Clinical trial NCT04604132
Conditions: Gastric Adenocarcinoma
Keywords: gastric cancer gastro-esophageal adenocarcinoma adenocarcinoma of the stomach or gastro-esophageal junction fibroblast growth factor receptor FGFR genetic aberration targeted therapy derazantinib atezolizumab Tecentriq paclitaxel ramucirumab Cyramza solid tumor
Sponsor: Basilea Pharmaceutica
Start date: 2020-10-06; Completion date: 2022-11-21
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy of derazantinib monotherapy or derazantinib in combination with paclitaxel and ramucirumab in patients with gastric adenocarcinoma (GAC) i.e. with human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring fibroblast growth factor receptor 2 (FGFR2) genetic aberrations (GA).

Detailed description:
The study comprised two open-label substudies in patients with HER2-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring FGFR2 gene translocations, FGFR2 gene amplifications, or FGFR1-3 mutations.

In Substudy 1, GAC patients with specified FGFR GAs, after either first- or second-line treatment, and no approved treatment alternative were treated with derazantinib 300 mg once daily or 200 mg twice daily, with the aim of evaluating the safety, tolerability, and efficacy of derazantinib monotherapy in this patient population.

In Substudy 2, GAC patients with specified FGFR GAs after standard first-line treatment, were treated with a derazantinib-paclitaxel-ramucirumab combination with the aim of evaluating the safety, tolerability, and efficacy of the combination therapy and determining the recommended phase 2 dose (RP2D).

The study originally planned to include three substudies but was prematurely terminated for administrative reasons before the third substudy (including combination therapy with derazantinib plus atezolizumab) was initiated.

Arms: arm 1: Patients with FGFR2 fusions or amplifications were treated with 300 mg Derazantinib monotherapy once daily arm 2: Patients with FGFR1-3 mutations were treated with 300 mg Derazantinib monotherapy once daily arm 3: Patients with FGFR fusions, amplifications or mutations were treated with 200 mg Derazantinib monotherapy twice daily arm 4: Patients with FGFR fusions, amplifications or mutations were treated with 200 mg Derazantinib once daily in combination with Paclitaxel and Ramucirumab arm 5: Patients with FGFR fusions, amplifications or mutations were treated with 300 mg Derazantinib once daily combination with Paclitaxel and Ramucirumab
Interventions: intervention 1: Derazantinib intervention 2: Derazantinib-paclitaxel-ramucirumab combination intervention 3: Derazantinib-paclitaxel-ramucirumab combination intervention 4: Derazantinib intervention 5: Derazantinib
Intervention descriptions: intervention 1: Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1 (Cohort 1.1). intervention 2: Derazantinib was administered orally at a dose of 200 mg once daily in combination with paclitaxel and ramucirumab.

Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab.

Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel. intervention 3: Derazantinib was administered orally at a dose of 300 mg once daily in combination with paclitaxel and ramucirumab.

Paclitaxel was administered intravenously at a dose of 80 mg/m² on days 1, 8, and 15 of a 28-day cycle in combination with ramucirumab.

Ramucirumab was administered intravenously at a dose of 8 mg/kg every 2 weeks in combination with paclitaxel. intervention 4: Derazantinib was administered orally at a dose of 200 mg twice daily as monotherapy in the Substudy 1 (Cohort 1.3). intervention 5: Derazantinib was administered orally at a dose of 300 mg once daily as monotherapy in the Substudy 1 (Cohort 1.2).

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
DZB-CS-202
Derazantinib
A Phase 1b/2 study of derazantinib as monotherapy and combination therapy with 
paclitaxel, ramucirumab or atezolizumab in patients with HER2-negative gastric 
adenocarcinoma harboring FGFR genetic aberrations (FIDES-03)
Protocol number / Version: DZB-CS-202 / Version 5.0
Compound:
Derazantinib
Phase of development:
1b/2
IND number:
146726
EudraCT number:
2019-004505-27
Date:
21 May 2021
Project Physician:
Clinical Pharmacologist:
Project Statistician:
Sponsor:
Basilea Pharmaceutica International Ltd
Grenzacherstrasse 487, 
PO Box, 4005 Basel, Switzerland
Confidentiality statement
All information contained in this document is confidential and proprietary information of Basilea 
Pharmaceutica International Ltd (‘Basilea’). This information is provided to you on a confidential basis 
as an Investigator or potential Investigator, for review by you, and for potential future discussion with an 
applicable Independent Ethics Committee / Institutional Review Board as needed. It may otherwise not 
be disclosed by you to any third party other than those members of your staff who have a need to know, 
without prior written authorization from Basilea, 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 another third party is required by applicable law or regulations, the person 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.
Note: This is an electronically controlled document (Document ID: Clinical-002557)
ClinicalTrials.gov ID: NCT04604132


 
 
   
 
 
 
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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.


 
 
   
 
 
 
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Protocol synopsis
TITLE:
A Phase 1b/2 study of derazantinib as monotherapy and combination 
therapy with paclitaxel, ramucirumab or atezolizumab in patients 
with HER2-negative gastric adenocarcinoma harboring FGFR 
genetic aberrations (FIDES-03)
PROTOCOL NUMBER:
DZB-CS-202 / Version 5.0
SPONSOR:
Basilea Pharmaceutica International Ltd, Switzerland
STUDY PHASE:
1b/2
INDICATION:
Gastric cancer
IND NUMBER:
146726
EUDRACT NUMBER:
2019-004505-27
DATE:
21 May 2021
STUDY DESIGN
Design and investigational products
This study is an open-label, multiple-cohort, multicenter study of derazantinib – a potent and well 
tolerated fibroblast growth factor receptor (FGFR) inhibitor of tyrosine kinases of FGFR 1, 2, and 3 
– as monotherapy and combination therapy with paclitaxel, ramucirumab, or atezolizumab in 
patients with human epidermal growth factor receptor 2 negative (HER2neg) adenocarcinoma of the 
stomach or gastro-esophageal junction harboring FGFR2 gene fusions or other rearrangements
(‘FGFR2fus’), high-level FGFR2 gene amplifications (‘FGFR2high-amp’; i.e., a quantitative correlate 
of > 10 FGFR2 gene copy numbers called by the NGS algorithm of the central diagnostic test), or 
FGFR1–3 mutations (‘FGFR1–3mt’). These gene abberations are collectively described in this 
protocol as ‘FGFRfus/amp/mt’.
As of Protocol Version 5.0, this study has been modified to explore two dosing regimens of 
derazantinib: 300 mg once daily (QD) and 200 mg twice daily (BID).
The study comprises three substudies:

Substudy 1:
A Phase 2a study comprising two cohorts:
– Cohort 1.1
FGFR2fus / FGFR2high-amp patients to be treated with 300 mg QD derazantinib
– Cohort 1.2
FGFR1–3mt patients to be treated with 300 mg QD derazantinib
– Cohort 1.3
FGFRfus/amp/mt patients to be treated with 200 mg BID derazantinib

Substudy 2: A Phase 1b/2 study of patients to be treated with derazantinib-paclitaxel-
ramucirumab1 in combination

Substudy 3: A randomized controlled Phase 2b study comprising four cohorts:
– Cohort 3.1
Patients to be treated with derazantinib (test)
– Cohort 3.2
Patients to be treated with derazantinib-paclitaxel-ramucirumab1 in 
combination (test)
                                                          
1 A combination of either derazantinib-paclitaxel or derazantinib-ramucirumab may be explored if the combination of 
derazantinib-paclitaxel-ramucirumab exceeds the preset toxicity threshold of 33% dose-limiting toxicities (DLTs).


 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
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– Cohort 3.3
Patients to be treated with derazantinib-atezolizumab in combination (test)
– Cohort 3.4
Patients to be treated with paclitaxel-ramucirumab in combination (control)
An overview of the study design is provided in Figure 1.
Figure 1
Overview of study design
Abbreviations: 2L/3L, second/third-line; BID, twice daily; CR/PR, complete/partial response as per RECIST 1.1; 
FGFRfus/amp/mt, tumor status with FGFR2 gene fusion or rearrangement / amplification, or FGFR1–3 mutation; FGFR2fus, 
FGFR2 fusion / rearrangement; FGFR2high-amp, high-level FGFR2 gene amplification; FGFR1–3mt, FGFR1–3 mutations; 
GAC, for either recurrent, locally advanced or metastatic gastric adenocarcinoma; HER2neg, negative HER2 tumor status; 
ORR, objective response rate; p, probability (of response); pts, patients; QD, once daily; R, randomization; 
r1/r2, response(s) observed during stage 1 (r1) and by the end of the cohort (r2), respectively; S, stratification by genetic 
aberration.
Patient population
The study enrolls patients with either metastatic or recurrent locally-advanced HER2-negative 
(HER2neg) adenocarcinoma of the stomach or gastro-esophageal junction (gastric adenocarcinoma
[GAC]) inoperable at the time of screening, and radiologically-confirmed disease progression after 
one (Substudies 2 and 3) or one or two (Substudy 1) standard treatment regimens. The safety 
cohorts of Substudy 2 comprise GAC patients considered fit to tolerate the novel combination 
adding derazantinib to the second-line standard-of-care treatment paclitaxel-ramucirumab.  


 
 
   
 
 
 
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Tumor molecular testing for eligibility
Molecular eligibility for enrollment will be established by a positive test result for FGFRfus/amp/mt. 
The molecular test is to be based on NGS of either tumor tissue DNA and/or RNA, or plasma cell-
free DNA (cfDNA).
For patients with no access to local NGS testing, central testing will be performed in a laboratory 
designated by the Sponsor; this ‘central testing’ will be based on NGS testing of cfDNA from a 
liquid biopsy obtained at Pre-screening. 
Alternatively, an eligible, positive FGFRfus/amp/mt 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, U.S.
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.
Substudy 1 
As of Protocol Version 5.0, this substudy has been modified with the addition of Cohort 1.3
targeting HER2neg FGFRfus/amp/mt GAC, a population identical to that being investigated in ongoing 
Cohorts 1.1 (FGFR2fus or FGFR2high-amp) and 1.2 (FGFR1–3mt) combined to better address medical 
and operational aspects of study conduct. In Cohort 1.3, patients with either metastatic or recurrent 
locally advanced HER2neg FGFRfus/amp/mt GAC, with radiologically confirmed disease progression 
after one or two standard treatment regimens are to be treated with derazantinib 200 mg BID. 
During enrollment into Cohort 1.3, enrollment into Cohorts 1.1 and 1.2 is paused.
Substudy 2
This substudy comprises second-line patients with HER2neg FGFRfus/amp/mt GAC and radiologically
confirmed disease progression after one standard treatment regimen, who after Investigator 
assessment are considered fit (per multidisciplinary tumor board endorsement) to tolerate the novel 
combination of derazantinib-paclitaxel-ramucirumab and would otherwise be eligible for the 
second-line standard-of-care treatment paclitaxcel-ramucirumab. 
Using a modified 3+3 dose-finding design for the Dose-finding Part followed by a Dose-expansion 
Part cohort of approximately 14 additional patients to reach 20 efficacy-evaluable patients dosed 
at the MTD, the Dose-finding Part will assess dose-limiting toxicities (DLTs) and safety to 
determine the MTD and subsequently the recommended Phase 2 dose (RP2D) of the triple 
combination of derazantinib-paclitaxel-ramucirumab. If the triple combination is not tolerated at 
the lowest dose level, a double combination of either derazantinib-paclitaxel or derazantinb-
ramucirumab may be explored instead (see Section 3.1.7.2). The rationale for combining 
derazantinib and paclitaxel-ramucirumab is based on non-clinical data indicating a potential 
synergistic effect of derazantinib and paclitaxel, possibly linked to the anti-angiogenetic effects 
attributable to both study drugs.
Sites enrolling patients to both Substudy 1 and 2 will decide which substudy to allocate a 
prospective study participant to based on eligibility criteria, individual patient and disease status, 
prior antitumor treatment, and the number of available places on the treatment plan of Substudy 2.


 
 
   
 
 
 
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Substudy 3
The design and statistical assumptions applicable to this substudy are contigent on findings from 
Substudies 1 and 2, and are currently under consideration. Prior to initiation of patient enrollment 
in this substudy, a protocol amendment may be submitted.
This substudy comprises four cohorts investigating the efficacy of derazantinib monotherapy, 
derazantinib-paclitaxel-ramucirumab, and derazantinib-atezolizumab, and comparing it to that of 
paclitaxel-ramucirumab as common control. Second-line patients with HER2neg FGFRfus/amp/mt GAC 
will be allocated by randomization following stratification by type of FGFR genetic aberration 
(FGFR2fus or FGFR2high-amp vs FGFR1–3mt) and geographic region (Americas-Europe-Australia vs 
Asia). A Simon’s two-stage design will be used in all test cohorts to investigate the primary 
objective.
The study rationale is based on non-clinical and clinical data supporting meaningful activity of 
FGFR inhibition (with and without concurrent paclitaxel administration) in GAC patients carrying 
FGFR genetic aberrations. Derazantinib, as a dual FGFR/CSF1R inhibitor, is hypothesized to
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 such as atezolizumab. The initiation of 
Substudy 3 is triggered by the availability of data considered sufficient and robust to support the 
rationale for monotherapy (Cohort 3.1), triple / double combination (Cohort 3.2), and the 
derazantinib-atezolizumab combination (Cohort 3.3). . 
In Cohort 3.4, patients with progressive disease after treatment with paclitaxel-ramucirumab will 
have the option to crossover to treatment with derazantinib if no standard alternative treatment 
options are available. 
INVESTIGATIONAL PRODUCT(S) 
Derazantinib, paclitaxel, ramucirumab, atezolizumab
TUMOR MOLECULAR TESTING FOR ELIGIBILITY
Molecular eligibility for study enrollment will be established by a positive test result for 
FGFRfus/amp/mt using a next-generation sequencing (NGS) test of either tumor tissue DNA and/or 
RNA, or plasma cell-free deoxyribonucleic acid (cfDNA). For patients with no access to local NGS 
testing, central testing will be performed in a laboratory designated by the Sponsor; this “central 
testing” will be based on NGS testing of cfDNA from a liquid biopsy obtained at Pre-screening. 
The liquid biopsy is ideally to be obtained after assessment of objective documented progression 
after prior anti-cancer treatment. For Substudy 3, the scope of eligible FGFR genetic aberrations 
may be modified, taking into consideration any findings obtained from Substudy 1. 
For molecular screening, patients are required to sign the study Informed Consent Form (ICF) and 
are not considered enrolled (i.e., patients are considered to be in pre-screening for the study) until 
receipt of a positive molecular test result, and second dated patient signature on the ICF.  
CLINICAL SCREENING
Upon receipt of a positive test result and after obtaining a dated patient signature in a designated 
section of the study ICF acknowledging the positive test result and documenting the informed 
decision to participate in the study, clinical study procedures and any other study-related procedures 
may be conducted. 


 
 
   
 
 
 
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The screening window for clinical screening procedures will be 28 days and ensuring sufficient 
time has elapsed after prior anti-tumor treatment to eliminate interference with study treatment. 
Taking the required period between prior anti-tumor treatment and initiation of study treatment into 
consideration, the screening period is recommended to be kept as short as possible to limit the 
number of patients experiencing clinical deterioration due to their disease progression.
PLANNED NUMBER OF PATIENTS
The planned enrollment is approximately 314 evaluable patients across all three substudies.
NUMBER OF SITES/LOCATIONS
Approximately 85 study sites in the Americas, Europe, Australia, and Asia.
OBJECTIVES 
Primary objectives

Substudy 1 
To evaluate the objective response rate (ORR; Cohorts 1.1 and 1.2) and 4-month progression-
free survival rate (PFS4; Cohort 1.3) of patients with HER2neg FGFRfus/amp/mt GAC treated with 
derazantinib monotherapy.

Substudy 2
To determine the RP2D of derazantinib-paclitaxel-ramucirumab in combination in patients with 
HER2neg FGFRfus/amp/mt GAC.

Substudy 3 
To evaluate the ORR of patients with HER2neg FGFRfus/amp/mt GAC treated with derazantinib, 
derazantinib-paclitaxel-ramucirumab, derazantinib-atezolizumab, or paclitaxel-ramucirumab.
Secondary objectives

To evaluate the efficacy of the study drugs, as measured by ORR (in Cohort 1.3 and Substudy 
2), and by disease control rate (DCR), duration of response (DOR), progression-free survival 
(PFS), and overall survival (OS). 

To compare the ORR, DCR, DOR, PFS, and OS of patients treated with derazantinib 
monotherapy, derazantinib-paclitaxel-ramucirumab, and derazantinib-atezolizumab each with 
that of patients treated with paclitaxel-ramucirumab (derived from data from Substudy 3).

To characterize the PK profile of derazantinib 200 mg BID monotherapy (and, if applicable, 
derazantinib metabolites) 

To compare antitumor efficacy in patients treated with derazantinib monotherapy to that of 
patients treated with derazantinib-paclitaxel-ramucirumab, and derazantinib-atezolizumab as 
well as patients treated with derazantinib-paclitaxel-ramucirumab compared to that of patients 
treated with paclitaxel-ramucirumab, as measured by ORR, DCR, DOR, PFS, and OS, to 
investigate the contribution of derazantinib in combination treatment.

To assess the safety and tolerability of the study drugs.

To characterize the pharmacokinetic (PK) profile of derazantinib and paclitaxel when 
administered in combination.

To evaluate changes, and assess the minimally important difference, in health-related quality of 
life (HR-QoL) and symptom response from baseline using the EQ-5D (5L) visual analogue scale 
(VAS), European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire-Stomach (QLQ-
STO-22), and the Global Self Evaluated Transition (G-SET) / Health Transition Index (HTI).


 
 
   
 
 
 
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STUDY DRUG / DOSE / ROUTE / REGIMEN
In Substudies 1 and 2, and in Cohorts 3.1, 3.2 and 3.4, a treatment cycle is 28 days.
In Cohort 3.3, a treatment cycle is 21 days.
Derazantinib is an investigational drug supplied as 100 mg immediate-release powder-filled
capsules for oral administration. The initial dose for patients treated with derazantinib monotherapy 
in Cohorts 1.1, 1.2, and 3.1 will be 300 mg QD, the initial dose for patients treated with derazantinib 
monotherapy in Cohort 1.3 will be 200 mg BID. In Substudy 2, the starting dose of derazantinib 
will be 200 mg QD in combination with ramucirumab and paclitaxel (see Section 3.1.7.2). In 
Substudy 3, the RP2D of the triple/double combination obtained from Substudy 2 and the RP2D of 
derazantinib-atezolizumab obtained from study DZB-CS-201 (FIDES-02, NCT04045613) will be 
used (details on clinical management of combinations are provided in Section 6.1.6). The adoption 
of the RP2D to be used in Substudy 3 is based on the joint decision of the respective study 
Independent Data Monitoring Committees (IDMCs) and Investigators in accordance with the 
IDMC Charter, and with the involvement of qualified Sponsor representatives (see Section 3.1.7.1).
Paclitaxel is an approved medication supplied as a non-aqueous 6 mg/mL solution in multidose 
vials for dilution with a suitable parenteral fluid prior to intravenous (IV) infusion. The target dose 
for all patients will be 80 mg/m2 body-surface area (BSA), administered as a 1-hour IV infusion on 
D1, D8, and D15 of a 28-day cycle. In Substudy 2, various dose levels of paclitaxel may be 
investigated.
Ramucirumab is an approved medication supplied as a 10 mg/mL solution in either 10 mL or 50 mL 
vials. The target (and registered) dose for all patients will be 8 mg/kg body weight, administered 
as a 1-hour IV infusion on D1 and D15 of a 28-day cycle. In Substudy 2, various dose levels of 
ramucirumab may be investigated.
Atezolizumab is an approved medication supplied as 1200 mg/20 mL concentrate solution for IV 
infusion. The dose for all patients will be 1200 mg every 3 weeks (Q3W); with no dose reduction 
permitted.
KEY INCLUSION CRITERIA
(The full list of inclusion criteria is in Section 4.2 of the protocol)
1.
Informed consent 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 adenocarcinoma of the gastro-esophageal junction or stomach.
Note: Every effort is requested to submit archival tumor tissue samples for correlative and 
confirmatory diagnostic and biomedical research.
4.
Negative HER2 status obtained from the most recent available tissue sample.
Note: The HER2 status of GAC patients should be assessed using approved standard protocols, 
including, but not limited to FISH, chromogenic or silver in situ hybridization (CISH) or 
immunohistochemistry (IHC), in accordance with institutional standards. Patients with a 
HER2-positive (HER2pos) status based on either HER2 amplification (by FISH or CISH) or, if 
FISH/CISH is unavailable, a HER2 IHC score of 3+, are not eligible and should not be tested 
molecularly for FGFRfus/amp/mt expression.


 
 
   
 
 
 
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5.
Inoperable1
recurrent, locally-advanced adenocarcinoma or progressing stage IV 
adenocarcinoma of the gastro-esophageal junction or stomach, and prior antitumor treatment 
as specified for each Substudy:

Substudy 1: Patients with radiographically-documented disease progression after either 
standard first- or second-line treatment, and no approved treatment alternative.

Substudy 2: Patients with radiographically-documented disease progression after standard 
first-line treatment, and per Investigator assessment considered suitable to tolerate the 
treatment regimen. 

Substudy 3: Patients with objective radiographically-documented disease progression:
–
During, or within 6 months after, administration of the last cycle of adjuvant / 
neoadjuvant / perioperative chemotherapy (platinum plus fluoropyrimidine with or 
without anthracycline and/or taxane and/or irinotecan) for locally advanced disease, 
or 
–
During, or any time after, administration of the last cycle of first-line taxane-free 
chemotherapy (platinum plus fluoropyrimidine with or without anthracycline) for 
metastatic disease or locally advanced disease.
Note: If the patient has received prior taxane, a 6-month taxane-free interval after the last 
administration of taxane-containing treatment needs to be respected.
6.
Eligible FGFRfus/amp/mt positive test result (see Appendix 1 and Section 3.1.4).
7.
Measurable disease as defined by the Investigator using Response Evaluation Criteria in Solid 
Tumors 1.1 criteria (RECIST 1.1)
8.
ECOG PS 0 or 1.
9.
Adequate organ functions, as indicated by Screening visit local laboratory values.
10. Men and women of childbearing potential must agree to avoid impregnating a partner or 
becoming pregnant, respectively, during the study, and for at least 150 days after the last dose 
of study drug.
KEY EXCLUSION CRITERIA
(The full list of exclusion criteria is in Section 4.3 of the protocol)
1.
Receipt of prior cancer treatment within specific interval periods (see Section 4.3, Exclusion 
criterion 1).
2.
For patients enrolled in Substudy 1, prior treatment with FGFR inhibitors.
3.
For patients enrolled in Substudy 2 and 3, prior treatment with

Taxanes within 6 months prior to randomization

FGFR inhibitors or pathway-targeting agents

Anti-VEGF(R) therapeutic antibody or pathway-targeting agents.
4.
For patients enrolled in Substudy 3, prior treatment with anti-programmed cell death receptor-
1 (PD-1) or anti-programmed death ligand-1 (PD-L1) therapeutic antibody or pathway-
targeting agents.
                                                          
1 Patients are required to be staged as inoperable at the time of screening in order to avoid interference of any 
potentially planned surgery with RECIST requirements during the study.


 
 
   
 
 
 
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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: New York Heart Association Class II to IV 
congestive heart failure, or any arterial thrombotic event, including myocardial infarction, 
unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months of the
first dose of study drug;
concurrent and clinically significant abnormalities on 
electrocardiogram [ECG] at Screening, including a QT interval corrected by Fridericia’s 
formula [QTcF]1 > 450 ms for males or > 460 ms for females (mean values from triplicate 
ECGs; see Section 5.3.2.4). 
7.
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, and Grade 2 anemia, from previous anti-tumor treatment and/or 
from medical/surgical procedures/interventions).
8.
Known central nervous system (CNS) metastases.
…
18. Pregnant or breast feeding.
Applicable to patients considered for enrollment in Substudy 2 or 3
19. Concurrent uncontrolled or active infection with human immunodeficiency virus (HIV; known 
HIV 1/2 antibodies positive).
20. Active hepatitis B or chronic hepatitis B without current antiviral therapy and HBV DNA 
≥100 IU/mL. 
Note: Active hepatitis B is defined as a known positive hepatitis B surface antigen (HBsAg) 
result. 
21. Active hepatitis C
Note: Active hepatitis C is defined by a known positive hepatitis C antibody result and known 
quantitative hepatitis C virus (HCV) RNA results greater than the lower limits of detection of the assay.
22. Active tuberculosis.
23. Lack of recovery from major surgery after 4 weeks, or major elective surgery is planned during 
the foreseeable duration of the patient’s participation in the study, or placement of a central 
venous access device within 7 days prior to randomization.
24. Uncontrolled arterial hypertension, with a systolic blood pressure ≥ 150 mm Hg or a diastolic 
blood pressure ≥90 mm Hg despite standard medical management.
25. History of gastrointestinal perforation and/or fistulae within 6 months prior to study entry.
26. History of clinically relevant bleeding disorders, vasculitis, or had a significant bleeding 
episode from the gastrointestinal tract within 3 months prior to study entry
Note: Patients with a past gastrointestinal bleeding episode may be considered for enrollment 
if an upper gastrointestinal endoscopy performed after the bleeding event has demonstrated 
that the source of gastrointestinal bleed has been identified and the risk of re-bleeding is low.
                                                          
1 The averaged QTcF value from a triplicate set of ECGs will be taken for decision making (see Section 5.3.2.4).


 
 
   
 
 
 
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27. History of deep vein thrombosis, pulmonary embolism, or any other significant 
thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not 
considered ‘significant’) during the 3 months prior to randomization.
28. The patient is receiving therapeutic anticoagulation with warfarin, low-molecular weight 
heparin, or similar agents. 
Note: Patients receiving prophylactic anticoagulation therapy for cancer-associated 
thrombosis are eligible provided that the coagulation parameters defined in the inclusion 
criteria (international normalized ratio [INR] ≤1.5 and partial thromboplastin time 
[PTT/aPTT] ≤1.5 upper limit of normal [ULN] or prothrombin time [PT] ≤1.5 ULN, and
PTT/aPTT ≤1.5 ULN) are met.
29. The patient is receiving chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs, 
e.g., indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (e.g., 
clopidogrel, ticlopidine, dipyridamole, anagrelide). Acetylsalicylic acid (aspirin) is permitted 
at doses up to 325 mg/day.
30. Child-Pugh B or C liver cirrhosis, or a history of hepatic encephalopathy, hepatorenal 
syndrome, or clinically-meaningful ascites related to cirrhosis.
...
Applicable only to patients considered for enrollment in Substudy 3.
32. Administration of a live, attenuated vaccine within 30 days prior to randomization.
33. Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
within 2 weeks prior to first dose of study drug or anticipated requirement for systemic 
immunosuppressive medications during the study; inhaled, intranasal, intraocular, topical, and 
intra-articular joint injections are allowed.
34. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently).
35. History of allogeneic stem cell or solid organ transplantation.
…
38. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia, or evidence of active pneumonitis on Screening chest computed 
tomography (CT) scan
MAIN STUDY ENDPOINTS
Primary endpoints
In Substudy 1, for Cohorts 1.1 and 1.2, the primary endpoint is ORR, as measured by the proportion 
of patients with confirmed complete response (CR)or partial response (PR) by blinded independent 
central review (BICR) per RECIST 1.1. For Cohort 1.3, the primary endpoint is PFS4, as measured 
by the proportion of patients alive and free of disease progression by blinded independent central 
review (BICR) per RECIST 1.1 after the second on-study tumor assessment, i.e., approximately 
after 4 months of study treatment.
In Substudy 2, the primary endpoint is the RP2D of derazantinib-paclitaxel-ramucirumab in 
combination, estimated from safety and tolerability according to the aggregate of DLT criteria and 
adverse event (AE) data, and considering further PK and efficacy data of the combination. If the 
triple combination is not tolerated at the lowest dose level, the combination of derazantinib and 
paclitaxel or derazantinib and ramucirumab will be explored instead. In a joint decision, the IDMC, 
Investigators, and the Sponsor will determine the RP2D.


