 
 
Appetite loss 
AP 
1 
3 
13 
 
Constipation 
CO 
1 
3 
16 
 
Diarrhea 
DI 
1 
3 
17 
 
Financial difficulties 
FI 
1 
3 
28 
 
 
Raw score (RS) is calculated as the average of item score when at least half of the items are not missing. 
A linear transformation to 0–100 will then be applied to get the score (S) using the item range provided in 
Table 9. 
For functional scales S = (1-(RS-1)/range) x 100 
For symptom scales/items and global health status S = ((RS-1)/range) x 100 
Each scale will be summarized at each visit as a continuous variable using descriptive statistics per 
substudy and cohort for the total scores, change from baseline and percent change from baseline for all 
visits where the EORTC QLQ-C30 is collected. In addition, at C5D1, the change from C3D1 at C5D1 and 
the percentage change at C5D1 from C3D1 will also be reported. For each of the functional scales, the 
minimally important change from baseline at C3D1 and change from C3D1 at C5D1 will be determined 
using the two methods detailed in Section 6.6.1. 
6.6.4. FACT-Bl 
The FACT-Bl is an instrument which was developed for patients with bladder cancer. It contains 40 items 
and consists of the five subscales, physical well-being (PWB), functional well-being (FWB), emotional well-
being (EWB), social well-being (SWB) and an additional scale specific to bladder cancer. In addition, the 
PWB, FWB, EWB and SWB subscales can be summed to form the FACT-General (FACT-G) score and the 


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FACT-Bl total score (FACT-G and the bladder cancer specific scale). The items are scored on a 5-point 
scale from 0 (not at all) to 4 (very much). 
FACT-Bl scores are derived by recording the answers in the item response column, performing reversals 
as indicated and then summing individual items to obtain a score. This is then multiplied by the number of 
items in the subscale and divided by the number of items answered, this produces the subscale score. A 
higher score indicates higher quality of life. 
Table 10: Scoring FACT-Bl (Version 4.0) 
Subscale
Item Code
Reverse Item
Physical Well-Being (PWB) 
 
Score range: 0–28 
GP1 
Yes 
GP2 
Yes 
GP3 
Yes 
GP4 
Yes 
GP5 
Yes 
GP6 
Yes 
GP7 
Yes 
Social/Family Well-Being (SWB) 
 
Score range: 0–28 
GS1 
No 
GS2 
No 
GS3 
No 
GS4 
No 
GS5 
No 
GS6 
No 
GS7 
No 
Emotional Well-Being (EWB) 
 
Score range: 0–24 
GE1 
Yes 
GE2 
No 
GE3 
Yes 
GE4 
Yes 
GE5 
Yes 
GE6 
Yes 
Functional Well-Being (FWB) 
 
Score range: 0–28 
GF1 
No 
GF2 
No 
GF3 
No 
GF4 
No 
GF5 
No 
GF6 
No 
GF7 
No 
Bladder Cancer Subscale 
Score range: 0–48 
BL1 
Yes 
C2 
Yes 
C3 
No 
BL2 
Yes 
C5 
Yes 
C6 
No 
C7 
No 
BL3 
Yes 
BL4 
No 
BL5 
No 
C8 
Yes 
C9 
Yes 
 
Each subscale, FACT-G and FACT-Bl will be summarized as a continuous variable using descriptive 
statistics per substudy and cohort for the total scores, change from baseline and percent change from 


Statistical Analysis Plan for Phase I/II Oncology 
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Filing requirement: TMF 
 
 
baseline for all visits where the FACT-Bl is collected. In addition, at C5D1, the change from C3D1 at C5D1 
and the percentage change at C5D1 from C3D1 will also be reported. For each of the functional scales, the 
minimally important change from baseline at C3D1 and change from C3D1 at C5D1 will be determined 
using the two methods detailed in Section 6.6.1. 
6.6.5. G-SET 
G-SET is a patient-rated change in health between two time periods using a five-point ordinal scale. The 
response consists of a single question regarding health rating compared to 6 weeks previous. G-SET will 
be provided after 6 weeks (at Cycle 3 Day 1) and 12 weeks (at Cycle 5 Day 1). The responses at each time 
point will be summarised as a categorical variable. All G-SET data will be listed. 
 
6.7. 
Independent Data Monitoring Committee  
An IDMC will be established by the Sponsor to evaluate accumulating safety data in patients enrolled in the 
study, to ensure their safety and wellbeing, and to provide recommendations to the clinical teams in charge 
of conducting the study. For Substudy 2, the IDMC will be additionally responsible for determining the RP2D 
of derazantinib-atezolizumab in combination. This decision will be taken in an open session in which study 
Investigators and Sponsor representatives will be able to participate. For Substudy 3 and 5, the IDMC will 
be additionally responsible for determining whether derazantinib 200 mg BID, either as monotherapy or in 
combination with atezolizumab, can be declared as tolerable regimens. This decision will be taken in an 
open session in which study Investigators and Sponsor representatives will be able to participate. As 
detailed in the IDMC Charter, the IDMC will comprise experts in the field of oncology and biostatistics, who 
will be required to disclose their relevant financial interests to the Sponsor. None of the IDMC members 
may be involved in the conduct or reporting of any ongoing clinical study of which Basilea is the Sponsor. 
Full details of the IDMC’s roles and responsibilities are outlined in the IDMC charter. 
6.8. 
Changes to Methods Planned in the Protocol  
The planned Inverse Probability of Censoring Weighted (IPCW) modelling approach (Rimawi 2012) for 
crossover patients will not be undertaken due to low sample size of crossover patients. 
 


Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 45 of 50 
Filing requirement: TMF 
 
 
7. Tables, Listings, And Figures 
7.1. 
Programming Guidelines 
Computer-generated output will adhere to the following specifications. The standard operating procedures 
(SOPs) of 
 will be followed in the creation and quality control of all tables, listings and figures. 
7.1.1. Format of Output 
Unless otherwise specified, all computer-generated output should be produced in landscape mode. 
Required margins: 3.36cm on top (the binding margin [or left for portrait output]), 2.11cm on right, 3.65cm 
on left, and 3.3cm on bottom. Courier New 8 pt font will be used for all outputs. All output should have the 
Sponsor name, protocol number, the type of delivery, and page number. Tables/listings/figures should be 
internally paginated in relation to total length (i.e., page number should appear sequentially as page n of N, 
where N is the total number of pages in the table). All output should have the following header at the top of 
the page:  
Sponsor Name 
Protocol XXXXXXX 
Confidential 
Data Cut Off Date: ddmmmyyyy 
Page n of N 
 
1. Output numeration will conform to International Conference on Harmonization (ICH) recommendations. 
When applicable, the final number will indicate the substudy the output applies to, e.g. 14.1.1.1 would 
indicate output for substudy 1 and 14.1.1.2 would indicate output for substudy 2. In this case, the study 
population should be identified immediately following the title in the format Substudy X – Analysis 
Population. 
2. Column headings should be in initial upper-case characters. 
3. For numeric variables, include “unit” in column or row headings where appropriate. 
4. Footnotes should be single spaced, but separated by at least a double space from the bottom line of 
the table. The notes are aligned vertically by the left vertical border of the table. 
5. If the categories are not ordered (e.g., race), then only those categories for which there is at least 1 
patient represented in 1 or more groups should be included. 
6. An Unknown or Missing category should be added to any parameter for which information is not 
available for 1 or more patients. 
7. Listings should be sorted by substudy, cohort/dose level and patient numbers. 
8. In a listing, display the patient number only once for the patient with multiple records. If a patient’s 
records run into multiple pages, display the patient number once for every page. 
 
7.1.2. Format of Data 
1. Unless otherwise specified for continuous variables, the estimated mean, median, Q1 and Q3 for a set 
of values should be printed out to 1 more significant digit than the individual units of measurement. 
Standard deviation will be printed out to 2 more significant digits than the individual units of 
measurement.  The minimum and maximum should report the same significant digits as the original 
values. 


Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 46 of 50 
Filing requirement: TMF 
 
 
2. Data in columns of a table should be formatted as follows: 
 
Alphanumeric values are left-justified.  
 
Whole numbers (e.g., counts) are right-justified. 
 
Numbers containing fractional portions are decimal aligned. 
3. Unless otherwise specified, percentage values should be printed with 1 digit to the right of the decimal 
point (e.g., 12.8%, 5.4%).  Less-than signs “0.1%” should be printed when values are 0.0 and 0.1% 
(not 0.0%). 
4. Missing data should be represented on patient listings as either a hyphen (“-“) with a corresponding 
footnote (“ - = unknown or not evaluated”), or as “N/A,” with the footnote “N/A = not applicable,” 
whichever is appropriate. 
5. Dates should be printed in SAS DATE9.format (“DDMMMYYYY”: 01JUL2000).  Missing portions of 
dates 
should 
be 
represented 
on 
patient 
listings 
as 
dashes  
(--JUL2000).  Dates that are missing because they are not applicable for the patient are output as “N/A”, 
unless otherwise specified. 
6. Time should be printed in SAS TIME5.format (“HH:MM”: 17:30). Missing portions of time should be 
represented on patient listings as dashes (--:30). Times that are missing because they are not 
applicable for the patient are output as “N/A”, unless otherwise specified. 
 
7.2. 
Table of Contents for Tables, Listings and Figures 
Tables, listings and figures shells are specified in a separate document. 


Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 47 of 50 
Filing requirement: TMF 
 
 
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Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 48 of 50 
Filing requirement: TMF 
 
 
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Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 49 of 50 
Filing requirement: TMF 
 
 
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Statistical Analysis Plan for Phase I/II Oncology 
Studies 
 
Sponsor: Basilea Pharmaceutica International Ltd; 
Protocol No.: DZB-CS-201
 
 
SAP Version: 2.0 26-May-2022 
Controlled Document ID: 3903C.00, Effective Date 30-Apr-2018 
Page 50 of 50 
Filing requirement: TMF 
 
 
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