 
 
   
 
 
 
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For all cohorts in Substudy 3, the primary endpoint is ORR, as measured by the proportion of 
patients with confirmed complete response (CR) or partial response (PR) by blinded independent 
central review (BICR) per RECIST 1.1. To determine the study population for Substudy 3, the 
outomes of patients with HER2neg FGFRfus/amp/mt GAC treated with derazantinib in Substudy 1 are 
to be analyzed per cohort.
Secondary endpoints
Efficacy, safety and pharmacokinetics of derazantinib will be measured overall and in pre-specified 
subsets. Secondary endpoints are detailed in Sections 3.2.2.1, 3.2.2.2, and 3.2.2.3.
STATISTICAL ANALYSIS
Key analysis populations
Safety population
All patients who received at least one dose of study drug. Data will be summarized according to 
the treatment actually received. The Safety population will be used for secondary endpoint analyses 
and sensitivity analyses.
Intent-to-treat (ITT) population
All patients allocated and/or randomized to treatment, regardless of the administration of the study 
drug will be used for between-cohort efficacy analyses in Substudy 3, including pooled analyses of 
Substudy 1 and 3.
Modified ITT (mITT) population for single-arm non-comparison efficacy analyses
All patients who received at least one dose of study drug, 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 died from any 
cause. The mITT population will be used for all primary single-arm non-comparison efficacy 
analyses in Substudies 1, 2 and 3. 
Analyses
Analysis of the primary endpoint of Cohorts 1.1 and 1.2, and Substudy 3 (ORR)
The primary efficacy endpoint of ORR is defined as the achievement of confirmed CR or PR using 
RECIST 1.1, as assessed by BICR. Point estimates and confidence intervals (CIs) will be provided. 
The primary analysis will be performed on the mITT population, and repeated on both the ITT and 
the Per-protocol (PP) population. 
Analaysis of the primary endpoint of Cohort 1.3 (PFS4)
PFS4 will be the proportion of patients who are alive and have no disease progression at the second 
on-study tumor assessment at approximately 4 months from the first date of receiving study drug 
as assessed by survival status and response status using RECIST 1.1, as assessed by BICR. The 
4-month analysis is intended to support the two-stage design, and PFS in general will a key 
secondary endpoint to determine the anti-cancer efficacy of derazantinib in the indication. The 
primary analysis for PFS4 will be performed on the subset of the mITT population who fulfilled 
the minimum exposure requirement (relative dose of > 0.50) until the second on-study tumor 
imaging assessment, or who experienced progression before the minimum exposure requirement. 
Analysis of the primary endpoint of Substudy 2
Dose-limiting toxicities within the DLT interval (i.e., the first 28 days of the first treatment cycle) 
will be analyzed in the MTD Part population to determine whether derazantinib-paclitaxel-
ramucirumab in combination is considered safe and tolerable (for details see Section 8.2.5 and 
8.2.6). The MTD is defined as the highest dose level at which < 33% of patients experience a DLT. 


 
 
   
 
 
 
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If the triple combination is not tolerated at the lowest dose level, the double combination of 
derazantinib and paclitaxel or derazantinib and ramucirumab will be explored.
The Dose-finding Part is followed by enrollment of a Dose-expansion Part cohort of approximately 
14 additional patients in order to reach 20 efficacy-evaluable patients dosed at the MTD.. The RP2D 
will be determined by a joint decision taken by the IDMC, Investigators, and the Sponsor after 
reviewing the aggregate of DLT and AE data, and considering further PK, efficacy, and PD data of 
the combination and potential toxicity-response modeling.
Analysis of secondary endpoints
Progression-free survival
Next to ORR as the primary endpoint, progression-free survival (PFS) is a key secondary endpoint, 
and is to be measured from patient enrollment to the first date of objectively measured radiographic 
progression by RECIST 1.1 (the recorded progression date [PD date]), or the date of death from 
any cause, whichever occurs first. Progression-free survival will be summarized using Kaplan-
Meier methods and compared between groups using a log-rank test at a one-sided 5% alpha level
(ITT and mITT poulations). 
The censoring date for a patient with no documented progression before data cutoff or dropout is 
defined as the date of the last tumor assessment with no documented progression. Further sensitivity 
analyses will be specified in the Statistical Analysis Plan to assess the impact of the censoring rules 
applied. 
Comparison of experimental treatment and common control
The comparisons of the efficacy of derazantinib, derazantinib-paclitaxel-ramucirumab and 
derazantinib-atezolizumab
with that of either derazantinib monotherapy or paclitaxel-
ramucirumab, as measured by ORR and PFS, will be investigated. For the comparison between 
derazantinib and paclitaxel-ramucirumab for ORR and PFS, the ITT populations of the completely 
enrolled cohorts of Substudy 3 will be used, and completely enrolled cohorts of Substudy 1 and 
Substudy 3 will be combined for additional analyses. The comparisons of derazantinib-paclitaxel-
ramucirumab and derazantinib-atezolizumab in combination with that of either derazantinib 
monotherapy or paclitaxel-ramucirumab will be performed in the Substudy 3 ITT population.
Other secondary endpoints
Disease control rate (and ORR for Substudy 2) will be summarized in the same way as the primary
endpoint. Duration of response (mITT population) and OS analyses (ITT population) will be 
performed using Kaplan-Meier methods. The analysis will be repeated on the PP population. 
Subgroup analyses within Substudies 1 and 3 will be performed according to the stratification 
factors. 
ASSESSMENTS
Pharmacokinetics
Derazantinib (and any identified derazantinib metabolite) plasma concentrations will be measured 
in plasma samples. Concentrations at each nominal time point and all relevant PK parameters 
(maximum plasma concentration [Cmax], time to peak [maximum] plasma concentration [tmax], area 
under the plasma concentration-time curve from 0 to 12 [AUC0–12] and from 0 to 24 hours 
[AUC0–24], AUC from time 0 to the last measurable concentration [AUClast]) will be summarized 
using descriptive statistics.


 
 
   
 
 
 
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In the paclitaxel-ramucirumab PK population, paclitaxel plasma concentrations and ramucirumab 
serum concentrations will be summarized at each nominal time point using descriptive statistics. 
Relevant PK parameters for paclitaxel (Cmax, tmax, AUC0–24, AUClast, t1/2, AUCinf, T> 0.05) will be 
summarized using descriptive statistics.
In the atezolizumab PK population, atezolizumab and anti-drug antibodies (ADA) serum 
concentrations at each nominal time point will be summarized using descriptive statistics.
Safety/tolerability
AE monitoring will be performed on an ongoing basis throughout the study, with severity graded 
according to the guidelines outlined in the CTCAE Version 5.0 (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. The incidence of treatment-emergent AEs (TEAEs) will 
be presented, including serious AEs (SAEs), AEs by severity, AEs by relationship to study drug, 
discontinuation of patients from study therapy due to AEs, and deaths. 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, and summarized using 
descriptive statistics and two-sided 90% CIs. Actual values and changes from baseline in tumor 
burden will be summarized by time point. PFS, DOR, and OS will be summarized using Kaplan-
Meier analysis, including the number and percentage of patients with events, and the number of 
censored patients.
Biomarker analysis
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
PROTOCOL SYNOPSIS....................................................................................................3
TABLE OF CONTENTS ..................................................................................................15
LIST OF TABLES ............................................................................................................20
LIST OF FIGURES...........................................................................................................21
LIST OF APPENDICES ...................................................................................................21
LIST OF ABBREVIATIONS ...........................................................................................22
INTRODUCTION.......................................................................................................27
1.1
Gastric and gastro-esophageal adenocarcinoma ................................................27
1.2
Epidemiology and prognosis of gastric adenocarcinoma...................................27
1.3
Systemic therapy of advanced-stage or metastatic gastric adenocarcinoma......28
1.4
Molecular targets for targeted treatment of gastric adenocarcinoma.................29
1.5
FGFR inhibition in gastric adenocarcinoma ......................................................29
1.5.1
Current clinical evidence...............................................................................29
1.5.2
Derazantinib...................................................................................................30
1.5.3
Combination of derazantinib with either paclitaxel-ramucirumab or 
atezolizumab..................................................................................................32
1.6
Study rationale....................................................................................................34
1.6.1
Study design rationale ...................................................................................34
1.6.2
Rationale for patient reported outcomes........................................................35
1.6.3
Dosage and cycle length................................................................................36
1.7
Risk-benefit assessment .....................................................................................39
1.7.1
Derazantinib...................................................................................................39
1.7.2
Derazantinib in combination with paclitaxel, ramucirumab and 
atezolizumab..................................................................................................40
1.7.3
Conclusion to risk-benefit assessment...........................................................42
STUDY OBJECTIVES ...............................................................................................42
2.1
Primary objectives..............................................................................................42
2.1.1
Primary objective of Substudy 1 (Cohorts 1.1 and 1.2)................................42
2.1.2
Primary objective of Substudy 1 (Cohort 1.3) ..............................................42
2.1.3
Primary objective of Substudy 2 ...................................................................42
2.1.4
Primary objective of Substudy 3 ...................................................................43
2.2
Secondary objectives..........................................................................................43
2.2.1
Secondary objectives of Substudy 1..............................................................43
2.2.2
Secondary objectives of Substudy 2..............................................................43
2.2.3
Secondary objectives of Substudy 3..............................................................43


 
 
   
 
 
 
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2.3
Exploratory objectives........................................................................................44
2.3.1
Exploratory objectives specific to efficacy-estimating Substudies...............44
2.3.2
Exploratory PK objectives.............................................................................44
INVESTIGATIONAL PLAN......................................................................................44
3.1
Overview of study design...................................................................................44
3.1.1
Overview of Substudy 1 ................................................................................45
3.1.2
Overview of Substudy 2 ................................................................................46
3.1.3
Overview of Substudy 3 ................................................................................46
3.1.4
Molecular eligibility......................................................................................47
3.1.5
Pre-screening .................................................................................................47
3.1.6
Screening .......................................................................................................48
3.1.7
Treatment period............................................................................................48
3.1.8
End of Treatment / Safety Follow-up period.................................................50
3.1.9
Post-discontinuation study treatment crossover (Cohort 3.4) .......................51
3.1.10 Survival Follow-up period.............................................................................52
3.1.11 Beginning and end of the study.....................................................................53
3.2
Endpoints............................................................................................................53
3.2.1
Primary endpoints..........................................................................................53
3.2.2
Secondary endpoints......................................................................................54
3.2.3
Exploratory endpoints ...................................................................................56
3.3
Number of patients.............................................................................................56
3.4
Study sites ..........................................................................................................57
3.5
Independent Data Monitoring Committee..........................................................57
STUDY POPULATION..............................................................................................57
4.1
Target population ...............................................................................................57
4.2
Inclusion criteria.................................................................................................57
4.3
Exclusion criteria................................................................................................60
4.4
Method of treatment assignment........................................................................64
4.4.1
Substudy 1 .....................................................................................................64
4.4.2
Substudy 2 .....................................................................................................64
4.4.3
Substudy 3 .....................................................................................................64
4.5
Discontinuation from the study treatment or the study......................................65
4.5.1
Patient discontinuation from study treatment................................................65
4.5.2
Patient discontinuation from the study..........................................................66
4.5.3
Replacement of patients.................................................................................66
4.5.4
Study discontinuation ....................................................................................67
SCHEDULE OF ASSESSMENTS AND PROCEDURES.........................................67
5.1
Summary of schedule of assessments ................................................................67


 
 
   
 
 
 
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5.2
Study visits .........................................................................................................77
5.2.1
Informed consent...........................................................................................77
5.2.2
Pre-screening visit .........................................................................................77
5.2.3
Screening visit ...............................................................................................77
5.2.4
Treatment period............................................................................................79
5.2.5
Survival follow-up period..............................................................................84
5.3
Study procedures................................................................................................85
5.3.1
Screening procedures.....................................................................................85
5.3.2
Safety assessments.........................................................................................85
5.3.3
Efficacy assessments .....................................................................................89
5.3.4
Pharmacokinetic and immunogenicity assessments......................................93
5.3.5
Biomarker assessments..................................................................................96
5.3.6
PRO assessments (Substudy 3 only) .............................................................97
STUDY TREATMENTS.............................................................................................99
6.1
Investigational products .....................................................................................99
6.1.1
Derazantinib...................................................................................................99
6.1.2
Paclitaxel .....................................................................................................105
6.1.3
Ramucirumab ..............................................................................................107
6.1.4
Atezolizumab...............................................................................................110
6.1.5
Dosing schedule...........................................................................................112
6.1.6
Dose modifications of combination treatments...........................................112
6.1.7
Duration of treatment...................................................................................118
6.2
Treatment compliance......................................................................................118
6.2.1
Treatment compliance for derazantinib.......................................................118
6.2.2
Treatment compliance for paclitaxel-ramucirumab and atezolizumab .......119
6.3
Prior treatment..................................................................................................119
6.4
Concomitant treatments....................................................................................119
6.4.1
Permitted treatment......................................................................................120
6.4.2
Prohibited treatment / Treatment to be avoided or used with caution.........120
SAFETY ....................................................................................................................122
7.1
Warnings and precautions................................................................................122
7.1.1
Derazantinib.................................................................................................122
7.1.2
Paclitaxel .....................................................................................................122
7.1.3
Ramucirumab ..............................................................................................122
7.1.4
Atezolizumab...............................................................................................122
7.1.5
Contraception and pregnancy......................................................................123
7.2
Definitions........................................................................................................123
7.2.1
Adverse event ..............................................................................................123


 
 
   
 
 
 
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7.2.2
Serious adverse event ..................................................................................124
7.2.3
Unexpected adverse event or serious adverse event....................................125
7.2.4
Suspected adverse event or serious adverse event.......................................125
7.2.5
Suspected unexpected serious adverse reaction ..........................................125
7.2.6
Adverse events of special interest ...............................................................125
7.2.7
Further adverse event and serious adverse event definitions ......................126
7.2.8
Treatment-emergent adverse events............................................................126
7.3
Evaluation of adverse events............................................................................126
7.3.1
Grading of severity......................................................................................126
7.3.2
Assessment of causality...............................................................................126
7.3.3
Dose-limiting toxicities ...............................................................................127
7.4
Handling of safety information and collection periods....................................128
7.4.1
Responsibilities and procedures ..................................................................128
7.4.2
Handling of safety data during the pre-treatment period.............................128
7.4.3
Handling of safety data during the treatment period and up to the last 
scheduled follow-up and post-follow up period..........................................128
7.4.4
Handling of post-study safety data..............................................................131
7.4.5
Reporting and handling of pregnancies.......................................................131
7.5
Adverse events associated with an overdose or error in drug 
administration...................................................................................................132
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ............................132
8.1
Sample size considerations by substudy ..........................................................132
8.1.1
Substudy 1 ...................................................................................................133
8.1.2
Substudy 2 ...................................................................................................134
8.1.3
Substudy 3 ...................................................................................................135
8.2
Analysis populations ........................................................................................135
8.2.1
Safety population.........................................................................................135
8.2.2
Intent-to-treat population.............................................................................136
8.2.3
Modified intent-to-treat population .............................................................136
8.2.4
Per-protocol population...............................................................................136
8.2.5
MTD population (Substudy 2 only) ............................................................136
8.2.6
RP2D population (Substudy 2 only)............................................................137
8.2.7
Pharmacokinetic analysis population ..........................................................137
8.3
Statistical and analytical methods ....................................................................137
8.3.1
Patient demographics, medical history, and other baseline 
characteristics ..............................................................................................137
8.3.2
Study drug exposure and compliance..........................................................138
8.3.3
Prior and concomitant treatments................................................................138
8.3.4
Dose-limiting toxicity..................................................................................138


 
 
   
 
 
 
 
 
 
 
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8.3.5
Efficacy analysis..........................................................................................138
8.3.6
Safety data analysis .....................................................................................140
8.3.7
Pharmacokinetic analysis ............................................................................141
8.3.8
Biomarker analysis ......................................................................................142
8.3.9
PRO analysis ...............................................................................................142
8.3.10 Handling of missing data and discontinuations...........................................142
STUDY ADMINISTRATION AND REGULATORY ASPECTS ..........................142
9.1
Study records....................................................................................................142
9.1.1
Investigator Site File....................................................................................142
9.1.2
Case report forms ........................................................................................143
9.1.3
Patient source documents ............................................................................143
9.1.4
Document retention and archiving ..............................................................143
9.2
Sample retention...............................................................................................143
9.3
Clinical monitoring ..........................................................................................144
9.4
Audits and inspections .....................................................................................144
9.5
Protocol amendments.......................................................................................144
9.6
Premature termination of the study..................................................................145
9.7
Publication policy.............................................................................................145
ETHICS AND GOOD CLINICAL PRACTICE .......................................................146
10.1 Good Clinical Practice .....................................................................................146
10.2 Informed consent..............................................................................................146
10.3 Patient confidentiality and data protection.......................................................147
10.4 Independent Ethics Committees / Institutional Review Boards.......................147
PROTOCOL VERSION HISTORY..........................................................................147
REFERENCES ..........................................................................................................148
APPENDICES ...........................................................................................................156


 
 
   
 
 
 
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LIST OF TABLES
Table 1
Schedule of assessments for Substudy 1...................................................68
Table 2
Schedule of assessments for Substudy 2...................................................70
Table 3
Schedule of assessments for Substudy 3 (except Cohort 3.3)..................72
Table 4
Schedule of assessments for Cohort 3.3 ...................................................75
Table 5
ECOG performance status ........................................................................86
Table 6
Imaging and treatment after first radiologic evidence of PD if 
iRECIST is followed (for Cohort 3.3 only)..............................................92
Table 7
Rich PK in Substudy 1 (first ten patients in Cohorts 1.3) with 
derazantinib 200 mg BID as monotherapy ...............................................93
Table 8
Rich PK in the Dose-finding Part of Substudy 2 with derazantinib-
paclitaxel-ramucirumab combination therapy ..........................................94
Table 9
Sparse PK sampling in Cohorts 1.1, 1.2, 1.3, and 3.1 with 
derazantinib monotherapy.........................................................................94
Table 10
Sparse PK sampling in Cohort 3.2 with derazantinib-paclitaxel-
ramucirumab combination therapy...........................................................95
Table 11
Sparse PK and ADA sampling in Cohort 3.3 with derazantinib-
atezolizumab combination therapy...........................................................95
Table 12
Sparse PK sampling in Cohort 3.4 with paclitaxel-ramucirumab 
combination therapy .................................................................................96
Table 13
Derazantinib dose reduction scheme ......................................................101
Table 14
Dose delays/reductions for drug-related toxicity....................................103
Table 15
Criteria for paclitaxel treatment on D1 of Cycles 2+..............................113
Table 16
Criteria for ramucirumab treatment on D1 and D15 of each cycle.........113
Table 17
Criteria for paclitaxel treatment on D8 and D15 of each cycle ..............114
Table 18
Criteria for derazantinib-paclitaxel-ramucirumab combination 
treatment on D1 of Cycle 2+...................................................................116
Table 19
Criteria for derazantinib-paclitaxel-ramucirumab combination 
treatment on D8 and/or D15 of each cycle .............................................117
Table 20
Estimated type I and II errors (Cohorts 1.1 and 1.2)..............................134
Table 21
Metrics of Fleming’s two-stage design (Cohort 1.3)..............................134
Table 22
Estimated type I and II errors in efficacy-estimating cohorts in 
Substudy 3...............................................................................................135


 
 
   
 
 
 
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LIST OF FIGURES
Figure 1
Overview of study design ...........................................................................4
Figure 2
Frequency of FGFR genetic aberrations in HER2neg gastric cancer.........32
Figure 3
Overview of study design .........................................................................45
Figure 4
Overview of Substudy 2 ...........................................................................50
LIST OF APPENDICES
Appendix 1
Eligible FGFR genetic aberrations .........................................................156
Appendix 2
Assessment of anti-tumor activity per RECIST v. 1.1 ...........................157
Appendix 3
Comparison of RECIST 1.1 and iRECIST criteria.................................166
Appendix 4
Management of atezolizumab-specific adverse events...........................167
Appendix 5
Collection and management of specimens for future biomedical 
research ...................................................................................................179
Appendix 6
Understanding the intent, scope and public health benefits of 
exploratory biomarker research ..............................................................182
Appendix 7
Examples of in vivo substrates, inhibitors, and inducers for specific 
CYP enzymes..........................................................................................194
Appendix 8
Examples of in vivo substrates, inhibitors, and inducers of 
P-glycoprotein.........................................................................................198
Appendix 9
Drugs with the potential to prolong QT and/or cause Torsades de 
Pointes.....................................................................................................200
Appendix 10
Criteria for evaluating relationship between adverse events and 
study drug ...............................................................................................204
Appendix 11
Investigator’s protocol signature page....................................................206


 
 
   
 
 
 
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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 
ACRG
Asian Cancer Research Group
ADA
Anti-drug antibodies
ADCC
Antibody-dependent cellular cytotoxicity
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-time curve
BICR
Blinded independent central review 
BS
Bone scan
BSA
Body-surface area
Bx
Biopsy
cfDNA
Cell-free DNA
CI
Confidence interval
CIN
Chromosomal instability
CISH
Chromogenic or silver in situ hybridization
CLCR
Creatinine clearance
Cmax
Maximum plasma concentration
CNS
Central nervous system
CRP
C-reactive protein
CSF1R
Colony-stimulating factor-1 receptor 
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse 
Events 
ctDNA
Circulating tumor DNA
                                                          
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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CxDx
Cycle (cycle number), Day (day number), e.g. 
C4D1 = Cycle 4, Day 1
CYP
Cytochrome-P450
CyTOF
Cytometry by time of flight
D0
Pretreatment phase
DCR
Disease control rate
DL
Dose level
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of response 
Dx
Day (day number)
EBV
Epstein-Barr virus
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EMT
Epithelial-mesenchymal transition
EORTC
European Organization for Research and 
Treatment of Cancer
ERK
Extracellular signal-regulated kinase
ESMO
European Society of Medical Oncology
EU
European Union
FFPE
Formalin-fixed paraffin-embedded 
FGFR
Fibroblast growth factor receptor 
FGFRfus/amp/mt
FGFR2 gene fusion, rearrangement or
amplification, or FGFR1–3 mutation
FGFR1–3mt
FGFR1–3 mutation
FGFR2fus
FGFR2 gene fusion or rearrangement
FGFR2high-amp
High-level FGFR2 gene amplification
FISH
Fluorescence in-situ hybridization
FSH
Follicle stimulating hormone 
fT3
Tri-iodothyronine
fT4
Thyroxine
GA
Genetic aberration
GAC
Gastric adenocarcinoma
GCP
Good Clinical Practice
GDPR
General Data Protection Regulation
GPP3
Good Publication Practice


 
 
   
 
 
 
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G-SET / HTI
Global Self Evaluated Transition / Health 
Transition Index 
H0
Null hypothesis 
HA
Alternative hypothesis 
HBsAg
Hepatitis B surface antigen
hCG
Local serum pregnancy test 
HCV
Hepatitis C virus
HER2
Human epidermal growth factor receptor 2
HER2neg
HER2-negative
HER2pos
HER2-positive
HIV
Human immunodeficiency virus
HR
Hazard ratios
HR-QoL
Health-related quality of life 
IB
Investigator’s Brochure
IC50
50% inhibition
iCCA
Intrahepatic cholangiocarcinoma 
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee 
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional Review Board
IRR
Infusion-related reaction
ISF
Investigator Site File
ITT
Intent-to-treat
IV
Intravenous(ly)
JAK
Janus kinase
MAPK
Mitogen-activated protein kinase
MedDRA
Medical Dictionary for Regulatory Activities 
MEK
Mitogen-activated protein kinase/extracellular 
signal-regulated kinase kinase
mITT
Modified intent-to-treat 
MMR-D
Mismatch repair-deficient 
MRI
Magnetic resonance imaging 
MSI
Microsatellite instability
MSS
Microsatellite stable
MTD
Maximum tolerated dose


 
 
   
 
 
 
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mTOR
Mammalian target of rapamycin
n
Number
NCCN
National Comprehensive Cancer Network
NE
Not evaluable
NGS
Next-generation sequencing 
OCT
Ocular coherence tomography
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD-1
Programmed cell death receptor-1 
PDGFRβ
Platelet-derived growth factor receptor β
PD-L1
Programmed death ligand-1 
PDX
Patient-derived xenograft 
PE
Polyethylene
PFS
Progression-free survival
P-gp
P-glycoprotein
PI
Prescribing Information
PI3K
Phosphatidylinositol 3-kinase
PK
Pharmacokinetic(s)
PO
Orally
PopPK
Population PK
PP
Per protocol
PRO
Patient-reported outcome
PS
Performance status
PT
Prothrombin time
PTT/aPTT
Partial thromboplastin time
PVC
Polyvinyl chloride 
QxW
Every (number) weeks
QALY
Quality-adjusted life-year
QD
Once daily
QLQ-C30
Quality of Life Questionnaire-Core 30
QLQ-STO22
Quality of Life Questionnaire-Stomach
QOD
Every other day
QTc
Corrected QT interval
QTcF 
Difference between QTc corrected by 
Fridericia’s formula
RET
Rearranged during transfection
RNA
Ribonucleic acid
RNAseq
RNA sequencing


 
 
   
 
 
 
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RP2D
Recommended Phase 2 dose
RTK
Receptor tyrosine kinase
RTSM
Randomization and Trial Supply Management
SAE
Serious adverse event
SAP
Statistical Analysis Plan 
SIAP
Safety interim analysis patients
SmPC
Summary of Product Characteristics
SoC
Standard of care
SOP
Standard Operating Procedure
STAT
Signal transducer and activator of transcription
SUSAR
Suspected unexpected serious adverse reaction
SV
Screening visit
t1/2
Elimination half-life
TCGA
The Cancer Genome Atlas
TEAE
Treatment-emergent adverse event
tmax
Time to peak (maximum) plasma concentration
TP53
Tumor protein p53
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
UPCR
Urine protein-creatinine ratio
USA
United States of America
UTI
Urinary tract infection
VAS
Visual analog scale 
VEGFR
Vascular endothelial growth factor receptor
WBMRI
Whole-body magnetic resonance imaging


 
 
   
 
 
 
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INTRODUCTION
1.1
Gastric and gastro-esophageal adenocarcinoma
Gastric adenocarcinoma is the most common histological type (~95%) of all stomach 
malignancies and can originate from the fundus, corpus or antrum of the stomach. 
Gastro-esophageal adenocarcinomas originate from the cardia and gastro-esophageal 
junction region and are further anatomically classified by the Siewert-Stein classification 
(Siewert 1998). Gastric and gastro-esophageal adenocarcinomas (hereafter sub-
summarized under ‘gastric adenocarcinoma’ and abbreviated as GAC) have two major 
histological phenotypes: the intestinal type with well-to-moderately-well-differentiated 
histology and the diffuse type with poorly differentiated histology (Ajani 2017, 
Lauren 1965). A World Health Organization (WHO) classification provides detailed 
descriptions of histological features and classifies GAC into tubular, papillary, mucinous, 
mixed and poorly cohesive carcinomas (Bosman 2010). 
At the molecular level, The Cancer Genome Atlas (TCGA) has proposed four subtypes: 
1) Epstein-Barr virus-positive (EBV+) tumors; 2) microsatellite instability (MSI)-high 
tumors; 3) genomically stable tumors; and 4) tumors with chromosomal instability (CIN) 
(Bass 2014). Although different terminology and somewhat different groupings to the 
TCGA were used, the Asian Cancer Research Group (ACRG) subtyping generally (but not
exactly) validated the TCGA findings and four subgroups: 1) tumors that are microsatellite 
stable (MSS) and have intact tumor protein p53 (TP53; MSS/TP53+); 2) MSI-high; 3) MSS
and expressing epithelial-mesenchymal transition signatures (EMT; MSS/EMT); and 4) 
MSS and have TP53 mutations (MSS/TP53–). In addition, ACRG provided clinical 
information: patients with MSI-high or EBV-associated GAC had longer survival than 
those with the MSS/EMT subtype, and patterns of recurrence suggested that patients with 
MSS/EMT group tumors had higher rates of recurrence than the MSI-high group (63% 
versus 23%) and more frequently developed peritoneal metastases (Cristescu 2015). To 
date, these two classifications have some similarity and may guide novel target therapies 
to improve unsatisfactory outcomes, although neither has been validated as clinically 
relevant tools as of now.
1.2
Epidemiology and prognosis of gastric adenocarcinoma
In 2018, there were an estimated 1,033,700 new cases of GAC and 783,000 deaths from 
the disease worldwide (Bray 2018), making it the fifth most frequently diagnosed cancer 
and the third leading cause of cancer death. Incidences are 2-fold higher in men than in 
women, with rates of 32.1 and 13.2 per 100,000 men and women, respectively, in Eastern 
Asia (eg, in Mongolia, Japan and the Republic of Korea [the country with the highest rates 
worldwide in both sexes]). The incidence in Northern America is generally low with rates 
of 5.6 and 2.8 per 100,000 men and women, respectively (Bray 2018). There is a notable 
difference across Europe with incidence rates lowest in Northern Europe (6.2 and 3.1 per 
100,000 men and women, respectively) increasing to 8.2/3.7, 10.4/5.0 and 17.1/7.5 per 
100,000 men and women in Western, Southern and Eastern Europe, respectively 
(Bray 2018). 


 
 
   
 
 
 
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While early stage GAC is associated with a 5-year survival rate of up to 95% (Crew 2006), 
advanced-stage GAC (which cannot be surgically treated) has a median survival of 
~9–10 months (Ajani 2016). Despite improvements in endoscopic, surgical and systemic 
treatments the global 5-year survival rates remain unsatisfactory (~25–30%;
Verdecchia 2007), with the exception of those in Japan and South Korea (> 50%;
Torre 2016), a difference that can be attributed to early detection efforts in these Asian 
countries.
1.3
Systemic therapy of advanced-stage or metastatic gastric adenocarcinoma
Only patients with early stage disease and deemed medically fit are considered candidates 
for surgical procedures with curative intent. Patients with surgically unresectable GAC (or 
deemed unfit for surgery), and all patients with metastatic disease are candidates for 
conventional chemotherapy consisting of a platinum compound (with oxaliplatin preferred 
over cisplatin) and a fluoropyrimidine (oral or intravenous) (Ajani 2016, Smyth 2016a). 
Three-drug chemotherapeutic regimens and the use of epirubicin are discouraged
(Ajani 2016, Elimova 2017, Smyth 2016a). Trastuzumab (an anti-human epidermal growth 
factor receptor 2 [HER2] antibody) is recommended with chemotherapy in the first-line 
setting for patients with HER2pos GAC (Bang 2010). From a scientific and medical 
perspective, ramucirumab (an anti-vascular endothelial growth factor receptor [VEGFR] 2 
antibody) plus paclitaxel is recommended as a standard second-line treatment 
(Wilke 2014); single-agent ramucirumab may be used as a salvage treatment (Fuchs 2014).
The cost-effectiveness of the combination of paclitaxel and ramucirumab has been 
questioned (Hall 2016a, Lam 2017, Saito 2017), which led to variable reimbursement 
decisions. For patients with HER2-negative (HER2neg) metastatic GAC, the most widely 
recommended first-line regimen is fluoropyrimidine and platinum, and the most widely 
recommended second-line regimen is the combination of paclitaxel and ramucirumab. Per 
European Society of Medical Oncology (ESMO) and National Comprehensive Cancer 
Network (NCCN) guidelines for the treatment of gastric cancer, there is evidence and 
consensus for second-line chemotherapy with a taxane (docetaxel, paclitaxel), or 
irinotecan, or ramucirumab (either as a single agent or in combination with paclitaxel) for 
patients who are of Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) 0–1 (Ajani 2016, Smyth 2016a).
Given the propensity for tumors to develop resistance, the role of taxanes as a first-line 
treatment option is under debate, however, from a global perspective, taxanes are usually 
reserved for second-line treatment after failure of first-line treatment for metastatic disease 
or disease progression within 6 months of (neo)adjuvant or perioperative treatment 
(including radiotherapy in some regions). Given the sometimes preserved susceptibility of 
some tumors to repeated taxane-challenge, some Investigators have adopted the possibility 
to re-expose patients to taxane treatment under certain considerations and criteria for 
patient predisposition, even though this approach has not been systematically investigated 
(Ghosn 2016).


 
 
   
 
 
 
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1.4
Molecular targets for targeted treatment of gastric adenocarcinoma
At the molecular level, four subtypes have been proposed by TCGA and ACRG 
(Cristescu 2015, Bass 2014). Of these subtypes, CIN (50% of all GACs) and MSS/TP53–
(36% of all GACs) tumors frequently harbor molecular aberrations in receptor tyrosine 
kinases (RTKs) and some of their signaling molecules are common in GACs (Bass 2014,
Riquelme 2015, Elimova 2015, Ajani 2017). RTK amplifications are caused by 
chromosomal instability, whereby deoxyribonucleic acid (DNA) breaks lead to gene 
amplifications (Tanner 2005). Targeted therapies against these RTKs using either 
small-molecule inhibitors or antibodies have been extensively developed and tested in 
non-clinical and clinical trials. Although clinical outcomes for most have been 
disappointing (Ajani 2017), targeted therapies against HER2, VEGFR and related kinases 
have shown modest benefits (Bang 2010, Wilke 2014, Fuchs 2014, Li 2016). Interestingly, 
HER2 amplifications and fibroblast growth factor receptor 2 (FGFR2) gene rearrangement 
/ amplification appear to be almost completely mutually exclusive as previously reported 
(Das 2014) and per a recent search in Foundation Medicine’s FoundationInsight™ 
database (Basilea data on file, FoundationInsights™, 2020).
The RAINBOW trial was the landmark trial that established the role of ramucirumab, a 
monoclonal antibody inhibiting VEGFR2, as a valuable addition to second-line treatment 
for GAC patients. The RAINBOW trial, a double-blind, phase III, randomized trial, 
indicated that the addition of ramucirumab to paclitaxel resulted in a significant survival 
advantage when compared with paclitaxel monotherapy, with a median overall survival 
(OS) of 9.6 months ([95% confidence interval (CI): 8.5-10.8] versus 7.4 months [95%CI: 
6.3-8.4], hazard ratio [HR] = 0.807 [95%CI: 0.678-0.962], p = 0.017); progression-free 
survival (PFS) of 4.4 months versus 2.9 months (HR = 0.635, p < 0.0001) and an objective 
response rate (ORR) of 28% versus 16% (p < 0.0001) (Wilke 2014). Combination therapy 
also resulted in an increased incidence of adverse events (AEs) including neutropenia (but 
not febrile neutropenia) and hypertension, but global quality of life scores were similar in 
both treatment arms, attesting to the tolerability of adding the anti-angiogenic agent 
(Wilke 2014).
1.5
FGFR inhibition in gastric adenocarcinoma
Activation of FGFR is a common oncogenic mechanism, occurring in a subset of nearly 
all common cancers (Babina 2017, Turner 2010). Activating genetic aberrations in the 
FGFR genes in carcinomas result in receptor amplification, mutation, and generation of 
aberrant receptor fusions through translocation (Babina 2017, Turner 2010).
1.5.1
Current clinical evidence
Among several druggable molecular alterations found in GAC, amplification and/or
overexpression of the FGFR2 gene have elicited continued interest for target therapy of 
GAC (Van Cutsem 2017, Pearson 2016, Smyth 2016b, Lee 2016, Bang 2015). This is 
despite results from a recent randomized Phase 2 study that demonstrated that the 
monotherapy with an FGFR inhibitor (AZD4547) was not superior to paclitaxel with 
regard to progression-free survival of patients with any FGFR2 amplification or polysomy 
(Van Cutsem 2017, Pearson 2016). Data from an accompanying translational research 


 
 
   
 
 
 
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effort, however, indicated that the strategy for patient stratification for AZD4547 treatment 
may not have been optimal (Pearson 2016). Using cell lines and patient-derived xenograft 
(PDX) models, the translational clinical study showed that only high-level FGFR2
amplification (i.e., a ratio of FGFR2 gene to chromosome-10 centromer signals > 5) 
initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated 
transactivation of alternative receptor kinases and bringing phosphatidylinositol 3-kinase
(PI3K)/mammalian target of rapamycin (mTOR) signaling under FGFR control (Pearson 
2016). Further independent studies using the selective covalent FGFR inhibitor TAS-120
and the antibody-dependent cellular cytotoxicity (ADCC)-enhanced, FGFR2b isoform-
specific monoclonal antibody bemarituzumab (FPA144) reported clinical activity in 
patients with high-level FGFR2 amplification (Kuboki 2017) and high FGFR2b expression 
(Catenacci 2017), respectively.
1.5.2
Derazantinib
Derazantinib is an FGFR1–3 inhibitor with potential activity against other kinases. In 
biochemical studies, derazantinib showed potent activity against both wild-type and 
variants of the FGFR kinases (FGFR1–3), with inhibitor concentration values required for 
50% inhibition (IC50) in the low nM range. Less activity, but within 2–10 fold of FGFR2 
activity (IC50 of 5.2 nM), was observed for a number of other kinases relevant to anti-tumor 
treatment, i.e., VEGFR2, platelet-derived growth factor receptor β (PDGFR, KIT, 
rearranged during transfection (RET), colony-stimulating factor-1 receptor (CSF1R), and 
the Src family kinases (Hall 2016b).
With regard to the study treatment and drug combinations investigated in this study, it 
should be noted that derazantinib also has an IC50 of 31.7 nM for VEGFR2 (with a 
VEGFR2-to-FGFR2 ratio of 6) and an IC50 of 16.2 nM for CSF1R (with a CSF1R-to-
FGFR2 ratio of 3). In addition, CSF1R kinase inhibition seems to be a unique characteristic 
of derazantinib among FGFR inhibitors (Basilea, data on file, 2019). Structural CSF1R 
kinase inhibition seems to be a unique characteristic of derazantinib among FGFR 
inhibitors (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 adenosine triphosphate (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 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 90 human tumor
cell-lines, IC50s for inhibition of proliferation ranged from 0.01–20 µM, with the more 
sensitive lines being associated with high FGFR expression (1/2/3) or specific activating 
mutations. Non-clinical studies demonstrated potent inhibition of tumor growth in FGFR 
pathway-activated models, including in FGFR-driven (amplification/fusion/mutation) 
tumor xenografts grown subcutaneously in nude mice (Hall 2016b, Basilea data on-file).


 
 
   
 
 
 
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In PDX models, a similar distinct oncogene addiction phenotype, characterized by FGFR2
gene fusions has been observed. Gastric cancer PDX models with FGFR2 gene fusions 
showed a strong response to derazantinib characterized by regressions of more than 50%, 
which was consistent across all fusion-carrying models. PDX models as well as cell lines 
with FGFR2 amplification also responded to some extent, and response seemed to be 
associated with concurrent gene expression, while no correlation between amplification 
and gene expression was noted, which was consistent with previous reports 
(Pearson 2016). Models with other FGFR genetic aberrations (including FGFR1, 2 or 3
mutations) showed variable responses to treatment with derazantinib (Basilea data on file, 
2019), sufficient to warrant clinical investigation.
As outlined in Appendix 1, FGFR2 gene fusions or other rearrangements with breakpoints 
up- or downstream of the kinase domain will include in-strand and in-frame fusions, as 
well as those rearrangements likely to be a functional event but with insufficient data for a 
fusion call by the NGS test algorithm. Also included will be FGFR2 in-gene 
rearrangements (translocations, deletions, truncations, splice site variants) as well as 
nonsense variants C-terminal of the TK domain (exon 17 and downstream). For high-level 
FGFR2 gene amplification, the quantitative correlate of > 10 FGFR2 gene copy numbers  
called by the NGS algorithm of the central diagnostic test will be considered for enrollment
to reflect the findings of translational clinical studies in gastric cancer specimens 
(Pearson 2016). For small variants in FGFR1–3 (‘FGFR1–3mt’), missense point mutations 
(single base substitutions) other than known inactivating substitutions, in-frame deletions,
and insertions, will be included. Patients with GAC harboring nonsense variants and frame 
shifts either in or upstream of the kinase domain will be excluded.
As shown in Figure 2, it is estimated that approximately 9% of patients with advanced or 
metastatic gastric cancer have an FGFR2 gene fusion or rearrangement (‘FGFR2fus’), high-
level FGFR2 gene amplification (‘FGFR2high-amp’), and/or small variants (i.e., mutations) 
in either FGFR1, 2 or 3 (FGFR1–3mt) annotated as functional genetic aberrations, hereafter 
collectively 
summarized 
as 
‘FGFRfus/amp/mt’
(Basilea 
data 
on 
file
2020, 
FoundationInsights™, January 2020, Pearson 2016, Helsten 2016, Das 2014, Su 2014,
Liu 2014, Ahn 2016, Van Cutsem 2017). Some studies suggest an adverse prognostic 
impact of FGFR2 signalling (Kim 2019, Ahn 2016), supporting a clinical role for 
therapeutic FGFR targeting. Based on a recent search in FoundationInsights™, known or 
likely functional FGFR2 gene rearrangements, FGFR2 copy number changes (more than 
10 gene copies), or FGFR1–3 mutations were found at a prevalence of approximately 
2.8%, 
3.2% and 4.6% of
specimens, respectively 
(Basilea 
data on file, 
FoundationInsights™, 2020), among 5,210 largely advanced HER2neg gastric cancer test 
specimens, supporting data found in various series reported in recent literature as indicated 
above. 
Of note, a majority of cases harboring known or likely functional FGFR2 gene fusions or
rearrangements (93 of 144 cases, 65%) are reported to also harbor high-level FGFR2 copy 
number changes (Figure 2), and for both genetic aberrations, non-clinical studies, including 
studies with derazantinib, have consistently reported susceptibility to FGFR-inhibiting 
treatment (McSheehy 2020, Chen 2019, Pearson 2016). Consequently, it is hypothesized 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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that derazantinib may be a suitable treatment option for advanced or metastatic patients 
with gastric and gastro-esophageal adenocarcinoma harboring FGFR genetic aberrations.
Figure 2
Frequency of FGFR genetic aberrations in HER2neg gastric cancer
Abbreviations: CN, copy number; RE, fusion or rearrangement; SV, small variant.
Source: Basilea data on file, FoundationInsights™, January 2020.
1.5.3
Combination of derazantinib with either paclitaxel-ramucirumab or 
atezolizumab
Derazantinib is an investigational drug and is not yet registered in any indication globally. 
Paclitaxel itself is not approved for the treatment of patients with GAC but is approved in 
combination with ramucirumab (Cyramza®) in patients with GAC whose cancer has 
progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. 
In addition, both ESMO and NCCN guidelines consider paclitaxel-ramucirumab as a 
preferred treatment option for GAC patients whose cancer has progressed on or after prior 
fluoropyrimidine- or platinum-containing chemotherapy (Ajani 2016, Smyth 2016a). 
The anti-vascular effects and anti-angiogenesis effects of weekly administration of 
paclitaxel has been comprehensively reviewed (Bocci 2013) and with the approval of 
ramucirumab, the paradigm of anti-angiogenesis treatment with VEGFR2-blocking 
compounds has been recommended for the treatment of GAC patients in current EU and 
U.S. guidelines (Ajani 2016, Smyth 2016a). Of note, derazantinib may provide additional 
inhibition of VEGFR2 signaling based on its low IC50 of 31.7 nM for VEGFR2 (with a 
VEGFR2-to-FGFR2 ratio of 6), which may augment the treatment effect of the standard 
paclitaxel-ramucirumab regimen.
Clinical studies have suggested an adverse prognostic impact of FGFR2 signalling (Kim 
2019, Ahn 2016). Non-clinical in vivo studies using patient-derived gastric cancer 
xenografts harboring FGFR2 fusions or rearrangements have suggested a clearly 


 
 
   
 
 
 
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differential and superior efficacy of derazantinib over that of paclitaxel in these 
FGFR-driven tumors (McSheehy 2020). These findings support the clinical research 
approach of challenging paclitaxel as the mainstay of second-line treatment as proposed in 
Substudy 3, provided that the efficacy-estimating Substudy 1 provides a clinically 
meaningful efficacy signal in the biomarker-defined patient population.
The rationale for combining derazantinib with paclitaxel is further supported by the 
findings from non-clinical in vivo studies with SNU-16 gastric cancer cell line xenografts 
in mice, which is known to harbor both FGFR2 fusions or rearrangements and high-level 
FGFR2 amplification. These studies have shown that the combination of paclitaxel at the 
MTD with derazantinib at approximately half the MTD in a comparative study design 
clearly and consistently outperformed the efficacy of either drug as monotherapy, 
suggesting a potential synergistic effect of a paclitaxel-derazantinib combination treatment 
(Basilea, data on file 2020). The recommended phase 2 dose (RP2D) of the derazantinib-
paclitaxel-ramucirumab combination will be established in Substudy 2.
Atezolizumab (Tecentriq®) is a programmed death ligand-1 (PD-L1) blocking antibody 
indicated for the treatment of patients with locally advanced or metastatic urothelial 
carcinoma or metastatic non-small cell lung cancer. In the Phase 3 study DANTE 
(Al-Batran 2019), atezolizumab is currently being investigated as a perioperative treatment 
in combination with FLOT chemotherapy (fluorouracil-leucovorin, oxaliplatin and 
docetaxel) in GAC patients (NCT03421288). The role of adding immune-checkpoint 
blockade to the treatment armamentarium is currently the subject of extensive clinical 
research (Moehler 2020, Tabernero 2019). 
With regard to derazantinib and from data obtained in comparative kinase screens of known 
FGFR inhibitors, CSF1R kinase inhibition seems to be a unique characteristic of 
derazantinib (Basilea, data on file, 2019). In the context of the putative role of CSF1R 
inhibition to bypass tumor-induced immunosuppression, restore T cell activity, 
downregulate immunosuppressive macrophage activity and improve susceptibility to 
therapeutic immune checkpoint blockade using anti-programmed cell death receptor-1 
(PD-1)/PD-L1 antibodies (Fleming 2018, Kim 2015, Ries 2014), the dual targeting of 
immunosuppressive stromal cells via CSF1R and PD-L1 to revert immune escape of tumor 
cells plus the target therapy of FGFR-driven tumor cells form a rationale to explore the 
potential benefit of derazantinib-atezolizumab in combination, which is investigated in 
Substudy 3 under this protocol. Of note, derazantinib may provide clinically meaningful 
inhibition of CSF1R signaling based on both its low IC50 of 16.2 nM for CSF1R (with a 
CSF1R-to-FGFR2 ratio of 3) and the derazantinib-related reduction of phospho-CSF1R in 
a concentration-dependent manner observed in vitro, which are hypothesized to augment 
the treatment effect of the immune-checkpoint blockade recently indicated by results from 
the study KEYNOTE-062 (Tabernero 2019).
The dose for derazantinib-atezolizumab in combination is currently being established in an 
ongoing Phase 1b study DZB-CS-201 (FIDES-02, NCT04045613).


 
 
   
 
 
 
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1.6
Study rationale
1.6.1
Study design rationale
Data from derazantinib studies using PDX models (Basilea, data on file, 2019), together 
with non-clinical
and clinical data from other studies
with FGFR inhibitors 
(Catenacci 2017, Kuboki 2017, Van Cutsem 2017, Pearson 2016), have indicated activity 
of FGFR inhibiting treatment in target patient populations enriched for FGFR-driven 
tumors. Combining the potentially beneficial impact of FGFR inhibition (using 
derazantinib) and dual targeting of immunosuppressive stromal cells via CSF1R (conferred 
by derazantinib) and PD-L1 (using atezolizumab), the study will also investigate whether 
the addition of derazantinib to atezolizumab results in a clinical benefit for GAC patients. 
This study design also takes into consideration that derazantinib may provide sufficient 
efficacy (McSheehy 2020) to replace a cytotoxic agent like paclitaxel in a patient 
population defined by FGFR-driven tumors.
Paclitaxel-ramucirumab is the recommended standard-of-care for GAC patients with 
disease progression after first-line treatment with fluoropyrimidine and a platinum 
compound. The standard therapy of paclitaxel-ramucirumab is considered a suitable 
treatment for GAC patients irrespective of the molecular characteristics of the underlying 
disease. The mode-of-action of both compounds is considered to target the general 
oncogenic characteristics of proliferation and angiogenesis. In select populations defined 
by a molecular marker with oncogenic potential that may not be sufficiently targeted by 
the mechanisms of standard treatment, the approach of using both alternative and additional 
treatments may provide better and additive, or even synergistic, benefits, This approach is 
supported by the superior non-clinical efficacy of derazantinib monotherapy over 
paclitaxel, as well as the activity in FGFR2-driven patient-derived xenografts, and the 
potential synergistic effect of the derazantinib-paclitaxel combination in a cell line 
xenograft harboring both FGFR2 fusions and high-level FGFR2 amplification. Taken 
together, this provides the rationale for attempting to provide a well-tolerated effective 
targeted single-agent treatment, and/or improving the performance of paclitaxel-
ramucirumab in GAC patients carrying FGFR genetic aberrations.
Recent reports have indicated an anti-angiogenic effect of paclitaxel (Tonissi 2015,
Fung 2014, Bocci 2013) in addition to the known anti-proliferative effect. The combination
of the anti-angiogenic and anti-proliferative effects of paclitaxel with the growth-inhibiting 
and potentially additive anti-angiogenic effects of derazantinib may cause synergistic 
effects to better control disease progression in GAC patients (McSheehy 2020, Basilea data 
on file 2020).
Accordingly, this study is designed as a multiple cohort, multi-center Phase 1b/2 study to 
investigate the efficacy of derazantinib monotherapy or combination therapy with 
paclitaxel, ramucirumab or atezolizumab for the second-line treatment of GAC patients
harboring an activating FGFR genetic aberration. 


 
 
   
 
 
 
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Based on findings that the coexistence of HER2 amplification and FGFR genetic 
aberrations has been rarely found to date, the study will prescreen and enroll only patients 
with HER2neg GAC, and will therefore not compete with potentially emerging 
HER2-directed treatment options. 
The study comprises the following three open-label substudies:

Substudy 1: As of Protocol Version 5.0, this Substudy has been modified with the 
addition of Cohort 1.3 targeting a population identical to that being investigated in 
ongoing Cohorts 1.1 and 1.2. GAC patients with specified FGFR genetic aberrations, 
after either first- or second-line treatment, and no approved treatment alternative are 
to be treated with derazantinib 200 mg BID in Cohort 1.3, with the aim of evaluating 
the safety, tolerability, and efficacy of derazantinib monotherapy in this patient 
population (for the rationale, see Section 1.6.3.1). 

Substudy 2: This Substudy will enroll GAC patients with specified FGFR genetic 
aberrations after standard first-line treatment, with the aim of evaluating the safety, 
tolerability, and efficacy of derazantinib-paclitaxel-ramucirumab in combination and 
determining the RP2D.

Substudy 3: This Substudy will enroll GAC patients with FGFR genetic aberrations 
indicative of response to derazantinib (per Substudy 1), with the aim of evaluating the 
efficacy of derazantinib, derazantinib-paclitaxel-ramucirumab and derazantinib-
atezolizumab in combination, and comparing their efficacy to that of paclitaxel-
ramucirumab in this patient population.
1.6.2
Rationale for patient reported outcomes
Patient Reported Outcomes (PROs) provide an understanding of the impact a treatment has 
on a patient. For patients with GAC, it is imperative to balance survival benefit with health-
related quality of life (HR-QoL) (Ajani 2017). In Phase 3 studies investigating 
chemotherapy with the addition of trastuzumab or ramucirumab, the addition of target 
therapy improved overall survival without compromising HR-QoL, as measured by 
validated HR-QoL questionnaires (Quality of Life Questionnaire-Core 30 [QLQ-C30] and 
EQ-5D) (Al-Batran 2016, Satoh 2014).
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.
The European Organization for Research and Treatment of Cancer (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 EORTC Quality 
of Life Questionnaire-Stomach (QLQ-STO22) is a gastric cancer-specific module which 
has been developed to be used in combination with the EORTC QLQ-C30.


 
 
   
 
 
 
 
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Global Self Evaluated Transition (G-SET) / Health Transition Index (HTI) 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 EORTC 
QLQ-STO22 scales. It will be administered twice during the study.
1.6.3
Dosage and cycle length
In Substudies 1 and 2 as well as Cohorts 3.1, 3.2 and 3.4, a treatment cycle is 28 days to 
follow the routine cycle interval of derazantinib and paclitaxel-ramucirumab in 
combination, respectively. In Cohort 3.3, owing to the treatment schedule of atezolizumab, 
a treatment cycle is 21 days.
Derazantinib dose
In a clinical Phase 1/2 study (ARQ 087-101), the maximum tolerated dose (MTD) of 
derazantinib monotherapy was declared as 400 mg once daily (QD), and the RP2D was 
determined 
as 
continuous 
oral 
administration 
of 
300 mg 
derazantinib 
QD 
(Papadopoulos 2017). In the Phase 2 Part of this study, derazantinib demonstrated 
encouraging anti-tumor activity and a manageable safety profile in patients with advanced, 
unresectable intrahepatic cholangiocarcinoma (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 transaminase 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 the food-effect study DZB-CS-103 and the mass 
balance study DZB-CS-102 have become 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), have been completed. 
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 GAC 
patients.
The primary endpoint of 4-month PFS rate in the Substudy 1.3 cohort will address the 
disease state of the emerging target population (predominant enrollment of third-line 
patients) and the acknowledged clinical objective of palliative disease stabilization with 


 
 
   
 
 
 
 
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prolonged progression-free intervals and moderate treatment-related toxicity rather than 
aggressive tumor shrinking regimens. Recent controlled phase 2 and 3 studies have 
demonstrated the clinical value of palliative third-line treatment of GAC patients using 
disease control rate and 4-month PFS rate as primary endpoints (Shitara 2018, 
Bando 2016).
Derazantinib dose in combination with paclitaxel-ramucirumab
To date, the safety profiles of derazantinib and paclitaxel-ramucirumab have only been 
studied individually (Mazzaferro 2019, Papadopoulos 2017,
Van Cutsem 2017,
Wilke 2014). The following safety-oriented considerations drive the dose-finding design 
to investigate the combination of standard paclitaxel-ramucirumab with derazantinib.
DLTs of paclitaxel are neutropenias with infections and severe acute hypersensitivity 
reactions across all dose levels routinely administered. Myelosuppression, neutropenia 
(with and without infections), anemia, thrombocytopenia, leukopenia, bleeding; minor 
hypersensitivity reactions (mainly flushing and rash); neurotoxicity (mainly peripheral 
neuropathy); nausea, vomiting and diarrhea; infections; mucosal inflammation; alopecia; 
arthralgia and myalgia are classified as very common side effects (Paclitaxel Ever Pharma 
SmPC). Taken together, the majority of anticipated side effects of pacalitaxel potentially 
overlapping with derazantinib, including diarrhea, vomiting, nausea, elevation in AST and 
bilirubin, can be managed by either supportive care measures or dose modifications 
routinely applied in the studied disease population (see Section 6.1.1.5 and 6.1.2.7).
In the Phase 1 study of ramucirumab, patients developed dose-limiting hypertension and 
deep venous thromboses at 16 mg/kg QW, and the next lower dose of 13 mg/kg QW was 
considered the MTD (Spratlin 2010). However, the recommended dose for single-agent 
ramucirumab was determined as 8 mg/kg Q2W, which was used in the REGARD trial, the 
pivotal Phase 3
study in patients with gastric or gastro-esophageal junction 
adenocarcinoma (Fuchs 2014). Hypertension, infusion-related reactions, impaired wound 
healing, hemorrhage, arterial thromboembolic events, gastrointestinal perforation and 
reversible posterior leukoencephalopathy syndrome are classified as AEs of special interest 
(AESIs) (Cyramza® USPI, Cyramza EPAR). 
The Grade 3 or higher treatment-emergent toxicities seen most frequently with 
ramucirumab-paclitaxel (8 mg/kg ramucirumab as a 1-hour infusion on Day 1 (D1) and 
D15 plus 80 mg/m2 paclitaxel as a 1-hour infusion on D1, D8, and D15 of a 28-day cycle) 
in the pivotal RAINBOW study (Wilke 2014) that could overlap with those seen with 
derazantinib in the combined analysis of data from studies ARQ 087-101 and DZB-CS-301 
are hypertension (15% and 6%, seen for paclitaxel-ramucirumab and derazantinib, 
respectively), fatigue (12% and 7%) and diarrhea (4% and 2%). Patients with increased 
baseline values of bilirubin, AST and/or ALT had a statistically nonsignificant higher 
incidence of severe myelosuppression in studies with paclitaxel dosed at 135 mg/m2 or 
higher. Derazantinib 300 mg QD administered to iCCA patients in studies ARQ 087-101 
and DZB-CS-301 resulted in Grade 3 or higher transaminase elevations in 18.3% of 
patients, while none of these cases were assessed by the Sponsor as a drug-induced liver 
injury related to derazantinib.


 
 
   
 
 
 
 
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To characterize the safety and tolerability profile of the triple combination of derazantinib-
paclitaxel-ramucirumab in Substudy 2, a modified 3+3 dose-finding design with inclusion 
of an additional expansion cohort, with treatment of up to 20 patients at the MTD level will 
be used to assess potential overlapping and/or DLTs and determine the adequate dose for 
the evaluation of efficacy of the combination. The nominal doses of derazantinib 200 mg 
QD, 300 mg QD, and 200 mg BID will be tested for tolerability in combination with the 
standard dosing regimen 80 mg/m2 paclitaxel and 8 mg/kg ramucirumab, the dosing 
regimen established and registered for the second-line treatment of gastric cancer patients 
(Wilke 2014, Cyramza® USPI, Cyramza EPAR). The starting dose of derazantinib will be 
200 mg QD to account for both the potentially addititive/synergistic effects of derazantinib 
added to paclitaxel, and a theoretical derazantinib-related CYP2C8 inhibition that may lead 
to a potentially increased paclitaxel exposure and increased frequency and severity of 
paclitaxel-related myelosuppression. Following the principles of modified 3+3 dose-
finding design, individual dose de-escalation dose levels (DLs) may be explored in reaction 
to the nature and severity of emerging adverse drug reactions (ADRs).
Derazantinib in combination with atezolizumab
To date, the safety profiles of derazantinib and atezolizumab have only been studied 
individually (Mazzaferro 2019, Petrylak 2018, Papadopoulos 2017, O’Donnell 2017, 
Balar 2017, Herbst 2014). With regard to combination treatment adding derazantinib to 
standard-of-care treatment regimens, the safety profile of derazantinib is described in 
Section 1.6.3.2.
In the first-in-human study of atezolizumab (formerly known as MPDL3280A), the 
pharmacokinetics (PK) for atezolizumab were shown to be consistent with those of typical 
immunoglobulins, with a mean terminal serum half-life of approximately 3 weeks. Neither 
DLTs nor an MTD were reported (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 for single-agent atezolizumab
were pneumonia (3.1%), dyspnea (2.8%), pyrexia (2.5%), urinary tract infection (UTI)
(1.9%) and pleural effusion, pulmonary embolism, and sepsis (all 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) AEs were anemia (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 the Phase 1b cohort in the ongoing study DZB-CS-201 in 
patients with urothelial cancer confirmed the safety and tolerability of the novel 
derazantinib-atezolizumab combination, and the resulting RP2D allows combination of the 
full doses established for monotherapy treatment with either study treatment. Investigation 


 
 
   
 
 
 
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of the combination treatment in Substudy 3 is contingent on the determination of the RP2D 
by a joint decision of the Independent Data Monitoring Committee (IDMC), Investigators,
and the Sponsor in that study, based on a review of the aggregate of DLT and AE data, and 
considering PK and efficacy data.
1.7
Risk-benefit assessment
1.7.1
Derazantinib
Derazantinib is a potent FGFR inhibitor that shows strong anti-proliferative activity in cell 
lines harboring FGFR2 aberrations. In a clinical study in iCCA patients (Mazzaferro 2019, 
Papadopoulos 2017, Droz Dit Busset 2019), derazantinib was shown to be active in 
patients with FGFR2 fusions, mutations and amplifications with a manageable safety 
profile. In exploratory gastric cancer PDX studies of derazantinib, a consistently strong 
anti-tumor activity was found, leading to complete responses in several animals, and a 
tolerable level of toxicity (McSheehy 2020).
The SHINE study of the FGFR inhibitor AZD4547 recently reported poor efficacy data for 
FGFR inhibition in a gastric cancer target population defined by FGFR2 amplification and 
polysomy (Van Cutsem 2017). According to non-clinical data and a recent publication of 
the translational study using the same investigational compound (Basilea, data on file 2020,
Pearson 2016), the definition of the target population may have been inadequate due to the 
inclusion of low-level FGFR2 amplification and FGFR2 polysomy (Van Cutsem 2017), 
which may explain the study results (Pearson 2016). The current protocol for study 
DZB-CS-202 therefore considers only prior clinical and non-clinical evidence supporting 
the functionality of high-level FGFR2 amplification, and requires a more stringent 
definition of the putative target population. The inclusion of FGFR1–3 mutations is 
exploratory based on the existing non-clinical data in models of gastrointestinal and 
urothelial tumors (McSheehy 2020, McSheehy 2019, Basilea data on file 2020).
Overall, it is expected that approximately 9% of GAC patients harbor a functional FGFR
genetic aberration (Figure 2). Owing to the uncertainty of the predictive value of 
FGFR1–3 mutations compared to the substantial non-clinical and clinical evidence for 
FGFR2
rearrangements 
and 
high-level 
FGFR2
amplification,
respectively 
(McSheehy 2020, Chen 2019, Catenacci 2017, Kuboki 2017, Pearson 2016), the protocol 
will first aim to establish evidence of the predictive nature of FGFR2 fusions, FGFR2
amplifications, and FGFR 1–3 mutations in Substudy 1, using a  Fleming two-stage design 
that provides a reliable method for minimizing the number of patients exposed to potential 
futility of derazantinib monotherapy.
Increased transaminases is 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. 


 
 
   
 
 
 
 
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Hyperphosphatemia1, 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. Safety measures to monitor and 
mitigate these risks during the study are outlined in Section 5.3.2. 
The following events are assessed as potential risks for derazantinib: gastrointestinal 
disorders, hypertension, alopecia1, and QT2 prolongation. 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 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. 
1.7.2
Derazantinib in combination with paclitaxel, ramucirumab and 
atezolizumab
Combination of derazantinib with paclitaxel-ramucirumab
Treatment with paclitaxel-ramucirumab offers patients an effective second-line standard-
of-care treatment, however, the improvement compared with paclitaxel monotherapy, 
despite clear evidence of statistical significance from a well-designed clinical trial, may 
not be considered clinically meaningful according to the ESMO Magnitude of Clinical 
Benefit Scale (ESMO-MCBS; Del Paggio 2017, Cherny 2015, Ellis 2014). Patients with 
GAC harboring potentially actionable molecular, oncogenic targets are still in need of 
treatment to improve the overall dismal outcome of GAC disease progression after standard 
first-line chemotherapy. Based on emerging non-clinical and clinical data, derazantinib 
could be a valuable addition to the treatment armamentarium of GAC patients harboring 
FGFR genetic aberrations (McSheehy 2020, Basilea data on file 2020). In a systematic 
clinical research approach carefully weighing potential benefits over risks, this study 
explores the addition of targeted FGFR inhibition to established and emerging standard 
treatments in a molecularly defined target population.
Paclitaxel-ramucirumab is a broadly used combination regimen with routinely applied, 
well-established supportive care measures to address AEs consistent with a 
chemotherapeutic agent (Paclitaxel Ever Pharma SmPC) and a biologic agent 
(Cyramza® USPI, Cyramza EPAR). Overall, the safety profile and emerging treatment-
related toxicities of all three study drugs can be monitored and clinically managed.
In vitro data indicate that derazantinib might be an inhibitor of cytochrome-P450 (CYP) 
iso-enzymes 1A2, 2C8, and 2D6, and P-glycoprotein (P-gp, MDR1) efflux transporter. 
Paclitaxel is a known substrate for CYP2C8 (Paclitaxel Ever Pharma SmPC), and 
                                                          
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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derazantinib may therefore increase the plasma concentration of paclitaxel, potentially 
increasing the incidence of myelosuppression, the severity of myelosuppression or both. In 
contrast, inhibition of P-gp could increase the efficacy of paclitaxel through increased 
cellular penetration (Pires 2009), and/or increase the incidence or severity of, for example, 
liver toxicity and neurotoxicity, or both (Hubensack 2008). In addition, the potentially 
beneficial anti-angiogenic effect of VEGFR2 inhibition may also increase the incidence 
and severity of hypertension and hemorrhage, or both, as seen in previous studies 
combining paclitaxel and ramucirumab. No PK interactions are expected between a small 
molecule kinase inhibitor, such as derazantinib, and an antibody, such as ramucirumab. 
Prior to its use in Substudy 3, the PK of derazantinib, paclitaxel and ramucirumab in 
combination will be investigated in Substudy 2 together with the assessment of the 
tolerability, DLTs and the preliminary safety and efficacy profile of the combination of the 
three study drugs, using a modified 3+3 dose-finding design.
Combination of derazantinib with atezolizumab
Based on recently reported data from the KEYNOTE-062 study (Tabernero 2019), 
immune-checkpoint blockade offers the potential for clinical benefit in patients with GAC. 
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 7.1.4) is available in the US Prescribing Information (PI), and the EU 
Summary 
of 
Product 
Characteristics 
(SmPC) 
for 
Tecentriq®
(atezolizumab) 
(Tecentriq® USPI, Tecentriq® SmPC).
No PK interactions are expected between a small molecule kinase inhibitor such as 
derazantinib and an antibody, such as atezolizumab. The results obtained from the Phase 
1b cohort in the ongoing study DZB-CS-201 (NCT04045613) in patients with advanced 
solid tumors confirmed the safety and tolerability of the novel derazantinib-atezolizumab 
combination, and the resulting RP2D allows combination of the full doses established for 
monotherapy with either drug.
Summary of risk-benefit assessment of combination treatment arms
Overall, there is consensus that GAC patients with disease progression after first-line 
standard treatment are in need of effective treatment alternatives with a clinically 
meaningful magnitude of clinical benefit. In a molecularly defined target population of 
GAC patients harboring functional FGFR genetic aberrations, this study aims to establish 
such benefit in accordance with safety measures and stopping rules in accordance with
applicable guidelines. In the event that either derazantinib monotherapy or combinations 
with paclitaxel, ramucirumab or atezolizumab do not meet the efficacy targets explored in 
Substudy 3, 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
regimen.


 
 
   
 
 
 
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1.7.3
Conclusion to risk-benefit assessment
Patients generally should not agree to participate in a clinical study with the understanding 
that they are assured of receiving direct benefit from treatment during participation, as early 
clinical studies are primarily 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 be 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 profiles for paclitaxel, ramucirumab and atezolizumab, which are licensed medicines 
in several indications, are well characterized. The proposed two-stage designs permit the 
minimization of patient accrual in case of futility of study treatment, and an IDMC will 
reviewsafety data during the course of the study, and provide recommendations to the 
Sponsor.
The safety and tolerability profile of the novel combination treatment with 300 mg QD 
derazantinib and 1200 mg Q3W atezolizumab has been assessed as clinically manageable 
in Phase 1b cohort in the ongoing study DZB-CS-201 in patients with uretelial cancer. 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 drug.
All substudies will include close safety monitoring through AE collection, and assessment 
of clinical safety laboratory tests, pregnancy testing, vital signs, electrocardiograms 
(ECGs), physical examinations, ophthalmology examinations and performance status. 
The risk-benefit balance is therefore expected to be favorable in the intended GAC patient 
populations and across study cohorts.
STUDY OBJECTIVES
2.1
Primary objectives
2.1.1
Primary objective of Substudy 1 (Cohorts 1.1 and 1.2)
To evaluate the ORR of patients with HER2neg FGFRfus/amp/mt GAC treated with 
derazantinib monotherapy.
2.1.2
Primary objective of Substudy 1 (Cohort 1.3)
To evaluate the PFS4 of patients with HER2neg FGFRfus/amp/mt GAC treated with 
derazantinib monotherapy.
2.1.3
Primary objective of Substudy 2
To determine the RP2D of derazantinib-paclitaxel-ramucirumab in combination in patients 
with HER2neg FGFRfus/amp/mt GAC.


 
 
   
 
 
 
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2.1.4
Primary objective of Substudy 3
To evaluate the ORR of patients with HER2neg FGFRfus/amp/mt GAC treated with 
derazantinib, 
derazantinib-paclitaxel-ramucirumab,
derazantinib-atezolizumab, 
or
paclitaxel-ramucirumab.
2.2
Secondary objectives
2.2.1
Secondary objectives of Substudy 1
To evaluate the efficacy of derazantinib, as measured by ORR (Cohort 1.3), 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 monotherapy (and, 
if applicable, derazantinib metabolites)
2.2.2
Secondary objectives of Substudy 2
To evaluate the efficacy of derazantinib-paclitaxel-ramucirumab in combination, as 
measured by ORR, DCR, DOR, PFS and OS
To assess the safety and tolerability profile of derazantinib-paclitaxel-ramucirumab in 
combination
To characterize the PK profile of derazantinib (and, if applicable, derazantinib 
metabolites) when administered in combination with paclitaxel-ramucirumab
To characterize the PK of paclitaxel when administered in combination with 
derazantinib-ramucirumab.
2.2.3
Secondary objectives of Substudy 3
To evaluate the efficacy of the study drugs, as measured by DCR, DOR, PFS, and OS
To compare the ORR, DCR, DOR, PFS, and OS of patients treated with derazantinib 
monotherapy, derazantinib-paclitaxel-ramucirumab, and derazantinib-atezolizumab 
each with that of patients treated with paclitaxel-ramucirumab 
To compare the antitumor efficacy in patients treated with derazantinib monotherapy to 
that of patients treated with derazantinib-paclitaxel-ramucirumab, and derazantinib-
atezolizumab, as well as patients treated with derazantinib-paclitaxel-ramucirumab 
compared to that of patients treated with paclitaxel-ramucirumab, as measured by ORR, 
DCR, DOR, PFS and OS, to investigate the contribution of derazantinib in combination
treatment
To assess the safety and tolerability of the study drugs
To evaluate changes, and assess the minimally important difference, in HR-QoL and 
symptom response from baseline using the EQ-5D (5L) VAS, EORTC QLQ-C30, 
EORTC QLQ-STO-22, and the G-SET/HTI


 
 
   
 
 
 
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2.3
Exploratory objectives
2.3.1
Exploratory objectives specific to efficacy-estimating Substudies
To describe the type of FGFRfus/amp/mt genetic aberration in responders and non-
responders
To explore the efficacy of derazantinib-atezolizumab in combination by iRECIST 
(see Section 5.3.3.2.5) as measured by ORR, DCR, DOR and PFS
To explore the concordance of liquid biopsy and tumor biopsy results
To explore the molecular profile and gene expression profile of radiographic and 
metabolic responders versus non-responders by pre-treatment biopsy
To explore molecular profile and gene expression profile changes indicative of 
radiographic response versus non-response by Cycle 1 liquid biopsy 
To describe emerging genetic markers of resistance in (non)-responders
2.3.2
Exploratory PK objectives 
To explore the exposure of derazantinib alone (and, if applicable, derazantinib 
metabolites) and in combination with paclitaxel-ramucirumab
To explore the exposure of paclitaxel in combination with derazantinib-ramucirumab
To explore the exposure of atezolizumab and ramucirumab, when administered in 
combination with derazantinib and derazantinib-paclitaxel, respectively
To explore the emergence of anti-drug antibodies (ADA) directed against atezolizumab.
INVESTIGATIONAL PLAN
3.1
Overview of study design
This study is an open-label, multiple-cohort, multi-center Phase 1b/2 study, comprising 
three substudies. An overview of the overall study design is provided in Figure 3. 
Effective from Protocol Version 5.0, Substudies 1 and 2 have been modified.
In all efficacy-estimating cohorts, sample-size minimizing statistical designs with interim 
analyses for futility and efficacy will be used.
Only patients with GAC expressing FGFRfus/amp/mt will be enrolled (see Section 3.1.1).


 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
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Figure 3
Overview of study design
Abbreviations: 2L/3L, second/third-line; BID, twice daily; CR/PR, complete/partial response as per RECIST 1.1; 
FGFRfus/amp/mt, tumor status with FGFR2 gene fusion or rearrangement / amplification, or FGFR1–3 mutation; FGFR2fus, 
FGFR2 fusion / rearrangement; FGFR2high-amp, high-level FGFR2 gene amplification; FGFR1–3mt, FGFR1–3 mutations; 
GAC, for either recurrent, locally advanced or metastatic gastric adenocarcinoma; HER2neg, negative HER2 tumor status; 
ORR, objective response rate; p, probability (of response); pts, patients; QD, once daily; R, randomization; 
r1/r2, response(s) observed during stage 1 (r1) and by the end of the cohort (r2), respectivelyS, stratification by genetic 
aberration.
3.1.1
Overview of Substudy 1 

As of Protocol Version 5.0, this substudy has been modified with the addition of 
Cohort 1.3 targeting HER2neg FGFRfus/amp/mt GAC, a population identical to that being 
investigated in ongoing
Cohorts 1.1
(FGFR2fus
or
FGFR2high-amp) and 1.2
(FGFR1–3mt) combined to better address medical and operational aspects of study 
conduct. In Cohort 1.3, patients with either metastatic or recurrent locally advanced 
HER2neg FGFRfus/amp/mt GAC, with radiologically confirmed disease progression after 
one or two standard treatment regimens are to be treated with derazantinib 200 mg 
BID. During enrollment into Cohort 1.3, enrollment into Cohorts 1.1 and 1.2 is paused.

The primary objective of Substudy 1 is to assess the efficacy of derazantinib in patients 
with HER2neg FGFRfus/amp/mt GAC.

As of Protocol Version 5.0, the primary endpoint of Cohort 1.3 is the 4-month PFS 
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
If the new dose of 200 mg BID is not considered safe and tolerable, the initial 
Cohorts 1.1 and 1.2 may be reopened for further enrollment.

Up to 20 patients may be enrolled into Cohort 1.3 in addition to the planned 
32 patients, to further characterize efficacy and safety; enrollment may be restricted to 
patients with either FGFR2fus/amp or FGFR1–3mt.

The schedule of assessments for these patients is shown in Table 1.
3.1.2
Overview of Substudy 2 

This substudy comprises patients with HER2neg
FGFRfus/amp/mt
GAC
with 
radiologically confirmed disease progression after first-line standard treatment, who,
after Investigator assessment (and per multidisciplinary tumor board endorsement),
are considered fit to tolerate the novel combination of derazantinib-paclitaxel-
ramucirumab.

Patients in this substudy are initially planned to receive derazantinib-paclitaxel-
ramucirumab in combination; at the dose-finding stage, a decision may be taken to 
limit the study to investigate either derazantinib-paclitaxel or derazantinib-
ramucirumab in combination.

The primary objective of Substudy 2 is to determine the RP2D for the derazantinib-
paclitaxel-ramucirumab
(or 
derazantinib-paclitaxel/derazantinib-ramucirumab) 
combination, using a modified 3+3 dose-finding design.

The schedule of assessments for these patients is shown in Table 2.
3.1.3
Overview of Substudy 3 
The final design and statistical assumptions applicable to this substudy are contigent on 
findings from Substudies 1 and 2, and are currently under consideration. Prior to 
initiation of patient enrollment in this substudy, a protocol amendment will be submitted.

The initiation of Substudy 3 is triggered by the availability of data considered 
sufficient and robust to support the rationale for monotherapy (Cohort 3.1), 
triple/double combination (Cohort 3.2) and derazantinib-atezolizumab combination 
(Cohort 3.3). 

This substudy comprises patients with either metastatic, or recurrent, locally advanced 
and inoperable, HER2neg FGFRfus/amp/mt GAC, with radiologically confirmed disease 
progression after one standard treatment regimen.

Patients will be allocated to one of four cohorts:
– Cohort 3.1
Patients randomized to be treated with derazantinib (test)
– Cohort 3.2
Patients randomized to be treated with derazantinib-paclitaxel-
ramucirumab in combination (test)
– Cohort 3.3
Patients randomized to be treated with derazantinib-atezolizumab 
in combination (test)
– Cohort 3.4
Patients randomized to be treated with paclitaxel-ramucirumab in 
combination (control)


 
 
   
 
 
 
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
Allocation to these cohorts is stratified by type of FGFR genetic aberration (FGFR2fus
or FGFR2high-amp vs FGFR1–3mt) and geographic region (Americas-Europe-Australia 
vs Asia), and then randomized (1:1:1:1) between test and control cohorts. 

The primary objective of Substudy 3 is to assess the efficacy of derazantinib,
derazantinib-paclitaxel-ramucirumab and derazantinib-atezolizumab in combination,
while controlling for the efficacy of paclitaxel-ramucirumab in this patient population
is a secondary objective.

The Schedule of Assessments for these patients is shown in Table 3 (Cohorts 3.1, 3.2
and 3.4) and Table (Cohort 3.3).
3.1.4
Molecular eligibility
Molecular eligibility for enrollment will be established by a positive test result for 
FGFRfus/amp/mt. The molecular test is to be based on NGS of either tumor tissue DNA and/or 
RNA, or plasma cell-free DNA (cfDNA).
For patients with no access to local NGS testing, central testing will be performed in a 
laboratory designated by the Sponsor; this ‘central testing’ will be based on NGS testing 
of cfDNA from a liquid biopsy obtained at Pre-screening (see Section 3.1.2). 
Alternatively, an eligible, positive FGFRfus/amp/mt 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. For 
patients with a positive local test result, liquid biopsy samples for central confirmation of 
the FGFR status should be collected at the Screening visit, but the NGS test result from the 
central laboratory does not have an impact on the patient’s eligibility.
3.1.5
Pre-screening 
A Pre-screening visit is only required for prospective study participants if no documented 
local NGS test result with an eligible FGFRfus/amp/mt 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. It is recommended to conduct the 
Pre-screening visit for liquid biopsy sampling following assessment of objective 
documented progression after prior anti-cancer treatment. However, in the interests of 
patients and to reduce off-treatment time between the last anti-cancer treatment and study 
treatment, liquid biopsy sampling might be performed at any time point after the last 
administration of anti-cancer therapy when disease progression is suspected.


 
 
   
 
 
 
 
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No Pre-screening visit is required for patients with a known and FGFRfus/amp/mt status from 
local NGS testing; these patients may directly initiate clinical screening procedures. 
3.1.6
Screening
Clinical Screening procedures are required to confirm study-treatment eligibility (see 
Section 5.2.3). 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.
3.1.7
Treatment period
Efficacy-estimating substudies
In Substudies 1 and 2 and Cohorts 3.1, 3.2 and 3.4, a treatment cycle is defined as 28 days 
(Q4W). In Cohort 3.3, a treatment cycle is defined as 21 days (Q3W).
Substudy 1 Cohort 1.3, will include a safety interim assessment for ADRs indicative of 
DLT (see Section 7.3.3) in the first ten treated patients (the safety run-in phase). The 
process involves regular dose decision meetings (see Section 8.3.5.1). The schedule of AE 
assessments, including ECGs and clinical safety laboratory blood sampling, 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, to monitor exposure to derazantinib (and, if applicable, derazantinib metabolites), 
and to characterize the PK profile of derazantinib 200 mg BID as monotherapy to support 
safety and efficacy data. The PK sampling schedule is provided in Table 7.

In Substudy 1, if derazantinib 200 mg BID is considered safe and tolerable at the safety 
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 safe and tolerable, Cohorts 1.1 and 1.2 might 
be re-opened.

In Substudy 2, following determination of the MTD for the derazantinib-paclitaxel-
ramucirumab combination, an additional 14 patients will be enrolled for treatment at 
the MTD for this triple combination to assess efficacy and further investigate safety.

In Substudy 3, treatment will consist of either:
–
Derazantinib, or
–
Derazantinib-paclitaxel-ramucirumab at the RP2D determined in Substudy 2, or
–
Derazantinib at the RP2D determined in study DZB-CS-201 plus atezolizumab
1200 mg Q3W, or
–
Paclitaxel 80 mg/m2 as a 1-hour IV infusion on D1, D8, D15 Q4W plus 
ramucirumab 8 mg/kg as a 1-hour infusion on D1 and D15 (Q4W)


 
 
   
 
 
 
 
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Efficacy will be evaluated by blinded independent central review (BICR) using RECIST 
1.1 criteria on C3D1 ±7 days, then every 8 weeks (±7 days) for the first 6 months, and 
every 12 weeks (±7 days) thereafter (see Section 5.3.3.2). Patients randomized to 
Cohort 3.3 follow the same 8-week imaging assessment schedule; therefore scheduling of 
additional visits is required.
AEs will be assessed continuously and at every study visit. Dose delays and/or reductions 
are permitted with derazantinib if a derazantinib-related toxicity is observed 
(see Section 6.1.1.5). 
For 
paclitaxel
(see 
Section 
6.1.2.7) 
and 
ramucirumab
(see Section 6.1.3.7), dose delays and/or reductions may be applied based upon the grade 
of toxicity experienced by the patient. For atezolizumab, no dose reductions are allowed, 
but dose delays are permitted if an atezolizumab-related toxicity is observed (see 
Section 6.1.4.6). A related toxicity is defined as any toxicity considered related to any study 
medication (or combination thereof), i.e., probably or possibly related.
In Substudy 3, HR-QoL and symptom response will be measured using the EQ-5D,
EORTC QLQ-C30, EORTC QLQ-STO-22 and G-SET/HTI questionnaires. See Section 
5.3.6 for a description of these HR-QoL instruments. 
In Substudy 3, upon confirmed PD per RECIST 1.1, it is recommended that patients treated 
with paclitaxel-ramucirumab (in Cohort 3.4) are offered the option of crossing over to 
treatment with derazantinib (see Section 4.5.1 for details). However, crossing over remains 
at the Investigator’s discretion.
Dose-finding Substudy 2
This substudy comprises an algorithm-based dose-finding design using the 3+3 design 
principles modified to allow concurrent enrollment of up to three patients to determine the 
MTD per assessment of ADRs indicative of DLTs (Figure 4). The MTD is defined as the 
highest dose level (DL) at which < 33% of patients experience a DLT. The DLT interval 
is defined as the first 28-day interval (i.e., Cycle 1) of study treatment. The target DLT 
threshold for the Dose-finding Part is set at 33%.
The Dose-finding Part is followed by enrollment of a Dose-expansion Part cohort of 
approximately 14 additional patients to reach 20 efficacy-evaluable patients dosed at the 
MTD. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 4
Overview of Substudy 2
Abbreviations: DL, dose level; D, derazantinib [number gives dose in mg; BID, twice per day; qd, once per day]; MTD, 
maximum tolerated dose; P, paclitaxel [number gives dose in mg/m2]; R, ramucirumab [number gives dose in mg/kg]; 
RP2D, recommended Phase-2 dose.
Patients enrolled to the Dose-finding Part will be treated with increasing doses of 
derazantinib (planned DLs are 200 mg QD, 300 mg QD, 200 mg BID) and primarily fixed 
doses of 80 mg/m2 paclitaxel and 8 mg/kg ramucirumab. If one patient experiences a DLT 
in any DL cohort among the first three enrolled and DLT-evaluable patients, the cohort 
will be expanded to six DLT-evaluable patients. The MTD is defined as the highest DL at 
which none or one of six participants (0% to 17%) experience a DLT (see Section 7.3.3 for 
DLT definition). The MTD is exceeded when at least two of three to six participants 
(≥33% to 67%) experience a DLT in any DL cohort. Declaration of the RP2D may follow 
the MTD declaration or may be modified considering review of the totality of available 
safety, efficacy, PK, PD data and potential toxicity-response modeling. Replacement of 
patients is described in Section 4.5.3. 
If a patient experiences a DLT in Cycle 1, study therapy may be discontinued following 
discussion and agreement between the Sponsor and Investigator, or a dose modification 
(derazantinib), a dose delay (derazantinib and/or paclitaxel), or both may be implemented. 
The triple combination may not be considered to be feasible if DL1 cannot be declared 
tolerable. The Sponsor may pursue a triple combination with reduced doses of paclitaxel 
and/or ramucirumab, or a two-drug combination of either derazantinib-paclitaxel or 
derazantinib-ramucirumab based on the available safety, PK and PD data, and potential 
toxicity-response modeling. Substudy 2 will be terminated if no combinations can be 
declared tolerable.
Investigation of the combination therapy in Substudy 3 is contingent on the determination 
of the RP2D by a joint decision of the IDMC, Investigators, and the Sponsor in Substudy 
2, based on a review of the aggregate of DLT and AE data, and considering efficacy, PK, 
and PD data, and potential toxicity-response modeling. 
3.1.8
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 


 
 
   
 
 
 
 
 
 
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remove the patient from treatment; or until the Substudy, cohort or the study is terminated 
by the Sponsor, whichever occurs first.
In all substudies, once patients have been discontinued from treatment with the initially 
assigned study drug, other treatment options (including enrollment into the Crossover 
Phase for patients with confirmed disease progression after treatment with paclitaxel-
ramucirumab; see Section 3.1.9) will be at the discretion of the Investigator. All subsequent 
therapies should continue to be recorded on the appropriate electronic case report form 
(eCRF) for the duration of the study.
For further details on treatment and study discontinuation, see Section 4.5.
End of Treatment visit
An End of Treatment visit will be conducted within 7 days after the decision to permanently 
discontinue treatment. At this time, patients who received treatment with paclitaxel-
ramucirumab (Cohort 3.4) and who experienced disease progression may crossover to
derazantinib treatment (at the discretion of the Investigator; see Section 3.1.9).
Safety Follow-up visit(s)
For all patients, Safety Follow-up visits will be conducted 28 days (±3 days) and 90 days 
(±3 days) after study treatment discontinuation. See Section 5.2.4.10 for further details.
3.1.9
Post-discontinuation study treatment crossover (Cohort 3.4)
Patients from Cohort 3.4 with PD (as assessed by BICR) will have the opportunity to 
receive treatment with 300 mg derazantinib QD in a Crossover Phase. Crossover patients
may initiate treatment with derazantinib within 2 months of their last dose of paclitaxel-
ramucirumab, regardless of the time of progression. 
Crossover is optional and is at the discretion of the Investigator (with the Sponsor’s and 
patient agreement). 
Eligibility criteria for post-discontinuation study treatment crossover
Patients who withdraw consent, or discontinue paclitaxel-ramucirumab for any reason 
other than PD, or paclitaxel-ramucirumab-related toxicity, will not be eligible for 
crossover. 
Patients who meet the following criteria are eligible for crossover:

Documented PD on paclitaxel-ramucirumab as a participant of Cohort 3.4 (PD to be 
confirmed by BICR)

All ongoing AEs must have resolved to baseline or Common Terminology Criteria for 
Adverse Events (CTCAE) 5.0 Grade ≤1 (except alopecia and peripheral neuropathy) 

No new central nervous system (CNS) metastases

ECOG PS of 0–2

Patient has not received any other systemic anti-cancer therapies after paclitaxel-
ramucirumab administration during the treatment phase.


 
 
   
 
 
 
 
 
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
If required, completed palliative radiotherapy (30 Gy or less) ≥ 7 days before the first 
dose of crossover study treatment.

Patient has adequate organ function, as indicated by the laboratory values detailed in 
Inclusion criterion 9.
Abbreviated screening procedures prior to study treatment crossover
The following procedures should be scheduled and performed after eligibility for post-
discontinuation study treatment crossover is confirmed:

Physical examination, including height, weight, and vital signs (see Section 5.3.2.1)

ECOG PS (see Section 5.3.2.2)

Complete ophthalmic examination, including optical coherence tomography (OCT) 
(see Section 5.3.2.3)

Triplicate 12-lead ECG (see Section 5.3.2.4)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)

Urinalysis (see Section 5.3.2.6)

Serum pregnancy test, if applicable (see Inclusion criterion 10, Section 5.3.2.7, and 
Section 7.1.5

Tumor imaging assessments, according to RECIST 1.1 (see Section 5.3.3.2 and 
Appendix 2) 
Note: Tumor assessments or ophthalmic examinations performed within 28 days of the first dose of 
crossover derazantinib treatment on C1D1 may be used rather than repeating tests.
Assessments during post-discontinuation study treatment crossover
Once eligibility is confirmed and abbreviated screening procedures have been completed, 
crossover patients will follow the same schedule of assessments as patients treated with 
derazantinib, as detailed in Table 3, but without derazantinib PK sampling. In particular, 
safety-oriented assessments detailed in Section 5.3.2 need to be followed as specified; dose 
modifications for derazantinib treatment are detailed in Section 6.1.1.5.
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 required 
under Section 3.1.9.2 and completed at the time of withdrawal from the main study may 
be used for the start of the Crossover Phase of the study. C1D1 of the Crossover Phase may 
occur within 2 months of their last dose of paclitaxel-ramucirumab, regardless of the time 
of progression.
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 (see Section 5.3.3.2.4). 
3.1.10
Survival Follow-up period
Patients who are permanently discontinued from study treatment for reasons other than 
death, regardless of the reason, will enter the survival follow-up period (see Section 5.2.5). 


 
 
   
 
 
 
 
 
 
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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 study drug and will continue until the study has 
completed (see Section 3.1.11) or other discontinuation criteria are met (see Section 4.5).
All subsequent anti-cancer therapies should continue to be recorded on the appropriate 
electronic case report form (eCRF) for the duration of the patient’s survival follow-up.
3.1.11
Beginning and end of the study
The study begins when the first patient signs the 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
3.2.1
Primary endpoints
Primary endpoint in Substudy 1
3.2.1.1.1
Cohorts 1.1 and 1.2

ORR, as measured by the proportion of patients with confirmed CR1 or partial 
response (PR)2 by BICR.
3.2.1.1.2
Cohort 1.3 

PFS4, as measured by the proportion of patients alive and free of disease progression 
by survival status and BICR per RECIST 1.1 after approximately 4 months of study 
treatment.
Primary endpoint for Substudy 2

The RP2D of derazantinib-paclitaxel-ramucirumab in combination, estimated from 
safety and tolerability according to the aggregate of DLT criteria and AE data, and 
considering further PK and efficacy data of the combination. The IDMC, 
Investigators and Sponsor will jointly determine the RP2D.
Primary endpoint in Substudy 3 

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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3.2.2
Secondary endpoints
Secondary endpoints for Substudy 1

PFS of patients treated with derazantinib, as measured from patient enrollment to PD 
date (see Section 8.3.5.2.1) by BICR

ORR, as measured by the proportion of patients with confirmed CR or PR by BICR 
for Cohort 1.3

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 (or death if no documentation of PD is obtained)

OS, as measured from patient enrollment to time of death 

Safety and tolerability of study drugs, as measured by the frequency and severity of 
AEs (graded by CTCAE version 5.0), clinical laboratory parameters, vital signs, 
ECOG PS, physical examinations (including eye examinations), and ECG parameters 
over time

DLT in the first ten patients in Substudy 1.3

Derazantinib (and, if applicable, derazantinib metabolites) plasma concentrations, 
Cmax, tmax, AUC0–12, AUC0–24, AUClast assessed by measurements in blood samples 
Secondary endpoints for Substudy 2

ORR, as measured by the proportion of patients with confirmed CR or PR by BICR

DCR, as measured by the proportion of patients with confirmed CR, PR or SD by 
BICR

DOR, as calculated from the first date of documented tumor response to disease 
progression by BICR (or death if no documentation of PD is obtained)

PFS of patients treated with derazantinib-paclitaxel-ramucirumab, as measured from 
patient enrollment to PD date by BICR

OS, as measured from patient enrollment to time of death 

Safety and tolerability of study drugs, as measured by the frequency and severity of 
AEs (graded by CTCAE version 5.0), clinical laboratory parameters, vital signs, 
ECOG PS, physical examinations (including eye examinations), and ECG parameters 
over time

Derazantinib (and – if applicable –derazantinib metabolites) plasma concentrations, 
Cmax, tmax, AUC0-24, AUClast, assessed by measurements in blood samples
                                                          
1 Evaluating target lesions, SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for 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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
Paclitaxel plasma concentrations, Cmax, tmax, AUC0-24, AUClast, t1/2, AUCinf, T > 0.05 
assessed by measurements in blood samples.
Secondary endpoints for Substudy 3

ORR of patients treated with derazantinib, derazantinib-paclitaxel-ramucirumab, or 
derazantinib-atezolizumab, as measured by the proportion of patients with confirmed 
CR or PR by BICR, and for each treatment compared to that of paclitaxel-
ramucirumab.

PFS of patients treated with derazantinib, derazantinib-paclitaxel-ramucirumab, or 
derazantinib-atezolizumab, as measured from randomization to PD date by BICR, and 
for each treatment compared to that of paclitaxel-ramucirumab.

DCR of patients treated with derazantinib, derazantinib-paclitaxel-ramucirumab, or 
derazantinib-atezolizumab, as measured by the proportion of patients with confirmed 
CR, PR or stable disease (SD)1 by BICR, and for each treatment compared to that of 
paclitaxel-ramucirumab.

DOR of patients treated with derazantinib, derazantinib-paclitaxel-ramucirumab, or 
derazantinib-atezolizumab, as calculated from the first date of documented tumor 
response to disease progression by BICR (or death if no documentation of PD is 
obtained), and for each treatment compared to that of paclitaxel-ramucirumab.

OS of patients treated with derazantinib, derazantinib-paclitaxel-ramucirumab, or 
derazantinib-atezolizumab, as measured from patient enrollment to time of death, and 
for each treatment compared to that of paclitaxel-ramucirumab.

ORR, DCR, DOR, PFS and OS of patients treated with derazantinib monotherapy 
compared to that of patients treated with derazantinib-paclitaxel-ramucirumab and 
derazantinib-atezolizumab, as well as patients treated with derazantinib-paclitaxel-
ramucirumab compared to that of patients treated with paclitaxel-ramucirumab, to 
investigate the contribution of derazantinib in combination treatment.

Safety and tolerability of study drugs as measured by the frequency and severity of 
AEs (graded by CTCAE version 5.0), clinical laboratory parameters, vital signs, 
ECOG PS, physical examinations (including eye examinations), and ECG parameters 
over time.

Changes in HR-QoL and symptom response, measured by global, functional and 
symptom scores obtained from patient reported outcome instruments (EQ-5D [5L] 
VAS, EORTC QLQ C30, EORTC QLQ-STO-22 and G-SET/HTI) at baseline and 
over time.
                                                          
1 Evaluating target lesions, SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for 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
Exploratory endpoints specific to efficacy-estimating substudies

Responding and non-responding patients are to be analyzed by type of FGFR genetic
aberration.

The proportion of patients with concordant molecular assessment from plasma-based 
and tissue-based testing measuring FGFR genetic aberrations in tumor-liquid biopsy 
samples obtained at baseline will be described.

The ORR, DCR, DOR, PFS and OS of patients treated with derazantinib, 
derazantinib-paclitaxel-ramucirumab in combination, and derazantinib-atezolizumab 
in combination, respectively, will be evaluated by molecular profile, gene expression 
profile, and biomarkers.

The ORR, DCR, DOR and PFS of patients treated with derazantinib-atezolizumab in 
combination per iRECIST.

Changes in the molecular profile and emerging genetic markers of resistance in 
radiographic (non)responders (e.g., MAPK, PI3K/AKT, PTEN, JAK/STATwill be 
described .

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 separately.
Exploratory PK endpoints

Plasma concentrations of derazantinib (and, if applicable, derazantinib metabolites),
assessed by measurements from blood samples obtained from patients entered into 
Substudies 1, 2 and 3.

Plasma concentrations of paclitaxel, assessed by measurements from blood samples 
obtained from patients entered into Substudy 2
Note: Based on PK data obtained during Substudy 2, the Sponsor may consider blood sampling for 
paclitaxel plasma concentrations in patients entered into Substudy 3.

Serum concentrations of ramucirumab, assayed from blood samples obtained from 
patients entered into Substudies 2 and 3

Serum concentrations and ADA for atezolizumab, assayed from blood samples 
obtained from patients entered into Substudy 3.
3.3
Number of patients
The study plans to enroll approximately 314 patients across all three substudies.
An evaluable patient for Substudies 1 and 3, and the Dose-expansion part of Substudy 2,
is defined as a patient who qualifies for inclusion in the modified intent-to-treat (mITT) 
data analysis set (see Section 8.2.3). Non-evaluable patients will be replaced.
An evaluable patient in the Dose-escalation part of Substudy 2 is defined as a patient who 
qualifies for inclusion in the MTD analysis set (see Section 8.2.5). Non-evaluable patients 
will be replaced.


 
 
   
 
 
 
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3.4
Study sites
Approximately 85 study sites in the Americas, Europe, Australia, and Asia.
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.
The IDMC will assess safety data from all substudies and provide recommendations to the 
Sponsor after completing interim analyses of each cohort. For Cohort 1.3, the IDMC 
together with Investigators and the Sponsor will be responsible for determining whether 
derazantinib 200 mg BID as monotherapy can be declared a safe and tolerable regimen.
For Substudy 2, the IDMC together with Investigators and the Sponsor will be responsible 
for determining the RP2D of derazantinib-paclitaxel-ramucirumab in combination, to be 
administered to patients in Substudy 3. 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, and in accordance with the applicable regulations, 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 employees of the Sponsor, or involved in the conduct or reporting of study DZB-
CS-202, or have a financial interest in the outcome of the study. In addition, no member of 
an IDMC of a clinical study with a different sponsor investigating gastric adenocarcinoma 
is eligible for membership of the DZB-CS-202 IDMC.
The conduct of the IDMC will be governed by the IDMC Charter.
STUDY POPULATION
4.1
Target population
The target population for Substudy1 is patients with either metastatic, or recurrent, locally 
advanced and inoperable, HER2neg GAC harboring either FGFR2fus, FGFR2high-amp, or 
FGFR1–3mt, with radiologically confirmed disease progression after one or two standard 
treatment regimens, and no standard or approved treatment alternative.
The target population for Substudies 2 and 3 is patients with either metastatic or recurrent, 
locally advanced and inoperable, HER2neg GAC harboring either FGFR2fus, FGFR2high-amp, 
or FGFR1–3mt, with radiologically confirmed disease progression after one standard 
treatment regimen. 
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 
liquid biopsy was not evaluable for technical reasons).


 
 
   
 
 
 
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1. 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 adenocarcinoma of the gastro-esophageal junction or stomach
Note: Every effort is requested to submit archival tumor tissue samples1 for correlative and confirmatory 
diagnostic and biomedical research.
4. Negative HER2 status obtained from the most recent available tissue sample2
Note: The HER2 status of GAC patients should be assessed using approved standard protocols, 
including, but not limited to fluorescence in-situ hybridization (FISH), chromogenic or silver in situ 
hybridization (CISH) or immunohistochemistry (IHC), in accordance with institutional standards. 
Patients with a HER2 positive (HER2pos) status based on either HER2 amplification (by FISH or CISH) 
or, if FISH/CISH is unavailable, a HER2 IHC score of 3+, are not eligible and should not be tested 
molecularly for FGFRfus/amp/mt expression.
5. Inoperable3 recurrent, locally-advanced adenocarcinoma or progressing stage IV 
adenocarcinoma of the gastro-esophageal junction or stomach, and prior antitumor 
treatment as specified for each Substudy:
Substudy 1: Patients with radiographically-documented disease progression after 
either standard first- or second-line treatment, and no approved and/or tolerable 
treatment alternative (endorsed by multidisciplinary tumor board).
Substudy 2: Patients with radiographically-documented disease progression after 
standard first-line treatment, and per Investigator assessment considered suitable to 
tolerate the treatment regimen (endorsed by multidisciplinary tumor board). 
Substudy 3:
Patients with objective radiographically-documented disease 
progression:
–
During, or within 6 months after, administration of the last cycle of adjuvant / 
neoadjuvant / perioperative chemotherapy (platinum plus fluoropyrimidine 
with or without anthracycline and/or taxane and/or irinotecan) for locally 
advanced disease, or 
Note: If the patient has received prior taxane, a 6-month taxane-free interval after the last 
administration of taxane-containing treatment needs to be respected
–
During, or any time after, administration of the last cycle of first-line taxane-
free chemotherapy (platinum plus fluoropyrimidine with or without 
anthracycline) for metastatic disease or locally advanced disease.
                                                          
1 If tumor tissue from an archival tumor block is available for analysis, the minimum requirements for slides prepared 
from such tumor blocks for central molecular testing are one H&E-stained slide plus at least 10 consecutive, unstained, 
4 ± 1 µm thick sections placed on positively charged slides.
2 Use of an FDA-approved test for the determination of the HER2 status is recommended in the USA.
3 Patients are required to be staged as inoperable at the time of screening in order to avoid interference of any potentially 
planned surgery with RECIST requirements during the study.


 
 
   
 
 
 
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6. Eligible FGFRfus/amp/mt positive test result(see Appendix 1 and Section 3.1.4).
Note: The scope of eligible FGFR genetic aberrations for Substudy 3 may be modified and take into 
consideration findings obtained from Substudy 1. 
7. Measurable disease as defined by the Investigator using RECIST 1.1 criteria
8. ECOG PS of 0 or 1
9. Adequate organ functions as indicated by the following Screening visit laboratory 
values:

Hemoglobin ≥ 9 g/dL

Absolute neutrophil count (ANC) ≥ 1.5 × 109/L

Platelets ≥ 100,000/μL

Serum sodium, corrected calcium, potassium, magnesium and phosphate within 
institutional normal ranges

International Normalized Ratio (INR) ≤1.5 or Prothrombin Time (PT) ≤1.5 
upper limit of normal (ULN), and Partial Thromboplastin Time (PTT/aPTT) ≤ 1.5 
ULN

Total bilirubin ≤ 2 × ULN

AST and ALT ≤3 × ULN, or ≤ 5 × ULN for study patients with liver metastasis

Albumin ≥ 2.5 g/dL

Creatinine clearance (CLCR) ≥30 mL/min (as calculated by the Cockcroft-Gault 
formula)

Urinary protein ≤1+ on dipstick or ≤ 30mg/dL in routine urinalysis. 
Note: If urine dipstick or routine analysis indicates proteinuria ≥ 2+ or ≤ 30 mg/dL, then a 24-hour 
urine must be collected and must demonstrate < 1000 mg of protein in 24 hours to allow 
participation in the study. Alternatively, a spot urine protein-creatinine ratio (UPCR) can be 
obtained on first morning urine sample, and must demonstrate a UPCR < 1 (or < 100 mg/mmol) to 
allow participation in the study.

For women of childbearing1 potential only, negative serum human chorionic 
gonadotropin (hCG)2
                                                          
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 [FSH] 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 gastric cancer; plausibility of pregnancy 
should be established for women of childbearing potential with gastric cancer and positive serum beta-hCG values.


 
 
   
 
 
 
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10. Men and women of childbearing potential must agree to avoid impregnating a partner 
or becoming pregnant, respectively, during the study, and for at least 150 days 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 postmenopausal1, 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 study drug:
a) Abstinence from heterosexual activity2
b) Using (or having their partner use) a highly effective method of contraception 
during heterosexual activity. Highly effective methods of contraception are3:

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)

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 liquid biopsy was not evaluable for technical reasons).
                                                          
1 Postmenopausal is defined as at least 12 months with no menses without an alternative medical cause; in 
women < 45 years of age a high 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.
2 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 Evidence Review 
Committees (ERCs)/Institutional Review Boards (IRBs). Periodic abstinence (e.g., calendar, ovulation, sympto-
thermal, post-ovulation methods, etc.) and withdrawal are not highly effective methods of contraception.
3 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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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 with an unknown half-life.
Four weeks of curative radiotherapy.
Seven days of palliative radiotherapy.
2. For patients enrolled in Substudy 1, prior treatment with FGFR inhibitors.
3. For patients enrolled in Substudy 2 and 3, prior treatment with:
Taxanes within 6 months prior to randomization
FGFR inhibitors or pathway-targeting agents
Anti-VEGF(R) therapeutic antibody or pathway-targeting agents.
4. For patients enrolled in Substudy 3, prior treatment with anti-programmed cell death 
receptor-1 (PD-1) or anti-programmed death ligand-1 (PD-L1) therapeutic antibody or 
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: 
New York Heart Association Class II to IV congestive heart failure, within 6 
months of the first dose of study drug.

Any arterial thrombotic event, including myocardial infarction, unstable angina, 
cerebrovascular accident, or transient ischemic attack, within 6 months of the first 
dose of study drug.

Concurrent and clinically significant abnormalities on ECG at Screening, including 
a QT interval corrected by Fridericia’s formula (QTcF) > 450 ms for males or > 
460 ms for females (mean values from triplicate ECGs; see Section 5.3.2.4)
Medical history
7. Any unresolved (at the time of Screening) clinically significant CTCAE Grade ≥ 2 
toxicity. (Exception: patients with alopecia, Grade ≤ 2 platinum-therapy related 
neuropathy, or Grade ≤ 2 anemia from previous anti-tumor treatment and/or from 
medical/surgical procedures/interventions, may be enrolled).
8. Known CNS metastases. 
9. Severe bacterial, fungal, viral and/or parasitic infections on therapeutic oral or IV 
medication at the time of first dose of study drug administration.


 
 
   
 
 
 
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10. Significant gastrointestinal disorders that could, in the opinion of the Investigator, 
interfere with the absorption, metabolism, or excretion of derazantinib (e.g., Crohn’s 
disease, ulcerative colitis, diarrhea, functionally relevant gastrointestinal obstruction, 
or vomiting).
11. 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. 
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.
12. Chronic leg ulcers, decubitus ulcers, or unhealed incisions.
General patient disposition
13. Known hypersensitivity or allergy to any component of the derazantinib, paclitaxel or 
ramucirumab formulation.
14. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric 
or humanized antibodies or fusion proteins.
15. Unable or unwilling to swallow the complete daily dose of derazantinib, or 
contraindicated to receive derazantinib, paclitaxel, ramucirumab and/or atezolizumab
16. 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.
17. 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.
18. Pregnant or breast feeding.
In addition, the following exclusion criteria are applicable only to patients to be 
enrolled into Substudy 2 or Substudy 3:
19. Concurrent uncontrolled or active infection with human immunodeficiency virus (HIV; 
known HIV 1/2 antibodies positive).
20. Active hepatitis 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. 
21. Active hepatitis C
Note: Active hepatitis C is defined by a known positive hepatitis C antibody result and known quantitative 
hepatitis C virus (HCV) RNA results greater than the lower limits of detection of the assay.
22. Active tuberculosis.


 
 
   
 
 
 
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23. 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, or placement 
of a central venous access device within 7 days prior to randomization.
24. Uncontrolled arterial hypertension, with a systolic blood pressure ≥ 150 mm Hg or a
diastolic blood pressure ≥ 90 mm Hg despite standard medical management.
25. History of gastrointestinal perforation and/or fistulae within 6 months prior to 
randomization.
26. History of clinically relevant bleeding disorders, vasculitis, or had a significant 
bleeding episode from the gastrointestinal tract within 3 months prior to randomization.
27. History of deep vein thrombosis, pulmonary embolism, or any other significant 
thromboembolism (venous port or catheter thrombosis or superficial venous 
thrombosis are not considered ‘significant’) during the 3 months prior to 
randomization.
28. The patient is receiving therapeutic anticoagulation with warfarin, low-molecular 
weight heparin, or similar agents. 
Note: Patients receiving prophylactic, anticoagulation therapy for cancer-associated thrombosis  are 
eligible provided that the coagulation parameters defined in the inclusion criteria (INR ≤1.5 and 
PTT/aPTT ≤1.5 ULN or PT ≤1.5 ULN, and PTT/aPTT ≤1.5 ULN) are met.
29. The patient is receiving chronic therapy with nonsteroidal anti-inflammatory agents 
(NSAIDs, e.g., indomethacin, ibuprofen, naproxen, or similar agents) or other 
anti-platelet agents (e.g., clopidogrel, ticlopidine, dipyridamole, anagrelide). 
Acetylsalicylic acid (aspirin) is permitted at doses up to 325 mg/day.
30. Child-Pugh B or C liver cirrhosis, or a history of hepatic encephalopathy, hepatorenal 
syndrome, or clinically-meaningful ascites related to cirrhosis.
31. The patient has a serious or non-healing wound, ulcer, or bone fracture within 28 days 
prior to randomization.
In addition, the following exclusion criteria are applicable only to patients to be 
enrolled into Substudy 3:
32. Administration of a live, attenuated vaccine within 30 days prior to randomization.
33. 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.
34. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently).
35. History of allogeneic stem cell or solid organ transplantation.


 
 
   
 
 
 
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36. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster 
ovary cells or any component of the atezolizumab formulation.
37. Patients requiring systemic treatment within 3 months prior to randomization 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).
38. 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 treatment assignment
For all substudies, a unique patient code will be assigned after written informed consent 
has been obtained, on entering the patient in Medidata RAVE EDC. If a patient withdraws 
from participation in the study, his or her patient code will not be reused.
4.4.1
Substudy 1 
Patients in Substudy 1 are to be stratified by type of FGFRfus/amp/mt (see Section 3.1.1) to 
be allocated to Cohort 1.1 (FGFR2fus / FGFR2high-amp) and Cohort 1.2 (FGFR1–3mt)1 and 
treated with derazantinib 300 mg QD monotherapy. As of Protocol Version 5.0, enrollment 
into Cohorts 1.1 and 1.2 is paused, and eligible patients are enrolled into Cohort 1.3.
As of Protocol Version 5.0, patients with GAC harboring FGFRfus/amp/mt allocated to 
Cohort 1.3 are to be treated with derazantinib 200 mg BID monotherapy
4.4.2
Substudy 2
All eligible patients in Substudy 2 will receive derazantinib-paclitaxel-ramucirumab in 
combination; treatment with either derazantinib-paclitaxel or derazantinib-ramucirumab 
may be considered if the triple combination is not tolerable. Assignment to a specific dose 
level and cohort will be controlled by the Medidata RAVE EDC system. 
4.4.3
Substudy 3 
Patients in Substudy 3 are to be stratified for type of FGFRfus/amp/mt and geographic region
(see Section 3.1.3), and then randomized (1:1:1:1) to receive the following study treatment,
based on a computer-generated randomization schedule via Medidata RAVE EDC:
Cohort 3.1: Patients randomized to be treated with derazantinib (test)
Cohort 3.2: Patients randomized to be treated with derazantinib-paclitaxel-
ramucirumab (test)
Cohort 3.3: Patients randomized to be treated with derazantinib-atezolizumab (test)
Cohort 3.4: Patients randomized to be treated with paclitaxel-ramucirumab (control)
                                                          
1 Patients with FGFR2fus or FGFR2high-amp concurrent to any FGFR1–3 mutation will be allocated to Cohort 1.1. 


 
 
   
 
 
 
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4.5
Discontinuation from the study treatment or the study
4.5.1
Patient discontinuation from study treatment
Patients must be discontinued from study treatment at any time if they meet any of the 
following criteria:
Objective documented radiographic progression of disease per RECIST 1.1 (and/or 
iRECIST per Investigator discretion; see Section 5.3.3.2.4). 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 study treatment.
Documented clinical progression of disease. 
Furthermore, patients should be discontinued from study treatment if any of the following
occur: 
Any clinically unacceptable treatment-emergent toxicity occurring in patients treated 
with derazantinib monotherapy that persists despite optimal treatment or dose reduction.
Any clinically unacceptable treatment-emergent toxicity clearly attributable to 
derazantinib, paclitaxel, ramucirumab, or atezolizumab alone or in combination that 
persists despite optimal supportive care treatment or dose reduction of the respective 
study drug or combination. In combinations, one study drug could be discontinued while
continuation of the other study drug is at the discretion of the Investigator.
Any severe hypersensitivity reactions, such as hypotension requiring treatment, dyspnea
requiring bronchodilators, angioedema, or generalized urticaria require immediate 
discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have 
developed severe hypersensitivity reactions to paclitaxel should not be rechallenged 
with paclitaxel; patients who have developed severe hypersensitivity reactions to 
ramucirumab should not be rechallenged with ramucirumab (other study drugs may be 
continued).
During combination treatment with derazantinib, paclitaxel, and/or ramucirumab, all 
study drugs should be discontinued for instances of overlapping Grade > 3 toxicity at 
least possibly study-drug-related (e.g., uncontrolled hypertension, fatigue, uncontrolled 
diarrhea, ophthalmological and/or hepatic AEs, including, but not limited to, AST 
increase) (see Section 6.1.6).
Any clinically unacceptable treatment-emergent toxicities clearly attributable to 
atezolizumab occurring
in patients treated with derazantinib-atezolizumab in 
combination in Cohort 3.3 that require management, as detailed in Appendix 4. 
Note: In this instance atezolizumab should be discontinued, whilst continuation of derazantinib is at the 
discretion of the Investigator.
Both study drugs (derazantinib and atezolizumab) should be discontinued for instances of overlapping 
toxicity (e.g., ophthalmological and/or hepatic AEs) that cannot be clearly attributed to either drug.
Pregnancy (see Section 5.3.2.7).
Patient decision to discontinue treatment and study visits.


 
 
   
 
 
 
 
 
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Withdrawal of consent for treatment and study follow-up calls (i.e., study 
discontinuation).
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.
For all patients who discontinue treatment, AE monitoring must be continued for at least 
90 days after the last dose of study drug (see Section 5.3.2.7). 
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 (at least 
three documented attempts by telephone or mail correspondence). The outcome of these
contacts 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 3.1.11), either through direct contact 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
Substudy 1
Patients who are non-evaluable for efficacy in Substudy 1 may be replaced. Patients 
non-evaluable for efficacy are those patients who received less than 50% of the planned 
derazantinib dose, or have no post-baseline imaging assessment in accordance with 
RECIST 1.1 without documentation of their disease and/or survival status.
Substudy 2
4.5.3.2.1
Replacement of patients in the Dose-finding Part
In Substudy 2, patients who received < 80% of the scheduled derazantinib, paclitaxel, or 
ramucirumab dose, respectively, in Cycle 1 (e.g., due to the vomiting of derazantinib 
tablets, or the discontinuation of paclitaxel and/or ramucirumab infusions) and who did not 
experience a DLT (see Section 7.3.3) will not be included in the assessment of the MTD 
for the particular dose level cohort, and will be replaced. However, patients who received 
< 80% of the scheduled derazantinib, paclitaxel, or ramucirumab dose, respectively, in 
Cycle 1 (e.g., due to the vomiting of derazantinib tablets within 2 hours, or the 
discontinuation of paclitaxel and/or ramucirumab infusions) will be taken into 
consideration for determination of the RP2D.


 
 
   
 
 
 
 
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4.5.3.2.2
Replacement of patients in the Dose-expansion Part
Patients who are non-evaluable for efficacy in the Dose-expansion Part of Substudy 2 may
be replaced. Patients non-evaluable for efficacy are those patients who received no doses 
of derazantinib, or have no post-baseline imaging assessment in accordance with 
RECIST 1.1 without documentation of their disease and/or survival status.
Substudy 3
Patients who are non-evaluable for efficacy in Substudy 3 may be replaced. Patients 
non-evaluable for efficacy are those patients who received no treatment, or have no post-
baseline imaging assessment in accordance with RECIST 1.1 without documentation of 
their disease and/or survival status.
4.5.4
Study discontinuation
The Sponsor reserves the right to temporarily or permanently discontinue a cohort, 
substudy, or the 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 Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC), as appropriate.
SCHEDULE OF ASSESSMENTS AND PROCEDURES
5.1
Summary of schedule of assessments
Study patients will be assessed in accordance with the items and schedules provided in
Table 1, Table 2, Table 3, and Table 4. 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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a.
Only applicable to Cycle 2.
b.
Only applicable to patients without a local positive FGFRfus/amp/mt result 
c.
Signature in a designated section of the study ICF acknowledging the positive FGFRfus/amp/mt test result and documenting the informed decision to participate in the study
d.
Safety laboratory blood samples will be tested locally at all study visits. The results of these assessments must be reviewed prior to dosing. 
e.
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, the 28-day Safety Follow-up visit and the 90-day 
Safety Follow-up visit. Monthly serum or urine pregnancy tests will subsequently be performed for 150 days following the last administration of study drug. Monthly 
pregnancy testing except the 28-day Safety Follow-up visit and the 90-day Follow-up visit 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.
f.
A research liquid biopsy should be obtained at the Screening and End of Treatment visits, and at the time point of the confirmatory CT scan (for complete response/partial 
response), and/or the time point of clinical assessment of progression or the time point for the first CT scan documenting objective/confirmed radiographic progression.
g.
Archival tumor tissue (FFPE block; or a minimum of two H&E-stained slipes plus at least 10 consecutive, unstained, 4 ± 1 μm thick sectons, placed on positively charged 
slides) should be collected at the SV from all enrolled patients for biomarker assessment.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.
h.
Tumor assessments performed as standard of care (SoC) prior to obtaining informed consent and within 28 days of the first dose of study drug on C1D1 may be used rather 
than repeating tests. All measurable and evaluable lesions should be assessed and documented at the SV. 
i.
Subsequent on-study tumor assessments are to be performed for all patients on C3D1 ±7 days and then every 8 weeks for 6 months (i.e., C5D1 and C7D1 ±7 days), and 
every 12 weeks (C10D1, C13D1, etc. ±7 days) thereafter (with additional scans as clinically indicated and as per RECIST 1.1 criteria) until disease progression, death, or 
loss of follow-up. 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.
j.
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 Section 5.3.3.2.3.
k.
For pre-dose PK blood sampling at C1D15, C2D1, C3D1, C4D1 (all patients), and C1D8, C1D22, C2D8, C2D15 and C2D22 (safety interim analysis patients), administer 
derazantinib at the study site.
l.
Derazantinib PK blood (plasma) sampling will be performed according to the schedules outlined in Section 5.3.4.
m. Survival contact can be in person, via phone, or, where applicable, by checking regional/national death registries. 




 
 
 
 
 
 
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a.
Only applicable to patient without a local positive FGFRfus/amp/mt result 
b.
Signature in a designated section of the study ICF acknowledging the positive FGFRfus/amp/mt test result and documenting the informed decision to participate in the study.
c.
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, the 28-day Safety Follow-up visit and the 90-day 
Follow-up visit. Monthly serum or urine pregnancy tests will subsequently be performed for 150 days following the last administration of study drug. Monthly pregnancy 
testing except the 28-day Safety Follow-up visit and the 90-day Follow-up visit 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.
d.
Archival tumor tissue (FFPE block; or a minimum of two H&E-stained slipes plus at least 10 consecutive, unstained, 4 ± 1 μm thick sectons, placed on positively charged 
slides) should be collected at the SV from all enrolled patients for biomarker assessment.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.
e.
Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of the first dose of study drug on C1D1 may be used rather than 
repeating tests. All measurable and evaluable lesions should be assessed and documented at the SV. 
f.
Subsequent on-study tumor assessments are to be performed for all patients on C3D1± 7 days and then every 8 weeks for 6 months (.i.e., C5D1 and C7D1 ± 7 days), and 
every 12 weeks (C10D1, C13D1 etc. ± 7 days) thereafter (with additional scans as clinically indicated and as per RECIST 1.1 criteria) until disease progression, death, or 
loss of follow-up. 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.
g.
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 Section 5.3.3.2.3).
h.
Blood (plasma or serum) sampling for derazantinib, paclitaxel and ramucirumab PK assessments will be performed shown in Section 5.3.4. No paclitaxel/ramucirumab 
PK assessment at 90-day Safety Follow-up visit.
i.
AEs occurring between C1D1 and C1D28 in patients in the dose-limiting toxicity (DLT) Part of Substudy 2 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 electronic case report form.
j.
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a.
Only applicable to Cohorts 3.2. and 3.4 in Substudy 3.
b.
Only applicable to patient without a local positive FGFRfus/amp/mt result 
c.
Signature in a designated section of the study ICF acknowledging the positive FGFRfus/amp/mt test result and documenting the informed decision to participate in the study.
d.
Safety laboratory blood samples at the Screening visit must include a tuberculosis blood test (e.g., interferon-gamma release assay) and serology for human 
immunodeficiency virus, chronic hepatitis B, or hepatitis C.
e.
Applicable to Cohorts 3.2 and 3.4 only: On D8 and D15 of all treatment cycles, patients should undergo safety laboratory blood sample testing within 1 day prior to 
paclitaxel-ramucirumab administration. The results of these assessments must be reviewed prior to dosing.
f.
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, the 28-day Safety Follow-up visit and the 90-day 
Follow-up visit. Monthly serum or urine pregnancy tests will subsequently be performed for 150 days following the last administration of study drug. Monthly pregnancy 
testing except the 28-day Safety Follow-up visit and the 90-day Safety Follow-up visit 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.
g.
A research liquid biopsy should be obtained at the Screening and End of Treatment visits, and at the time point of the confirmatory CT scan (for complete response/partial 
response), and/or the time point of clinical assessment of progression or the time point for the first CT scan documenting objective/confirmed radiographic progression.
h.
Tumor assessments performed as standard of care (SoC) prior to obtaining informed consent and within 28 days of the first dose of study drug on C1D1 may be used rather 
than repeating tests. All measurable and evaluable lesions should be assessed and documented at the SV. 
i.
Subsequent on-study tumor assessments are to be performed for all patients on C3D1 ±7 days and then every 8 weeks for 6 months (i.e., C5D1 and C7D1 ±7 days), and 
every 12 weeks (C10D1, C13D1, etc. ±7 days) thereafter (with additional scans as clinically indicated and as per RECIST 1.1 criteria) until disease progression, death, or 
loss of follow-up. 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.
j.
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 Section 5.3.3.2.3).
k.
Derazantinib will be administered QD, ramucirumab on D1 and D15 of each cycle and paclitaxel on D1, D8 and D15 of each cycle, when applicable. Paclitaxel must not 
be started earlier than 60 minutes after completion of the ramucirumab infusion; the 1-hour observation period between administration of ramucirumab and paclitaxel is 
mandatory for the first two cycles, but may be omitted in Cycle 3 and beyond provided there has been no evidence of infusion-related reaction.


 
 
 
 
 
 
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l.
Applicable to patients treated with derazantinib (Cohorts 3.1 and 3.2). Blood (plasma) sampling for derazantinib PK assessments will be performed per schedule shown in 
Table 7, Table 9, and Table 10. 
m. Applicable to patients treated with paclitaxel (Cohort 3.2). Blood (plasma) sampling for paclitaxel PK assessments will be performed per schedule shown in Section 5.3.4.5
Table 10.
n.
Applicable to patients treated with ramucirumab (Cohorts 3.2 and 3.4). Blood (serum) sampling for ramucirumab PK assessments will be performed per schedule shown 
in Section 5.3.4.5 Table 10 and Section 5.3.4.7 Table 12. No ramucirumab PK assessment at 90-day Safety Follow-up visit.
o.
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a.
Only applicable to patient without a local positive FGFRfus/amp/mt result
b.
Signature in a designated section of the study ICF acknowledging the positive FGFRfus/amp/mt test result and documenting the informed decision to participate in the study.
c.
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, the 28-day Safety Follow-up visit and the 90-day 
Follow-up visit. Monthly serum or urine pregnancy tests will subsequently be performed for 150 days following the last administration of study drug. Monthly serum or 
urine pregnancy testing except the 28-day Safety Follow-up visit and the 90-day Safety Follow-up visit 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.
d.
A research liquid biopsy should be obtained at the Screening and End of Treatment visits, and at the time point of the confirmatory CT scan (for complete 
response/partial response, or if applicable confirmed progressive disease [iCPD]), and/or the time point of clinical assessment of progression or the time point for the 
first CT scan documenting objective/confirmed radiographic progression.
e.
Tumor assessments performed as SoC prior to obtaining informed consent and within 28 days of the first dose of study drug on C1D1 may be used rather than repeating 
tests. All measurable and evaluable lesions should be assessed and documented at the SV. 
f.
Subsequent on-study tumor assessments are to be performed on C3D15, then every 8 weeks (i.e. C6D8 and C9D1, ±7 days) for 6 months, and every 12 weeks (C13D1, 
C17D1, etc. ±7 days) thereafter (with additional scans as clinically indicated and as per RECIST 1.1 criteria) until disease progression, death, or loss of follow-up. 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. 
g.
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 Section 5.3.3.2.3).
h.
Blood (plasma) sampling for derazantinib PK assessments will be performed per schedule shown in Section 5.3.4.6 Table 11. 
i.
Blood (serum) sampling for atezolizumab PK and ADA assessments will be performed per schedule shown in Section 5.3.4.6 Table 11 . No atezolizumab PK and ADA 
assessments at 90-day Safety Follow-up visit.
j.
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
Informed consent
For patients with no documented local NGS test result with an eligible FGFRfus/amp/mt, the 
IEC/IRB approved ICF for pre-screening must first be signed by each prospective study 
participant to permit central testing for eligible FGFRfus/amp/mt.
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. 
For patients who received paclitaxel-ramucirumab in Cohort 3.4 who are to be eligible for 
crossing over to derazantinib treatment (see Section 3.1.9), a separate specific Crossover 
Treatment ICF providing consent for the additional treatment and applicable extension of 
study-related procedures must be signed. The written informed consent acknowledges the 
specific benefit-risk profile of derazantinib treatment and the extension of study-related 
procedures aligned with Cohort 3.1 (see Table 3).
Patients who agree to participate in the study will sign the most recently approved 
applicable ICF(s) and will be provided with a copy of the document(s). Informed consent 
must be obtained within the 28 days prior to the first dose of study treatment on Cycle 1, 
Day 1 (C1D1). 
5.2.2
Pre-screening visit
A Pre-screening visit is only required for prospective study participants if no documented 
local NGS test result with an eligible FGFRfus/amp/mt is available at the Screening visit (see 
Section 3.1.4).
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 designated by the Sponsor and will be based on 
NGS testing of cfDNA from a liquid biopsy obtained at Pre-screening visit.
It is recommended to conduct the Pre-screening visit for liquid biopsy sampling following 
assessment of objective documented progression after prior anti-cancer treatment. 
However, in the interests of patients and to reduce off-treatment time between the last anti-
cancer treatment and study treatment, liquid biopsy sampling might be performed at any 
time point after the last administration of anti-cancer therapy when disease progression is 
suspected. Liquid biopsy re-screening for molecular inclusion criteria is not permitted, 
unless the liquid biopsy was not evaluable for technical reasons.
5.2.3
Screening visit
The screening window for clinical screening procedures will be 28 days. Taking the 
required interval period between prior antitumor treatment and initiation of study treatment 
into consideration, the screening period is recommended to be kept as short as possible to 
limit the number of patients experiencing clinical deterioration due to their disease 
progression.


 
 
   
 
 
 
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At the Screening visit, clinical eligibility of prospective study participants and baseline 
disease status will be assessed. 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.
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 5.3.1.2)
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 Section 5.3.2.2)
Complete ophthalmic examination, including optical coherence tomography (OCT) 
(see Section 5.3.2.3)
Triplicate 12-lead ECG (see Section 5.3.2.4)
Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)
Research liquid biopsy 
Urinalysis (see Section 5.3.2.6)
Serum pregnancy test, if applicable (see Inclusion criterion 10, Section 5.3.2.7, and 
Section 7.1.5
Tumor imaging assessments, 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 last dose of prior anti-tumor treatment).
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) 
AEs that occur following the full execution of the study ICF but prior to dosing, must 
be recorded in the medical history page of the eCRF. If the event is assessed as serious
and related to the study procedure, the AE must be reported as an SAE as described in 
Section 7.2.2
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 liquid biopsy was not evaluable for technical reasons. Under rare 
conditions and contingent on Sponsor approval, patients may be given the possibility to be 
re-screened after initially failing screening.
Patients who cannot be enrolled because they were planned for Substudy 2 but no slot was 
available should have the option to be enrolled into Substudy 1, either directly, or at a later 
stage when they progress under second-line treatment.


 
 
   
 
 
 
 
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Patients who meet molecular inclusion criteria but with disease progression not confirmed 
at the screening CT are allowed to be clinically re-screened at the time PD is established.
5.2.4
Treatment period
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. In Substudies 2, Cohorts 3.2 and 3.4, a 
minimum of at least 7 days needs to be maintained between two paclitaxel administrations 
and at least 14 days between two ramucirumab administrations. 
Adverse events (see Section 7.2) and concomitant medications (see Section 6.4) will be 
recorded on an ongoing basis during the treatment period, and at the selected time points 
as summarized in Table 1, Table 2, Table 3, and Table 4.
Cycle 1, Day 1 (all patients)
Patients will be considered enrolled, i.e., allocated/randomized on C1D1, or as close as 
possible to the date on which treatment is allocated. 
In all substudies, the following assessments will be made during this visit (all assessments 
except for AE assessment and post-dose PK blood collection [where applicable; see 
Section 5.3.4]) must be performed prior to the first dose):

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 (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

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 7.1.5) 

Blood samples for PK and ADA (see Section 5.3.4 for details of sampling schedule in
each substudy)

Assess and record any AEs after study medication administration (see Section 5.3.2.8)

Record concomitant medications (see Section 5.3.2.9)


 
 
   
 
 
 
 
 
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Furthermore, the following assessments will be made during this visit in specific substudies 
only: 

Substudy 1: 
– Dispense and administer derazantinib (see Section 6.1.1.4)

Substudy 2: 
–
Dispense and administer derazantinib, paclitaxel, ramucirumab (see Sections
6.1.1.4, 6.1.2.6, and 6.1.3.6)

Substudy 3: 
– PRO instruments (questionnaires should be completed by the patient prior to being 
evaluated by the physician) (see Section 5.3.6)
– Dispense 
and 
administer 
derazantinib, 
paclitaxel, 
ramucirumab 
and/or 
atezolizumab as applicable according to the patient’s treatment allocation (see 
respective Sections 6.1.1.4, 6.1.2.6, 6.1.3.6 and/or 6.1.4.5)
Cycle 1, Day 8 and Day 22 (3 days) – safety interim analysis patients in 
Substudy 1
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 5.3.4.2 for details of sampling 
schedule) 

Triplicate 12-lead ECGs (performed pre-dose and 6–8 hours post-derazantinib dosing) 
(see Section 5.3.2.3)

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)
Cycle 1, Day 8 (3 days) – paclitaxel-ramucirumab treatment cycles only
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)

Urinalysis (see Section 5.3.2.6)

Blood samples for PK (see Section 5.3.4 for details of sampling schedule in each 
substudy)

Administer paclitaxel (see Section 6.1.4.1)

Assess and record any AEs after study medication administration (see Section 5.3.2.8)

Record concomitant medications (see Section 5.3.2.9)


 
 
   
 
 
 
 
 
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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)

Triplicate 12-lead ECG (see Section 5.3.2.4)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)

Urinalysis (see Section 5.3.2.6)

Administer derazantinib capsules (if applicable) (see Section 6.1.1.1)Administer 
paclitaxel-ramucirumab (if applicable) (see Section 6.1.4.1)

Blood samples for PK and ADA (see Section 5.3.4 for details of sampling schedule in 
each substudy)

Assess and record any AEs after study medication administration (see Section 5.3.2.8)

Record concomitant medications (see Section 5.3.2.9)
Cycle 2+, Day 1 (3 days)
In all substudies, the following assessments will be made during this visit:

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 (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)

Triplicate 12-lead ECG (required on D1 of all cycles prior to dosing, or if clinically 
indicated; see Section 5.3.2.4). 

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 four cycles from C1D1; ; and 25-hydroxy vitamin D is required at C1D1, C3D1 and 
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 7.1.5) 

Blood samples for PK and ADA (see Section 5.3.4 for details of sampling schedule in 
each substudy)

Assess and record any DLTs (safety interim analysis patients in Substudy 1, Substudy 
2 (Dose-finding Part) patients only) (see Section 7.3.3)

Assess and record any AEs after study medication administration (see Section 5.3.2.8)

Record concomitant medications (see Section 5.3.2.9)

If applicable, perform drug accountability of returned drug (see Section 6.1.1.3) and 
dispense derazantinib capsules (see Section 6.1.1.4)
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. 


 
 
   
 
 
 
 
 
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
If applicable, dispense/administer study medication (see Sections 6.1.2.6, 6.1.3.6, 
6.1.4.5, and 6.1.5 for derazantinib, paclitaxel, ramucirumab and atezolizumab, 
respectively) and perform drug accountability for any incompletely administered 
study drug (see respective Sections 6.1.2.3, 6.1.3.3, 6.1.4.3, and 6.1.5)

Substudy 3 only: PRO instruments (questionnaires should be completed by the patient 
prior to being evaluated by the physician; see Section 5.3.6)

If applicable, tumor measurement and response evaluation until disease progression, 
death, or loss to follow-up (see Section 5.3.3.2 and Appendix 2).
Tumor imaging assessments are performed every 8 weeks (±7 days) for 6 months, and 
every 12 weeks (±7 days) (see Section 5.3.3.2 and Appendix 2). 
Additionally, all patients should undergo a research liquid biopsy (see Section 5.3.5.1) at 
the time point of the CT scan ( confirming response.
Cycle 2, Day 8, Day 15, and Day 22 (3 days) – safety interim analysis patients 
in Substudy 1
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 5.3.4.2 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
Cycle 2+, Day 8 (3 days) – paclitaxel treatment cycles only
The following assessments will be made during this visit: 

Physical examination, including weight and vital signs (see Section 5.3.2.1)

ECOG PS (see Section 5.3.2.2)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)

Urinalysis (see Section 5.3.2.6)

Dispense and administer paclitaxel (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)


 
 
   
 
 
 
 
 
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Cycle 2+, Day 15 (3days) – paclitaxel-ramucirumab treatment cycles only
The following assessments will be made during this visit: 

Physical examination, including weight and vital signs (see Section 5.3.2.1)

ECOG PS (see Section 5.3.2.2)

Clinical safety laboratory blood tests (see requirements in Section 5.3.2.5)

Urinalysis (see Section 5.3.2.6)

Dispense and administer paclitaxel-ramucirumab (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)
End of Treatment assessment (within 7 days after the decision to 
permanently discontinue all study drug) – 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 after the decision to 
permanently discontinue all study drug. 
The following assessments will be performed during the End of Treatment visit in all 
substudies:

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)
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 (see Section 5.3.2.7 and Section 7.1.5)

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 (if applicable) (see Section 
6.1.1.3)

Substudy 3 only: PRO instruments (questionnaires should be completed by the patient 
prior to being evaluated by the physician; see Section 5.3.6)


 
 
   
 
 
 
 
 
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Safety follow-up (28 days / 90 days after last dose ± 3 days)
All patients 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 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 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. 
At the safety follow-up visits, the following assessments will be performed:

Assess and record any AEs (see Section 5.3.2.8)

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)

Serum pregnancy testing. Subsequently, serum or urine pregnancy testing should be 
performed monthly until 150 days after the last administration of study drug (see 
Section 5.3.2.7, and Section 7.1.5).

Blood samples for PK and ADA (see Section 5.3.4)

Concommitant medications (see Section 5.3.2.9)

Substudy 3 only: PRO instruments (questionnaires should be completed by the patient 
prior to being evaluated by the physician; see Section 5.3.6)
5.2.5
Survival follow-up period
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-monthly intervals (±14 days) to 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 
anti-cancer 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 4.5).


 
 
   
 
 
 
 
 
 
 
 
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5.3
Study procedures
5.3.1
Screening procedures
Medical history / baseline medical conditions
A full medical history, including relevant abnormalities, surgeries, diseases, or disorders,
until signature of the informed consent must be obtained at Screening and recorded in the 
eCRF. Medical history should include any relevant worsening of a patient’s condition 
which occurs after informed consent, but prior to the start of first study-drug 
administration.
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).
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.
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] and causality assessment), 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, Table 2, Table 3, and Table 4). 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).
Physical examination, including vital signs
A complete physical examination of the major body systems should be performed at 
intervals indicated in the schedule of assessments (see Table 1, Table 2, Table 3, and
Table 4). 


 
 
   
 
 
 
 
 
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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 sitting, semi-supine or supine 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).
Eastern Cooperative Oncology Group performance status 
ECOG PS will be assessed at all study visits.
Table 5 provides the scale to be used for these assessments.
Table 5
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.
Complete ophthalmological examination 
A complete ophthalmological examination, including optical coherence tomography 
(OCT), should be performed by an ophthalmologist at the Screening visit, on D1 of the 
first four treatment cycles (i.e., Day 1 of Cycles 2–5)1, at the 28-day Safety Follow-up visit, 
and at the 90-day Safety Follow-up visit. Note, the examination may be performed up to 8 
days prior to the study visits. Thereafter, a complete ophthalmological examination is to be 
repeated if clinically indicated (e.g., new ocular symptoms occur, or vision is impaired).
                                                          
1 A more frequent schedule (i.e., every 3 months as of C5D1) may required in accordance with local regulations and 
where specified in a local ICF (e.g., for patients enrolled in France).


 
 
   
 
 
 
 
 
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The complete ophthalmological examination 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 
study should be referred to the ophthalmologist for a complete ophthalmological 
examination.
Electrocardiogram (12-lead) triplicates
A standard, triplicate, 12-lead ECG should be performed at the intervals indicated in the 
schedule of assessments (see Table 1, Table 2, Table 3, and Table 4).
ECGs must always be recorded after at least 5 minutes rest and while the patient is in a 
supine or semi-supine position. Measurements should be separated by ~1 minute and be 
taken within a 5-minute time window. 
In patients treated with derazantinib monotherapy in Substudies 1 and 3, on-treatment 
ECGs (up to Cycle 4) should be performed as close as possible to the corresponding PK 
blood collection time point during those visits (i.e., pre-dose and 6–8 hours after 
derazantinib administration; see Section 5.3.4.4); if possible, the 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 three QTcF values obtained should be averaged for a 
mean QTcF value for decision making. The ECG printouts are to be signed and dated by 
the Investigator or their designee. 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).
Clinical safety laboratory blood tests
Blood samples for clinical safety laboratory testing should be performed locally at all study 
visits. 
These assessments must be reviewed prior to dosing, and study drug administration after 
C1D1 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.


 
 
   
 
 
 
 
 
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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, amylase, lipase, sodium, potassium, calcium, magnesium, 
chloride, phosphate, C-reactive protein (CRP), creatinine, glucose, and total protein
–
CRP is required at C1D1 and thereafter only if infection is suspected;
–
CLCR, as calculated by the Cockcroft-Gault equation (at the Screening Visit only);

Liver function tests: ALT, AST, alkaline phosphatase (ALP), total and direct bilirubin, 
lactate dehydrogenase

Coagulation tests: prothrombin time, INR, and partial prothrombin time (at the 
Screening and End of Treatment visits, and if clinically indicated)

Other tests: thyroid panel (TSH, fT3, fT4), and Vitamin D
–
TSH, fT3 and fT4 is required at C1D1 and subsequently every 4 cycles;
–
25-hydroxy vitamin D is required at C1D1, C3D1, C5D1, and the End of Treatment 
visit only. 
Furthermore, prospective Substudy 3 patients must undergo a tuberculosis blood test 
(e.g., interferon-gamma release assay) and serology for human immunodeficiency virus, 
chronic hepatitis B, or hepatitis C at the Screening visit.
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 an adverse 
clinical outcome (see Section 7.4.3.1.1).
Urinalysis
Urinalysis will be performed locally at the intervals indicated in the schedule of 
assessments (see Table 1, Table 2, Table 3, and Table 4).
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.
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, 
at the 28-day Safety Follow-up visit and at the 90-day Safety Follow-up visit. Monthly 


 
 
   
 
 
 
 
 
 
 
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serum or urine pregnancy tests must be performed for 150 days following the last 
administration of study treatment. 
Monthly serum or urine pregnancy testing after the 28-day Safety Follow-up visit may be 
performed by the patient’s local gynecologist (with the exception of the test to be 
performed at the 90-day Safety Follow-up visit) 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 7.1.5.
Adverse event monitoring
AEs will be monitored throughout the study and graded in severity according to the 
guidelines outlined NCI CTCAE 5.0. 
Please refer to Section 7 for details regarding AE collection and management.
Concomitant medications
Concomitant medications during the course of the study (until the safety follow-up visit at 
Day 90 for all patients) must be recorded in the eCRF (see Section 6.4).
5.3.3
Efficacy assessments
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 imaging assessments should comprise of CT 
(strongly preferred) or MRI of the chest, abdomen, and pelvis. MRI should primarily be 
used when CT is contraindicated. 
The same imaging technique regarding modality and use of contrast should be used in a 
patient throughout the study.
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.
Tumor measurement and response evaluations
5.3.3.2.1
Baseline tumor imaging
Baseline tumor imaging assessments must be done at the time of the Screening visit. 
However, if an assessment has been performed for routine clinical management prior to 
obtaining informed consent after administration of the last dose of any prior anti-tumor 
treatment, 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. 


 
 
   
 
 
 
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For initial tumor imaging of all patients at Screening, the site study team must review 
Screening images to confirm the patient has measurable disease per RECIST 1.1 
(Appendix 3).
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. Baseline imaging assessments 
must be submitted to the central imaging vendor and serve as baseline for subsequent 
central evaluations.
A bone scan (BS) – alternatively, a whole-body MRI (WBMRI) – should 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 (Ajani 2016, Smyth 2016a) 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 (see Section 5.3.3.2.2) 
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.
5.3.3.2.2
On-treatment tumor imaging
Study imaging assessments are identical to the imaging modalities used for baseline 
assessments. In general, and following common oncology practice, on-treatment tumor 
imaging assessments should be performed and evaluated prior to initiation of any new 
treatment cycle; results of all tumor imaging assessments must be reviewed by the 
Investigator before dosing at the next cycle to avoid treatment beyond objective 
radiographic disease progression. However, if necessary for administrative and 
organizational reasons, and in the absence of unequivocal signs of clinical worsening, it is 
acceptable to perform the on-treatment tumor imaging assessment after the start of a new 
treatment cycle, providing it is within 7 days of the start of the cycle.
Imaging timing should follow calendar days, and should not be adjusted for delays in cycle 
starts (i.e., the intervals indicated below should be followed throughout in all substudies 
irrespective of cycle intervals).
In all substudies, on-treatment tumor imaging is subject to BICR. In all substudies, the first 
on-study tumor imaging assessments will be performed on C3D1 ±7 days, and 
subsequently every 8 weeks (i.e., C5D1 and C7D1 ±7 days) for 6 months, then every 
12 weeks (C10D1, C13D1 etc, ±7 days) thereafter (or more frequently if clinically
indicated). New osseous uptake / lesions on BS/WBMRI in comparison to available prior 
BS/WBMRI will be assessed for progression per RECIST 1.1 (Appendix 3).
In Cohort 3.3 and with regard to the 3-week cycle interval, the first on-study tumor 
assessments will be performed on C3D15, and subsequently every 8 weeks (i.e. C6D8 and 
C9D1, ±7 days) for 6 months, and then every 12 weeks (C13D1, C17D1 etc, ±7 days) 
thereafter (with additional scans as clinically indicated). 


 
 
   
 
 
 
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5.3.3.2.3
Post-treatment tumor imaging
Patients who discontinue study treatment should have a tumor imaging assessment as soon 
as possible, but no later than 28 days after the event. If a previous scan was obtained within
28 days prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory but recommended if the clinical situation indicates an altered disease status. 
For patients who discontinue study treatment due to documented PD, this is the final 
required tumor imaging for the study. 
5.3.3.2.4
Tumor imaging of patients after treatment crossover
For patients enrolled in Cohort 3.4, the tumor imaging used to determine PD after 
paclitaxel-ramucirumab treatment 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 
monotherapy. 
Imaging timing should follow calendar days, and should not be adjusted for delays in cycle 
starts (i.e., the 8-/12-week intervals should be followed throughout in all substudies and 
irrespective of cycle intervals).
The first Crossover Phase tumor imaging assessments will be performed on C3D1 ±7 days, 
and subsequently every 8 weeks (i.e., C5D1 and C7D1 ±7 days) for 6 months, then every 
12 weeks (C10D1, C13D1 etc ± 7 days) thereafter (or more frequently if clinically 
indicated). New osseous uptake / lesions on BS/WBMRI in comparison to available prior 
BS/WBMRI will be assessed for progression per RECIST 1.1 (Appendix 3).
5.3.3.2.5
RECIST 1.1 and iRECIST
Efficacy will be measured by ORR and PFS4, both evaluated by BICR using RECIST 1.1 
(see Appendix 3).
In addition, in Cohort 3.3 an exploratory assessment will be performed using iRECIST
criteria (Seymour 2017) in patients treated with derazantinib-atezolizumab in combination 
(see Appendix 3 for comparison of RECIST 1.1 and iRECIST).
In patients undergoing combination treatment with derazantinib and atezolizumab, 
iRECIST will be used by the site Investigator / local 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.
For all patients with CR or PR per RECIST 1.1, and for all patients of Cohort 3.3 with 
immunotherapy-treated iUPD per iRECIST, the Investigator should make every attempt to 
perform the confirmation scan 4–8 weeks after the last scan was performed, unless criteria 
for clinical stability are not met (see below). 












 
 
   
 
 
 
 
 
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Archival tumor samples
For all patients with a positive test for FGFRfus/amp/mt, every reasonable effort should be 
undertaken to collect available archived tumor samples to facilitate correlative and
confirmatory diagnostic and biomedical research. An FFPE block; or minimum of two 
H&E-stained slides plus at least ten 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.. 
Future biomedical research
The Sponsor may 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; further details are provided in the 
Laboratory Manual.
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 6.
5.3.6
PRO assessments (Substudy 3 only)
Patient reported outcomes will be measured using the EQ-5D (5L), EORTC QLQ-C30 and 
EORTC QLQ-STO-22 instruments. HR-QoL and symptom response will be measured 
using the EQ-5D, EORTC
QLQ-C30, EORTC QLQ-STO-22 and G-SET/HTI 
questionnaires. The HR-QoL questionnaires will be completed by the patient before the 
patient sees the physician (i.e., at the start of the visit) on D1 of every cycle. EQ5D should 
be completed first, followed by EORTC QLQ-C30, EORTC QLQ-STO-22, and 
G-SET/HTI.
The EQ-5D (5L) is a standardized instrument for use as a measure of health outcomes. 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. 
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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 (Herdman 2011).
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), 
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 EORTC QLQ-STO-22 is a disease-specific questionnaire developed and validated to 
address measurements specific to gastric cancer. It is one of multiple disease-specific 
modules developed by the EORTC QLG (Quality of Life Group) designed for use in 
clinical studies, to be administered in addition to the QLQ-C30 to assess disease-specific 
treatment measurements. It contains 22 items with symptoms of dysphagia (4 items), pain 
or discomfort (3 items), upper gastrointestinal symptoms (3 items), eating restrictions 
(5 items), emotional (3 items), dry mouth, hair loss, and body image (Blazeby 2004).
The G-SET/HTI 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 EORTC QLQ-STO-22 scales. It will be administered twice during the study in 
line with the recent protocol by the EORTC Quality of Life Group (Musoro 2018) for 
evaluating the minimal important difference. The G-SET will be provided to participants 
in Cohorts 3.1, 3.2 and 3.4 after 8 weeks and 16 weeks, and to participants in Cohort 3.3
after 6 weeks and 15 weeks. The G-SET is a patient-rated change in health between two 
time periods using a five point ordinal scale (1 = much better now than 8 weeks ago; 
2 = somewhat better now than 8 weeks ago; 3 = about the same as eight weeks ago; 
4 = somewhat worse now than 8 weeks ago; 5 = much worse now than eight weeks ago, 
the recall period was adapted compared to the original item) (Ware 2002, Lloyd 2014). For 
cohort 3.3, G-SET timepoints will be adapted accordingly.
The HR-QoL questionnaires will be provided to the patients to complete prior to being 
evaluated by the physician on Day 1 of every cycle, at the End of Treatment visit, and at 
the safety follow-up visits.
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, EORTC QLQ-STO22, and the G-SET/HTI (if applicable).
STUDY TREATMENTS
Derazantinib, paclitaxel, ramucirumab
and atezolizumab are considered to be 
investigational medicinal products (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.
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 Medidata RTSM.
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 
Medidata RTSM and a resupply shipment will be made.
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. 


 
 
   
 
 
 
 
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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. 
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 Medidata RTSM 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 
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 destroyed locally and only returned to the designee as instructed 
by the Sponsor if the site cannot destroy locally. 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 
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6.1.1.5.1
Hyperphosphatemia
For all patients, it is recommended to restrict phosphorus intake to 600–800 mg daily. 
As hyperphosphatemia is only defined by 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 14 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)


 
 
   
 
 
 
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Table 14
Dose delays/reductions for drug-related toxicity
HYPERPHOSPHATEMIA
Serum phosphate level
Action
< 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
(see exception for AST/ALT elevations 
in Table 13)
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
(see exception for AST/ALT elevations 
in Table 13)
Permanently discontinue derazantinib if the event is at least
possibly related to derazantinib.
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events.
* 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.


 
 
   
 
 
 
 
 
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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.
6.1.1.5.2
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 and for the first four cycles (i.e. D1 of C2-5).
Further complete ophthalmological examinations only need to be performed if clinically 
indicated. Table 14
provides specific guidance for the management of dose 
delays/reductions in the case of retinal AEs possibly related to derazantinib.
6.1.1.5.3
Management of QTc prolongation or other significant ECG abnormalities
If significant corrected QT interval (QTc) prolongation and/or significant ventricular 
arrythmia is observed, i.e., an averaged 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 ≤460 msec. 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.
Once QTc prolongation has resolved, and if a decision was made to continue treatment 
with derazantinib, patients may continue treatment at a lower dose level per Table 13 with
an ECG monitoring schedule defined by the cardiologist.
Patients who experience a mean QTcF interval ≥501 ms on at least two ECGs at difference 
time points after dose reduction will be discontinued from study.
All significant QTc prolongations or other relevant ECG abnormalities, will also be 
evaluated centrally.
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 first dose 
of derazantinib, the patient may be re-challenged at the Investigator’s discretion.
Overdose
There is no specific guidance to be given in regard to overdose of any study drug.
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).
                                                          
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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6.1.2
Paclitaxel
Paclitaxel is an approved medication supplied as a nonaqueous 6 mg/mL solution in 
multidose vials for dilution with a suitable parenteral fluid prior to IV infusion. Paclitaxel 
is an investigational drug for its use in combination with derazantinib. Its use as a weekly 
IV infusion as second-line treatment in GAC is supported by international guidelines 
(Ajani 2016, Smyth 2016a).
In general, preparation, administration and clinical management of paclitaxel and patients 
treated with paclitaxel should follow the description provided by the SmPC 
(Paclitaxel Ever Pharma SmPC). Topics most relevant to this protocol only are addressed 
below.
Shipping and storage conditions
The Sponsor will provide paclitaxel vials 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 Medidata RTSM.
Drug supplies must be stored in a secure, limited access storage area.
Unopened vials of Paclitaxel Injection, USP are stable until the date indicated on the 
package when stored between 20° to 25°C (68° to 77°F), in the original package. 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 vials must be reported as damaged in the 
Medidata RTSM and a resupply shipment will be made.
Labeling and packaging
Paclitaxel is supplied as multidose 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.
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 Medidata RTSM 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. 


 
 
   
 
 
 
 
 
 
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A Drug Accountability Log will be provided for paclitaxel. 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 paclitaxel 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 destroyed locally, and only returned to the designee as instructed 
by the Sponsor if the site cannot destroy locally. Paclitaxel 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 paclitaxel 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.
Preparation and stability of study drug
Paclitaxel must be diluted prior to infusion. Details of drug shipment, storage, and 
preparation are provided in the Pharmacy Manual. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration whenever 
solution and container permit.
Paclitaxel solutions should be prepared and stored in glass, polypropylene, or polyolefin 
containers. Non-polyvinyl chloride (PVC) containing administration sets, such as those 
which are polyethylene-lined, should be used.
Paclitaxel premedication
All patients should be premedicated prior to paclitaxel administration in order to prevent 
severe hypersensitivity reactions. Such premedication may consist of dexamethasone 
20 mg orally (PO) administered approximately 12 and 6 hours before paclitaxel, 
diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to paclitaxel, and 
pantoprazole (40 mg) I.V. 30 to 60 minutes before paclitaxel.
Paclitaxel administration
Per recent publications and standard clinical practice, 80 mg/m² paclitaxel will be 
administered intravenously as a 1-hour infusion on days 1, 8, and 15 of a 28-day cycle 
(Ajani 2016, Smyth 2016a, Wilke 2014). Paclitaxel should be administered through an 
in-line filter with a microporous membrane not greater than 0.22 microns. 
When used in combination with ramucirumab, paclitaxel must not be started earlier than 
60 minutes after completion of the ramucirumab infusion; the 1-hour observation period 
between administration of ramucirumab and paclitaxel is mandatory for the first 
two cycles, but may be omitted in Cycle 3 and beyond provided there has been no evidence 
of infusion-related reaction.


 
 
   
 
 
 
 
 
 
 
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DZB-CS-202 (FIDES-03)
Version 5.0
21 May 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
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Dose modifications
In this protocol, paclitaxel will be administered in combination with ramucirumab. Dose 
modification of the combination treatment are specified below (see Section 6.1.6.1).
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the DLT. 
Neutrophil nadirs usually occurr at a median of 11 days. Paclitaxel should not be 
administered to patients with baseline neutrophil counts of less than 1.5 × 109/L. Frequent 
monitoring of blood counts should be instituted during paclitaxel treatment. Patients should 
not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level 
> 1.5 × 109/L and platelets recover to a level > 100 × 109/L.
Prior to D1, D8 and D15 of each administration of paclitaxel, hematology, urine protein 
(dipstick), liver, and renal function must be adequate (see Section 6.1.6.1), and all 
paclitaxel-related toxicities (except for alopecia) must have resolved to Grade < 2 or 
baseline. Pre-infusion laboratory data may not be older than 36 hours.
Missed-dose management
If a planned dose of paclitaxel is missed, it should be administered as soon as possible; it 
is recommended not to wait until the next planned dose. The schedule of administration 
must be adjusted to maintain the D1, D8 and D15 28-day schedule.
Overdose
There is no known antidote for paclitaxel overdosage. The primary anticipated 
complications of overdosage would consist of bone marrow suppression, peripheral 
neurotoxicity, and mucositis.
6.1.3
Ramucirumab
Ramucirumab is an approved medication supplied as a 10 mg/mL solution in single dose 
10 mL or 50 mL vials for dilution with 0.9% sodium chloride prior to IV infusion. 
Ramucirumab is an investigational drug for its use in combination with derazantinib. It is 
approved for use as weekly IV infusion, either as a single agent or in combination with 
paclitaxel, as a second-line treatment in GAC.
In general, preparation, administration and clinical management of ramucirumab and 
patients treated with ramucirumab should follow the description provided by US PI and 
SmPC (Cyramza® USPI, Cyramza EPAR). Topics most relevant to this protocol only are 
addressed below.
Shipping and storage
The Sponsor will provide ramucirumab vials 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 Medidata RTSM.
Drug supplies must be stored in a secure, limited access storage area.
Unopened vials of ramucirumab Injection, USP are stable for 3 years when stored between 
2° to 8°C in the original package. The vial should not be frozen and should be protected 


 
 
   
 
 
 
 
 
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Clinical Study Protocol
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Version 5.0
21 May 2021
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from light. 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 
Medidata RTSM and a resupply shipment will be made.
Labeling and packaging
Ramucirumab is supplied as single dose 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.
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 Medidata RTSM 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 ramucirumab. 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 
paclitaxel 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 destroyed locally, and only returned to the designee as instructed 
by the Sponsor if the site cannot destroy locally. Ramucirumab 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 ramucirumab 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.


 
 
 
 
 
 
 
 
 
 
 
 
 
Derazantinib
Clinical Study Protocol
DZB-CS-202 (FIDES-03)
Version 5.0
21 May 2021
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Preparation and stability
Ramucirumab must be diluted prior to infusion in 0.9% sodium chloride to a final volume 
of 250 mL. Dextrose solutions must not be used to dilute ramucirumab. Solutions of 
ramucirumab can be stored at ambient temperature (up to 25°C) for up to 4 hours and at 
2°C to 8°C for up to 24 hours. Diluted solutions should be inspected visually for particulate 
matter and discolouration prior to administration. 
Ramucirumab premedication
All patients should be premedicated prior to ramucirumab administration with an IV 
histamine-1 receptor antagonist (e.g., diphenhydramine hydrochloride or equivalent). 
Patients who have experienced a Grade 1 or 2 infusion-related reaction (IRR) should be 
premedicated with a histamine-1 antagonist, dexamethasone (or equivalent) and 
acetaminophen prior to infusion. 
Ramucirumab administration
For GAC, the recommended dose of ramucirumab is 8 mg/kg every 2 weeks administered 
via an infusion pump over 60 minutes through a separate infusion line. 
When used in combination with ramucirumab, paclitaxel must not be started earlier than 
60 minutes after completion of the ramucirumab infusion; the 1-hour observation period 
between administration of ramucirumab and paclitaxel is mandatory for the first 
two cycles, but may be omitted in Cycle 3 and beyond provided there has been no evidence 
of infusion-related reaction.
Dose modifications
In this protocol, ramucirumab will be administered in combination with paclitaxel. 
Dose modification of the combination treatment are specified below (see Section 6.1.6.1).
Prior to D1 and D15 of each administration of ramucirumab, urine protein (dipstick), bone 
marrow, hepatic and renal function must be adequate (see Section 6.1.6.1), and all 
ramucirumab-related toxicities must have resolved to Grade < 2 or baseline (except for 
hypertension, venous thromboembolic events, and proteinuria, for all three of which study 
drug discontinuation may be required; see Section 6.1.6.1). Pre-infusion laboratory data 
may not be older than 36 hours.
Missed dose management
If a planned dose of ramucirumab is missed, it should be administered as soon as possible; 
it is recommended not to wait until the next planned dose. The schedule of administration 
must be adjusted to maintain the D1 and D15 28-day schedule.
Overdose
There are no data on overdose in humans. Ramucirumab was administered at doses up to 
10 mg/kg every two weeks without reaching a maximum tolerated dose.


 
 
   
 
 
 
 
 
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6.1.4
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.
Shipping and storage conditions
Ship and store in a refrigerator (2° C to 8° C).
Do not freeze.
Store the vial in the outer carton in order to protect from light.
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.
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 Medidata RTSM 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 destroyed locally, and only returned to the designee as instructed 
by the Sponsor if the site cannot destroy locally. 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.


 
 
   
 
 
 
 
 
 
 
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Clinical Study Protocol
DZB-CS-202 (FIDES-03)
Version 5.0
21 May 2021
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Preparation and stability of study drug
Twenty mL of atezolizumab concentrate should be withdrawn from the vial and diluted 
into a 250 mL 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.
After dilution, chemical and physical in-use stability has been demonstrated for no more 
than 24 hours at 2 °C to 8 °C or 24 hours at ≤ 30 °C from the time of preparation.
If diluted atezolizumab infusion solution is not used immediately, store solution either:

At room temperature for no more than 6 hours from the time of preparation. This 
includes room temperature storage of the infusion in the infusion bag and time for 
administration of the infusion; or 

Under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for no more than 24 hours 
from time of preparation.
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.
Dose modifications
In this protocol, atezolizumab will be administered in combination with derazantinib; the 
RP2D of the combination has been determined in study DZB-CS-201 (FIDES-02,
NCT04045613). Dose modification of the combination treatment are specified below 
(see Section 6.1.6.3).
Missed-dose management
If a planned dose of atezolizumab is missed, it should be administered as soon as possible; 
it is recommended not to wait until the next planned dose. The schedule of administration 
must be adjusted to maintain a 3-week interval between doses.


 
 
   
 
 
 
 
 
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Clinical Study Protocol
DZB-CS-202 (FIDES-03)
Version 5.0
21 May 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
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Overdose
There is no information on overdose with atezolizumab.
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).
6.1.5
Dosing schedule 
In Substudy 1, patients allocated to Cohort 1.1 and 1.2 will receive oral derazantinib at a 
dose of 300 mg QD (three capsules of 100 mg each once per day); patients allocated to
Cohort 1.3 will receive oral derazantinib at a dose of 200 mg BID (two capsules of 100 mg 
each twice per day). 
The dosing schedule for patients enrolled in Substudy 2 is described in Section 3.1.7.2 and 
Figure 4. Intermediate dose levels not described here may be investigated.
In Substudy 3, patients randomized to Cohort 3.1 and 3.4 will receive 300 mg QD 
derazantinib and 80 mg/m2 paclitaxel-ramucirumab, respectively. Patients randomized to 
Cohort 3.2, will use the RP2D of derazantinib-paclitaxel-ramucirumab in combination 
from Substudy 2. Patients randomized to Cohort 3.3 will receive the RP2D determined in 
another clinical study investigating the RP2D of the derazantinib-atezolizumab
combination (DZB-CS-201).
6.1.6
Dose modifications of combination treatments
Paclitaxel-ramucirumab combination (Substudy 3)
To assess the in-cycle paclitaxel-related toxicity or abnormal laboratory values, blood 
counts and serum chemistry will be repeated regularly (Table 3) and prior to paclitaxel-
ramucirumab administration (see Table 15, Table 16 and/or Table 17), or more frequently 
if medically indicated. 
In the case of paclitaxel-related toxicity or abnormal laboratory values (Table 17) on D8 or 
D15, paclitaxel will be skipped at that day. The start of the next cycle will be delayed until 
recovery to the values of Grade < 2 or baseline. If the start of a cycle is delayed due to 
toxicity, radiographic tumor assessment should not be delayed, but should be performed as 
per schedule until documentation of disease progression.
In the event that paclitaxel is delayed due to paclitaxel-related toxicities on D8 and/or D15 
(Table 17), ramucirumab administrations should continue as scheduled until the next cycle 
has resumed. When the subsequent cycle of paclitaxel is initiated, administration of 
ramucirumab and paclitaxel will be resynchronized according to the study design described 
in this protocol (ie, the cycle will begin at D1 for both ramucirumab and paclitaxel, even if 
this requires ramucirumab to be administered on consecutive weeks). In case of 
discontinuation of paclitaxel for any reason, a new cycle will be started on D29 (D1 of the 
new cycle) with the administration of ramucirumab monotherapy, provided the criteria 
outlined in Table 16 are met. 


 
 
   
 
 
 
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Clinical Study Protocol
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Table 15
Criteria for paclitaxel treatment on D1 of Cycles 2+
Parameter
Value / Criterion
Absolute neutrophil count 
> 1.5 × 109 / L 
Platelets
> 100 × 109 / L 
Serum Creatinine
< 1.5 × ULN or creatinine clearance >60 ml/min by Cockcroft
Bilirubin
< 1.5 × ULN 
AST/ALT
≤3 × ULN for ALT/AST if no liver metastases, 
< 5 × ULN if liver metastases 
Any other paclitaxel-related
adverse event
CTCAE 5.0 Grade < 2 or baseline (except for alopecia)
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology
Criteria for Adverse Events; D, day; ULN, upper limit of normal.
Table 16
Criteria for ramucirumab treatment on D1 and D15 of each cycle
Parameter
Value / Criterion
Urine protein
Dipstick < 2+, UPCR < 2 (or <200 mg/mmol) or protein level < 2 g/24 h
Any other ramucirumab-
related adverse event
CTCAE 5.0 Grade < 2 or baseline (except for hypertension, venous 
thromboembolic events, proteinuria, as detailed in Section 6.1.3.7)
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; D, day.
In the case of ramucirumab-related toxicity on D15 (Table 16), ramucirumab will be 
delayed for one week and administered on D8 of the treatment cycle (with the second dose 
within the 28-day cycle administered on D15 of that cycle) provided that ramucirumab-
related toxicities have resolved to Grade < 2 or baseline (except for hypertension, venous 
thromboembolic events, and proteinuria, as detailed below). If toxicities have not resolved 
on D8, ramucirumab will be delayed for another week and administered on D15 according 
to the schedule described in this protocol. In both cases, paclitaxel (and derazantinib, if 
applicable) will continue according to the planned schedule. 


 
 
   
 
 
 
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Table 17
Criteria for paclitaxel treatment on D8 and D15 of each cycle
Parameter
Value / Criterion
Absolute neutrophil count 
> 1.0 × 109 / L 
Platelets
> 75 × 109 / L 
Bilirubin
< 1.5 × ULN 
AST/ALT
≤3 × ULN for ALT/AST if no liver metastases, 
< 5 × ULN if liver metastases 
Any other paclitaxel-related
adverse event
CTCAE 5.0 Grade < 2 or baseline (except for alopecia)
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology 
Criteria for Adverse Events; D, day; ULN, upper limit of normal.
If one or more criteria outlined in Table 15, Table 16 and/or Table 17 are not met at the 
time of a planned treatment, the following general rules for the management of treatment 
delays and dose modifications apply for: 
Paclitaxel

Drug-related AEs – In the case of paclitaxel-related toxicity or abnormal laboratory 
values on D8 or D15 (Table 17), paclitaxel will be skipped at that day. No dose 
reductions of paclitaxel are allowed within a given cycle. 

Dose modification – The paclitaxel dose will be reduced by 10 mg/m2 for the 
following cycle when Grade 4 hematological toxicity or Grade 3 paclitaxel-related 
non-hematological toxicity (except for alopecia) is observed. If the dose of paclitaxel 
is reduced because of potentially related AEs, subsequent dose increases are not 
permitted. 

Discontinuation – Paclitaxel will be permanently discontinued if dose reduction to 
less than 60 mg/m2 would be required, or in case of any paclitaxel-related event that 
is deemed life-threatening, regardless of assigned toxicity grade.
Ramucirumab

Drug-related AEs – In the case of ramucirumab-related toxicity on Day 15 
(Table 16), paclitaxel will be administered according to the planned schedule but 
ramucirumab will be delayed for one week and administered on D22 of the treatment 
cycle, provided that ramucirumab-related toxicities have resolved to Grade < 2 or 
baseline (except for hypertension, venous thromboembolic events, or proteinuria, as 
detailed in Section 6.1.3.7).

Dose modification for non-life-threatening and reversible Grade 3 clinical AEs –
Dose modifications are permitted for ramucirumab in the setting of AEs considered to 
be at least possibly related to ramucirumab and that resolve to Grade < 2 or 
pretreatment baseline within one treatment cycle (approximately 28 days); if after re-
administration a second and third instance of such an event occurs, ramucirumab 
should be subsequently re-administered at a dose of 6 mg/kg and 5 mg/kg, 
respectively.


 
 
   
 
 
 
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
Dose modification for Grade 4 AE deemed at least possibly related to ramucirumab –
Ramucirumab should be discontinued and only be considered for re-administration at 
the discretion of the Investigator in the specific case of Grade 4 fever or Grade 4 
laboratory abnormalities which resolve to Grade < 2 or pretreatment baseline within 1 
treatment cycle (approximately 28 days); if after re-administration a second and third 
instance of such an event occurs, ramucirumab should be subsequently re-
administered at a dose of 6 mg/kg and 5 mg/kg, respectively.

Patients with symptoms and laboratory abnormalities at baseline – Patients who 
enter the study with symptoms or laboratory values equivalent to CTCAE Grade 1 or 
2 AEs should not have dose reductions related to the persistence or mild worsening of 
those symptoms or laboratory values; dose reductions may be warranted if worsening 
of symptoms or laboratory values is clinically significant in the opinion of the 
Investigator, and asymptomatic laboratory abnormalities (except for proteinuria; see 
below) should not result in dose interruptions, modifications, or discontinuation of 
study therapy unless determined by the Investigator to be clinically significant or life-
threatening.

Skip drug – If toxicities have not resolved on D22, ramucirumab will be skipped for 
that cycle and administered on D1 of the following cycle provided that ramucirumab-
related toxicities have resolved to Grade < 2 or baseline.

Infusion-related reactions – For Grade 1 or 2 IRRs, the infusion rate should be 
reduced by 50% with premedication administered (see Section 6.1.3.5). For Grade 3 
or 4 IRRs, ramucirumab should be permanently and immediately discontinued. For 
severe hypertension, ramucirumab should be interrupted until the hypertension is 
controlled with medical management. 

Proteinuria – Patients should be monitored for the development of proteinuria during 
ramucirumab treatment. For urine protein levels ≥2 g/24 hours or UPCR ≥2 
(≥200 mg/mmol), ramucirumab should be temporarily discontinued. Once the urine 
protein level returns to < 2 g/24 hours or UPCR returns to < 2 (or < 200 mg/mmol), 
treatment should be reinitiated at a reduced dose of 6 mg/kg every 2 weeks. A second 
dose reduction to 5 mg/kg is recommended if a urine protein levels ≥2 g/24 hours or 
UPCR ≥2 (≥200 mg/mmol) reoccurs. Ramucirumab must be permanently 
discontinued for a third occurrence of proteinuria ≥2 g/24 hours or UPCR ≥2 (≥200 
mg/mmol). 
Permanently discontinue ramucirumab for urine protein levels > 3 g/24 hours or UPCR 
> 3 (or > 300 mg/mmol) or in cases of nephrotic syndrome.

Hypertension – Ramucirumab should be permanently discontinued in cases of severe 
hypertension that cannot be controlled with antihypertensive therapy, for urine 
protein levels > 3 g/24 hours in cases of nephrotic syndrome, arterial thromboembolic 
events, gastrointestinal perforation, CTCAE Grade 3 or 4 bleeding events, 
spontaneous development of fistula or hepatic encephalopathy or hepatorenal 
syndrome.


 
 
   
 
 
 
 
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
Permanent discontinuation – Ramucirumab should also be permanently discontinued 
in cases of severe arterial or venous thromboembolic events, gastrointestinal 
perforations, severe bleeding of CTCAE Grade 3 or 4 bleeding, spontaneous 
development of fistula and hepatic encephalopathy or hepatorenal syndrome, or in 
case of any ramucirumab-related event that is deemed life-threatening.

Surgery – Ramucirumab should be temporarily discontinued prior to scheduled 
surgery until the wound is fully healed. 
Derazantinib-paclitaxel-ramucirumab in combination (Substudy 3 only)
The management of derazantinib-paclitaxel-ramucirumab combination treatment during 
dose finding in Substudy 2 is detailed in Section 3.1.7.2.
To assess the in-cycle toxicity or abnormal laboratory values of paclitaxel, ramucirumab 
and derazantinib-related toxicity in Substudy 3, blood counts and serum chemistry will be 
repeated regularly (Table 3 and Table 4) and prior to D1 of study drug administrations 
(see Table 18 and Table 19), or more frequently if medically indicated.
Abnormal values and CTCAE toxicities exceeding the ranges in Table 18 and Table 19 are 
managed by dose modifications in relation to the cause of toxicity as described previously 
for the treatment with paclitaxel / ramucirumab (Section 6.1.6.1) and derazantinib
(Section 6.1.1.5).
Table 18
Criteria for derazantinib-paclitaxel-ramucirumab combination
treatment on D1 of Cycle 2+
Parameter 
Value / Criterion 
Serum phosphate
< 7.0 mg/dL (< 2.26 mmol/L)
Urine protein
Dipstick < 2+, UPCR <2 (or <200 mg/mmol) or protein level <2 g/24 h
Hemoglobin
≥ 8.0 g/dL
Absolute neutrophil count 
≥1.5 × 109/L 
Platelet count 
≥100 × 109/L 
Bilirubin 
≤1.5 × ULN 
AST/ALT 
≤3 × ULN for ALT/AST if no liver metastases, 
< 5 × ULN if liver metastases 
Any other study-drug–related
adverse event
CTCAE 5.0 Grade < 2 or baseline (except for paclitaxel or derazantinib-
related alopecia; and except for ramucirumab-related hypertension, 
venous thromboembolic events, and proteinuria, for all three of which 
study drug discontinuation may apply, as detailed in Section 6.1.3.7)
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology 
Criteria for Adverse Events; D, day; ULN, upper limit of normal.


 
 
   
 
 
 
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Table 19
Criteria for derazantinib-paclitaxel-ramucirumab combination 
treatment on D8 and/or D15 of each cycle
Parameter 
Value / Criterion 
Serum phosphate (D15 only)
< 7.0 mg/dL (< 2.26 mmol/L)
Urine protein (D15 only)
Dipstick < 2+, UPCR <2 (or < 200 mg/mmol) or protein level < 2 g/24 h
Absolute neutrophil count 
≥1.0 × 109/L 
Platelet count 
≥75 × 109/L 
Bilirubin 
≤1.5 × ULN 
AST/ALT 
≤3 × ULN for ALT/AST if no liver metastases, 
< 5 × ULN if liver metastases 
Any other adverse event
CTCAE 5.0 Grade < 2 or baseline (except for alopecia) 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology 
Criteria for Adverse Events; D, day; ULN, upper limit of normal.
CTCAE Grade 4 toxicities that warrant permanent and immediate discontinuation of 
derazantinib are detailed in Table 13, the respective Grade 4 toxicities that warrant 
permanent and immediate discontinuation of paclitaxel and/or ramucirumab are detailed in 
the previsous section (see Section 6.1.6.1). 
The following CTCAE Grade 4 toxicities do not warrant permanent and immediate 
discontinuation of derazantinib, paclitaxel or ramucirumab treatment:

The first occurrence of derazantinib-related hyperphosphatemia > 9.0 mg/dl

Grade 4 hematological toxicities

The first occurrence of paclitaxel-related Grade 4 neutropenia or febrile 
neutropenia that have been controlled by supportive G-CSF administration and 
returned to Grade < 2 or baseline within 28 days
Note: The paclitaxel dose should be reduced by 10 mg/m2 for the subsequent cycle.
In the event of discontinuation of any study drug for any reason, a new cycle will be started 
on D29 (D1 of the new cycle) with the administration of the remaining study drugs at the 
last dose level, provided the criteria outlined in Section 6.1.1.5 and/or Table 18 and 
Table 19 are met. In the event of toxicity clearly attributable to derazantinib during 
continued treatment and in particular outside of the DLT interval, the Investigator should 
consider early derazantinib dose modification measures to ensure that patients treated in 
this cohort are able to benefit from the proven activity of the paclitaxel-ramucirumab 
combination.


 
 
   
 
 
 
 
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Derazantinib-atezolizumab in combination
Dose modifications/reductions of atezolizumab are not permitted. 
Patients treated with derazantinib and atezolizumab in combination should be temporarily 
or permanently discontinued from atezolizumab and/or study treatment if any of the 
toxicities described in Appendix 4 occur, and are assessed by the Investigator as at least 
possibly related to atezolizumab.
CTCAE Grade 4 toxicities warrant permanent discontinuation of atezolizumab treatment, 
with the exception of endocrinopathies that have been controlled by hormone replacement.
If atezolizumab is discontinued in accordance with these guidelines, continuation of 
derazantinib is at the discretion of the Investigator (see Section 4.5.1).
6.1.7
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 Substudy, cohort 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 if, in the opinion of the Investigator and with the 
agreement of the Sponsor, they continue to derive benefit from derazantinib monotherapy, 
or derazantinib-paclitaxel-ramucirumab or derazantinib-atezolizumab in combination.
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 6.1.4.6 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 with the derazantinib regimen will be evaluated by counting unused capsules.
  
% 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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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. 
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 paclitaxel-ramucirumab and atezolizumab
Paclitaxel-ramucirumab and atezolizumab will be administered by site and/or institution 
staff in accordance with local SOPs and guidelines. The total volume of paclitaxel-
ramucirumab or atezolizumab infused will be compared to the total volume prepared to 
determine compliance for each dose of paclitaxel-ramucirumab or 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, 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. 
6.4
Concomitant treatments
Any medications (including any anti-tumor medication and supportive care) 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 90) must be 
recorded in the eCRF including the dosage, frequency of administration, route of 
administration, therapeutic indication, and start/stop dates of use.


 
 
   
 
 
 
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6.4.1
Permitted treatment
Palliative and supportive care for disease-related symptoms will be offered to all patients
as part of their routine clinical management. In addition, the following treatments are 
allowed:

Standard therapies for concurrent medical conditions

Erythropoietin Stimulating Agents (in accordance with American Society of Clinical
Oncology [ASCO], American Society of Hematology, or MEDICARE guidelines for 
the use of epoetin in patients with cancer and US Food and Drug Administration
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, considerating
potential drug-drug interactions (see Section 6.4.2 and Appendix 7)

Megestrol acetate (Megace®)

Use of topical corticosteroids, topical and systemic antibiotics according to standard 
of care or institutional guidelines

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 non-hepatic 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.


 
 
   
 
 
 
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
Immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide; these agents could potentially alter the 
activity and the safety of atezolizumab.

Patients must agree not to receive live, attenuated influenza vaccines (such as 
FluMist®) for 30 days prior to randomization (see Exclusion criterion 32), during 
treatment, or, for patients randomized to atezolizumab, within 5 months following the 
last dose of atezolizumab.
The following treatment in paclitaxel-treated patients (Substudy 2, Cohort 3.2, Cohort 3.4) 
is not allowed during the study:

co-administration of drugs known to inhibit or induce either CYP2C8 or CYP3A4.
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). 


 
 
   
 
 
 
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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. 
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 
(Chae 2017, 
Katoh 
2019, 
Mazzaferro 
2019, 
Van Cutsem 
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
Paclitaxel
The warnings and precautions for paclitaxel are listed in the EU SmPC for Paclitaxel 
(Paclitaxel Ever Pharma SmPC).
7.1.3
Ramucirumab
The warnings and precautions for ramucirumab are listed in the USPI and the EU EPAR
for Cyramza® (ramucirumab) (Cyramza® USPI, Cyramza EPAR).
7.1.4
Atezolizumab
The warnings and precautions for atezolizumab are listed in the atezolizumab 
Investigator’s Brocure (IB), and in the USPI and the EU SmPC for Tecentriq®
(atezolizumab) (Tecentriq® USPI, Tecentriq® SmPC).


 
 
   
 
 
 
 
 
 
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7.1.5
Contraception and pregnancy
Derazantinib may have adverse effects on a fetus in utero, and may have transient adverse 
effects on the composition of sperm. 
Paclitaxel can cause fetal harm when administered to a pregnant woman. If the patient 
becomes pregnant while receiving paclitaxel, the patient should be apprised of the potential 
hazard to the fetus. Women of childbearing potential should be advised to avoid becoming 
pregnant.
There are no known reproductive risks to the female partner of a male patient receiving 
atezolizumab.
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 (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.
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. 
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.
AEs that occur following the full execution of the ICF but prior to dosing must be recorded 
in the medical history page of the eCRF. If the event is assessed as serious and related to 
the study procedure, the AE must be reported as an SAE as described in Section 7.2.2.


 
 
   
 
 
 
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Adverse events, including SAEs, that occur after patients receive any anti-cancer therapy
in the follow-up period, other than the study-defined treatments, will not be recorded as 
AEs or SAEs.
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 as an important medical event or medically significant event
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 GAC, 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, both related and 
unrelated to GAC 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 
GAC and has not worsened.
–
Admission to a hospital or other institution for general care, not associated with 
any deterioration in condition.
Note: Prolongation of a scheduled hospitalization is considered an SAE. 


 
 
   
 
 
 
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
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 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, atezolizumab, paclitaxel and/or ramucirumab, 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 by the Sponsor to be related to the study treatment and for which the nature 
or severity or outcome is not consistent with the applicable Reference Safety Information 
(i.e., regardless of whether the nature or severity or outcome of an SAE has been previously 
observed/documented).
7.2.6
Adverse events of special interest 
The following are considered adverse events of special interest (AESIs) for the purposes 
of this study, based on the known safety profiles of derazantinib, paclitaxel, ramucirumab
and atezolizumab:

Hypersensitivity reactions

Immune-related AEs 

Liver function tests abnormal (compared to baseline)

Ocular/eye disorder

Bone marrow suppression

Serum creatinine increase or renal disorders

Hyper-/hypotension / cardiac disorders (including QT prolongation)

Neurotoxicity

Hyperphosphatemia/blood phosphorus increased 

Hyponatremia

Stomatitis

Nail disorder

Gastrointestinal disorders (e.g., nausea, vomiting, diarrhea)

Gastrointestinal perforation

Bleeding/hemorrhage (including gastrointestinal hemorrhage)

Proteinuria


 
 
   
 
 
 
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All AESIs 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
Further adverse event and serious adverse event definitions
Wherever possible, a specific disease or syndrome rather than individual associated signs 
and symptoms should be identified. 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/SAE.
Laboratory data are to be collected as stipulated in Section 7.4.3.1. Clinical syndromes 
associated with laboratory abnormalities are to be recorded as appropriate (e.g., diabetes 
mellitus instead of hyperglycemia).
Progression of disease is considered an efficacy outcome parameter and should not be 
captured as an AE or SAE unless its outcome is death. 
7.2.8
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 of 
mild, moderate, severe, life-threatening/disabling or death (CTCAE 5.0).
For AEs that can be described by the NCI CTCAE 5.0 guidelines (CTCAE 5.0), the 
CTCAE 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 CTCAE 
grades may or may not be assessed as serious based on the seriousness criteria.
7.3.2
Assessment of causality
The relationship between an AE and derazantinib, ramucirumab, paclitaxel 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


 
 
   
 
 
 
 
 
 
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7.3.3
Dose-limiting toxicities
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:
Any toxicities (hematologic or non-hematologic)
1. Resulting in death (Grade 5)
Hematologic toxicities
2. Febrile neutropenia ≥ Grade 3:
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 hour
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.
3. Thrombocytopenia ≥ Grade 3 (< 50 × 109/L) if associated with:
A bleeding event, or 
Requires platelet transfusion
4. Any other Grade 4 hematologic adverse drug reaction or laboratory abnormality, except 
for asymptomatic Grade 4 lymphocytopenia
Non-hematologic toxicities
5. Any Grade 4 non-hematologic adverse drug reaction or laboratory abnormality, except 
for asymptomatic Grade 4 elevations in alkaline phosphatase 
6. Any Grade 3 non-hematologic adverse drug reaction lasting > 3 days despite optimal 
supportive care with the following exceptions:
Grade 3 nausea, vomiting, or diarrhea that improves to Grade 1 with or without 
supportive care and/or with a light meal prior to prior to the next derazantinib 
administration
Grade 3 fatigue, malaise or flu-like symptoms that improve to Grade ≤2 with or 
without supportive care prior to the next derazantinib administration 
7. Any Grade 3 non-hematologic laboratory abnormality if:
The patient is symptomatic (and the abnormality is to be reported as an AE) and 
medical intervention is required to treat the patient, or
The abnormality leads to hospitalization, or
The abnormality persists for > 7 days.
Note: Asymptomatic Grade 3 abnormalities which can be corrected through oral supplements and 
persist for ≤ 7 days are not considered a DLT.


 
 
   
 
 
 
 
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8. For patients with Grade 2 AST/ALT abnormality at baseline, an increase in the baseline 
abnormality to > 10 × baseline will be considered a DLT.
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 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 is assessed as related to the 
study procedure, the AE is to be reported accordingly, and if this event is considered to be 
serious (i.e., meets one or more of the criteria for an SAE in Section 7.2.2), this information 
must 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 and post-follow up period
From the start of first dosing up to and including the Safety Follow-Up visit 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). SAEs 
must be additionally reported and recorded on the SAE page of the eCRF (see Section
7.4.3.2).
After the follow-up period, only study-drug-related SAEs and AESIs must be collected and 
reported; these must also be followed until they have, in the opinion of the Investigator, 
resolved to baseline or CTCAE Grade 1, stabilized, or are deemed to be irreversible.
Adverse event management
7.4.3.1.1
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.


 
 
   
 
 
 
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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 drug (causality assessment) (see Section 7.3.2).

Action(s) taken with regards to study drug 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/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 study drug, treatment (if applicable), and outcome (in 
initial or follow up report).
7.4.3.1.2
Follow-up
Once an AE is detected, it must be proactively followed at each visit (or more frequently 
if necessary) for any changes in severity, relationship to the study drug, interventions 
required for treatment, and the event’s outcome. Refer to the eCRF completion guidelines 
for further details on completing the AE/SAE in eCRF.
All AEs must be followed-up until they have returned to baseline status or have stabilized, 
or until the scheduled Safety Follow-Up visit(s).




 
 
   
 
 
 
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7.4.3.2.2
Sponsor’s responsibilities
The Sponsor will ensure the reporting of SUSARs and any expeditable SAEs to regulatory 
Authorities and IECs/IRBs 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 Reference Safety Information of the study drugs.
For 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. For paclitaxel-ramucirumab in combination, the Cyramza® USPI and Cyramza®
SmPC, respectively, are 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 90-day Safety Follow-up visit 
will be followed until they have, in the 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 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 in 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).
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
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
Two-stage designs (Fleming 1982, Simon 1989) will be used in this study. At the time 
point of analysis and decision to transition from Stage 1 to 2, all data collected in Stage 1 
patients will be used to inform the decision. 


 
 
   
 
 
 
 
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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 will be suspended to 
allow for all patients to be exposed to study treatment 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 42 for Substudy 1 and 68 for Substudy 3, should study treatment be 
ineffective in Stage 1, as compared to a maximum of approximately 314 patients if 
derazantinib, derazantinib-atezolizumab and derazantinib-paclitaxel-ramucirumab are 
considered to be effective in all cohorts.
Assuming an overall incidence of approximately 9% patients with qualifying FGFRfus/amp/mt
GAC (Van Cutsem 2017, Pearson 2016, Basilea data on file, FoundationInsights™, 2020), 
up to approximately 3,500 patients will be screened for FGFRfus/amp/mt, depending on the 
extent of preexisting molecular testing. 
The study design yields a type I error rate and power in relation to the anticipated true 
response rates for the respective cohorts as detailed in Sections 8.1.1 and 8.1.3.
8.1.1
Substudy 1
Cohorts 1.1 and 1.2
Simon’s two-stage design will be used to test the null hypothesis that the true ORR is 
p0 ≤0.05 against a one-sided alternative. Hypothesis testing (null hypothesis [H0] versus 
alternative hypothesis [HA]) will be performed at the interim and final analyses. H0 is 
p ≤0.05 and is tested against HA of p > 0.05.
In Stage 1, 13 evaluable patients will be enrolled. If no patients with an objective response 
(defined as a confirmed CR or PR) are observed in Stage 1, the cohort will be stopped. 
If 1 or more patients with an objective response are observed in these 13 patients, an 
additional 10 patients will be enrolled, for a total of 23 patients. The null hypothesis will 
be rejected if 4 or more objective responses are observed in these 23 patients (see Table 20). 
The Type I error rate is 0.0253 and power is 0.8037 when the alternative ORR is pA = 0.23.
The ORR of 5% for the null hypothesis reflects Phase 3 data of ramucirumab, the only 
approved targeted antitumor drug used as monotherapy in second-line GAC patients 
(Fuchs 2014), which achieved an ORR of 3.4%. The ORR of 23% for the alternative 
hypothesis reflects ORRs seen in recent clinical studies of patients with GAC treated with 
paclitaxel (Van Cutsem 2017, Wilke 2014).




 
 
   
 
 
 
 
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Approximately 32 evaluable patients will be enrolled in Substudy 2.
The RP2D will be declared, based on all observed safety, efficacy, PK and PD data, and 
potential toxicity-response modeling, by a joint decision taken by the IDMC, Investigators, 
and the Sponsor.
8.1.3
Substudy 3
The design and statistical assumptions applicable to this substudy are contigent on 
findings from Susbtudies 1 and 2, and are currently under consideration. Prior to 
initiation of patient enrollment in this substudy, a protocol amendment may be 
submitted.
Cohort 3.1
For Cohort 3.1, 3.2 and 3.3, the null hypothesis that the true ORR is p0 ≤ 0.125 will be 
tested against a one-sided alternative HA of p > 0.125. Hypothesis testing (null hypothesis 
[H0] versus alternative hypothesis [HA]) will be performed at the interim and final analyses. 
In Stage 1, 17 evaluable patients will be enrolled. If 2 or fewer patients with an objective 
response are observed in these 17 patients, the cohort will be stopped. If 3 or more patients 
with an objective response are observed, an additional 29 patients will be enrolled for a 
total of 46 patients. The null hypothesis will be rejected if 10 or more objective responses 
are seen in these 46 patients (see Table 22).
The ORR of 12.5% for the null hypothesis reflects the lower bound of the 95% confidence 
interval (95% CI) of the ORR observed for patients with GAC treated with paclitaxel 
(Wilke 2014). The ORR of 27.9% for the alternative hypothesis reflects the ORR observed 
for patients with GAC treated with paclitaxel-ramucirumab (Wilke 2014).
Table 22
Estimated type I and II errors in efficacy-estimating cohorts in Substudy 3
Cohorts
Type I error (α)
Power (1‒β)
True response rate (pA)
Cohort 3.1, 3.2 and 3.3
0.0464
0.8074
0.279
8.2
Analysis populations
The following analysis populations are defined for this study.
8.2.1
Safety population
The safety population comprises all patients who received at least one dose of study 
treatment (derazantinib, paclitaxel, ramucirumab or atezolizumab). Data will be 
summarized according to the treatment actually received.
In the primary safety comparison, patients who crossover to receive derazantinib after 
progression on the primarily assigned paclitaxel-ramucirumab treatment (in Cohort 3.4) 
are censored at time of crossover for the purpose of the primary substudy analyses. 


 
 
   
 
 
 
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8.2.2
Intent-to-treat population
The intent-to-treat (ITT) population comprises all patients enrolled for Substudy 1 or 
Substudy 2, or all patients randomized to treatment in Substudy 3, regardless of the 
administration of the study drug. The ITT population will be used for between-cohort 
efficacy analyses in Substudy 3, including pooled analyses of Substudy 1 and Substudy 3.
8.2.3
Modified intent-to-treat population
For single-arm non-comparison efficacy endpoint analyses in Substudies 1, 2 and 3, a
modified intent-to-treat (mITT) population will be used, comprising all patients who 
received at least one dose of derazantinib, paclitaxel, derazantinib-paclitaxel-ramucirumab, 
or derazantinib-atezolizumab in combination, and have at least one post-baseline imaging 
assessment in accordance with RECIST 1.1, documented clinical progression (every effort 
should be made to objectively assess radiographic progression) or died from any cause. 
Non-evaluable patients will be replaced. Data will be summarized according to the 
treatment actually received.
8.2.4
Per-protocol population
The per-protocol population will include all patients in the mITT population who have no 
major protocol violations 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.
8.2.5
MTD population (Substudy 2 only)
The MTD-determining population comprises all patients enrolled in the MTD Part of each 
dose level who meet the following minimum criteria during the first 28-day treatment cycle 
(Cycle 1):
received at least one dose of derazantinib-paclitaxel-ramucirumab in combination and 
has experienced a DLT 
received ≥80% of the derazantinib-paclitaxel-ramucirumab dose, respectively, in 
Cycle 1 and, have been observed for ≥ 28 days following the first dose, and have been 
evaluated for safety 
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 (see Section 4.5.3).
If one patient experiences a DLT in any DL cohort among the first three enrolled and 
evaluable patients, the cohort will be expanded to six evaluable patients. The MTD is 
defined as the highest DL at which none or one of six participants (0% to 17%) experience
a DLT (see Section 7.3.3 for DLT definition of treatment-related AEs). The MTD is 
exceeded when at least two of three to six participants (≥33% to 67%) experience a DLT 
in any DL cohort. Replacement of patients is described in Section 4.5.3. 


 
 
   
 
 
 
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8.2.6
RP2D population (Substudy 2 only)
The RP2D will be declared by joint decision taken by the IDMC (see Section 3.5), 
Investigators, and the Sponsor, based on the RP2D population, consisting of the MTD 
population (see Section 8.2.5) and patients treated in the Expansion Part of any dose level 
with at least Cycle 1 treatment. A decision on the RP2D will account for the aggregate 
safety data review, including consideration of PK and preliminary efficacy data of the 
combination.
The final analysis of Substudy 2 will be performed when the last patient completes the last
substudy-related phone-call or visit, discontinues from the substudy or is lost to follow-up 
(i.e., the patient is unable to be contacted by the Investigator).
8.2.7
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. Sub-populations are defined, according to 
the analytes and sampling schedule (see Section 5.3.4):

The rich derazantinib and paclitaxel PK profiling population (with PK parameter 
determination) consists of the patients enrolled in the rich sampling schedule 
(see Section 5.3.4.3) 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 5.3.4.4) who receive at least 1 dose of study drug 
and have at least one PK sample.

The atezolizumab PK population (see Section 5.3.4.6) consists of all patients who 
receive at least 1 dose of atezolizumab and have at least one PK sample.

The ramucirumab PK population consists of the patients enrolled in the sampling 
schedule (see Section 5.3.4.6) who receive at least 1 dose of study drug 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 90% 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 drug exposure and compliance
The dose, duration in days, and compliance with study drug 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
Dose-limiting toxicity
In the MTD population, DLTs will be listed and summarized using descriptive statistics. 
8.3.5
Efficacy analysis
Primary efficacy endpoint 
8.3.5.1.1
All except Substudy 1 Cohort 1.3 
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 two-sided 90% CIs 
will be provided. The primary analysis will be performed on the mITT population and 
repeated on the PP population.
To determine the study population for Substudy 3, the outcomes of patients with HER2neg
FGFRfus/amp/mt GAC treated with derazantinib in Substudy 1 are to be considered per 
molecular substype.
8.3.5.1.2
Substudy 1 Cohort 1.3
The primary efficacy endpoint will be progression-free survival at 4 months (PFS4) based 
on survival status or central radiology review per RECIST 1.1 (see Section 8.3.5.1 for 
details of PFS definition).PFS4 is measured as the proportion of patients alive and without 
disease progression with exposure not less than 50% of the planned dose, and a second 
post-baseline imaging assessment done approximately 4 months after treatment allocation.
A Fleming’s two-stage design will be used, with approximately 16 patients in Stage 1, and 
an additional 16 patients if the study proceeds to Stage 2.The subset of the mITT population 
with a minimum exposure to at least 50% relative to the intended dose will be the primary 
analysis population.
8.3.5.1.3
Operational aspects
Interim analyses for stage transition in the efficacy-estimating substudies will be performed 
when the number of patients required for Stage 1 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 8 (in all cohorts except Cohort 3.3) and 
Cycle 11 (in Cohort 3.3), when patients have received approximately 32–33 weeks of 
treatment and had up to four post-baseline study imaging assessments. 


 
 
   
 
 
 
 
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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, both interim analyses 
may be performed and stage transition may occur earlier. Additional patients may be 
enrolled during the preparations required for a formal stage (e.g., completion of BICR) 
transition decision, if the overall benefit-risk profile can be considered favorable based on 
the known outcomes of patients enrolled at that time.
The final analysis will be performed once the required number of efficacy-evaluable 
patients have been enrolled into the cohort and have been followed for approximately up 
to 32–33 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. 
Secondary efficacy endpoints
8.3.5.2.1
Progression-free survival and recorded progression date
PFS is an important secondary endpoint for evaluating the efficacy of derazantinib,
derazantinib-paclitaxel-ramucirumab
and derazantinib-atezolizumab. In the mITT
population as the primary efficacy analysis population, PFS will be measured from the date 
of patient enrollment (i.e., treatment allocation / randomization of the patient) to first date 
of objectively measured radiographic progression by RECIST 1.1 or date of death from 
any cause (recorded progression date [PD date]). PFS will be summarized using KM 
methods (including median duration and PFS rates at 6 months) and compared between 
groups using a stratified log-rank test at a two-sided 5% alpha level.
The censoring date for a patient with no documented progression before data cutoff or 
dropout is defined as the date of the last tumor assessment with no documented progression.
For the PFS analysis, a patient who discontinues the study for undocumented clinical 
progression, change of cancer treatment, or decreasing performance status will be censored 
at the date of the last adequate tumor assessment. Further sensitivity analyses will be 
specified in the Statistical Analysis Plan to assess the impact of the censoring rules applied.
8.3.5.2.2
Comparison of experimental treatment and common control
Important secondary endpoints will be the comparison of the efficacy of derazantinib, 
derazantinib-paclitaxel-ramucirumab, and derazantinib-atezolizumab in combination, as 
measured by ORR and PFS with that of paclitaxel-ramucirumab, as well as the comparison 
of derazantinib with derazantinib-paclitaxel-ramucirumab and derazantinib-atezolizumab 
in combination, as measured by ORR, DCR, DOR, PFS, and OS, to understand the 
contribution of derazantinib to the combination treatment regimens.
For the comparison of derazantinib with that of paclitaxel-ramucirumab for ORR and PFS, 
the ITT population of the cohorts of Substudy 3 will be used, and completely enrolled 
cohorts of Substudy 1 and 3 will be combined for exploratory analyses.


 
 
   
 
 
 
 
 
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The between-group comparisons of the ORR in each group will be performed using a 
Cochran-Mantel-Haenszel or Chi-square test at a one-sided 5% alpha level. The associated 
two-sided 90% confidence interval will be provided. PFS will be compared between groups 
using a stratified log-rank test at a one-sided 5% alpha level.
Additional secondary efficacy endpoints 
DCR (and ORR for Substudy 1 Cohort 1.3) 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 (ITT for OS analysis) 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 
date of death.
OS will be calculated from the date of treatment allocation / randomization by Medidata 
RAVE EDC 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.
Sensitivity analyses within Substudies 1 and 3 will be performed according to the 
stratification factors and further potentially confounding prognostic factors. 
8.3.6
Safety data analysis
Safety will be assessed through summaries of 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.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) for 
purposes of summarization. 
Dose-limiting toxicity in Cohort 1.3
Safety interim analyses will be performed once up to ten patients have been enrolled and 
safety data for the 28-day DLT period are available to determine if the revised dosing 
regimen of 200 mg BID derazantinib 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 π_d 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 | π_d  ~ "Binomial"(n,π_d)


 
 
   
 
 
 
 
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The relationship between monotherapy derazantinib doses, and DLT probabilities is 
modelled by the logistic curve:
log(	 (1 −	)
⁄
) = log() +  log( ∗
⁄
) ,                       ,  > 0
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*.
Doubling the dose results in an increase in odds of toxicity by a factor of 2.
The model parameters log() , log() are given a weakly informative multivariate normal 
prior distribution, following (Neuenschwander 2014), with prior means (−1.386, −0.781), 
prior standard deviations (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 will be assessed by a joint decision taken by the IDMC, 
Investigators, and the Sponsor in reviewing the aggregate of DLT, AE and PK data.
Other safety parameters
All AEs occurring during the study will be included in by-patient data listings and tabulated 
by MedDRA 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.  
8.3.7
Pharmacokinetic analysis
In the rich derazantinib and paclitaxel PK population, PK parameters will be determined 
by non-compartmental analysis. The PK parameters determined from rich PK sampling 
will be summarized using descriptive statistics. Plasma concentrations at each nominal 
time point will be summarized using descriptive statistics.
                                                          
1 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 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 overall, and 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 using descriptive statistics.
In the ramucirumab PK population, ramucirumab serum concentrations at each nominal 
time point will be summarized overall, and 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.
8.3.8
Biomarker analysis
The biomarker data will be summarized overall using descriptive statistics. Comparisons 
of clinical activity endpoints between biomarker defined groups may be performed.
8.3.9
PRO analysis
PRO scores from the EQ-5D, EORTC QLQ-C30, and EORTC QLQ-STO-22 instruments 
will be analyzed primarily using descriptive analysis. 
The minimal important difference of the EQ-5D visual analogue scale, EORTC QLQ-C30 
scales and EORTC QLQ-STO-22 scales will be determined using the G-SET/HTI as an 
external anchor.
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.
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 Investigator’s 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.


 
 
   
 
 
 
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9.1.2
Case report forms
For each patient enrolled in the study via the Medidata RAVE EDC, 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, patient screening and 
enrollment logs, and patient diaries. 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.
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.


 
 
   
 
 
 
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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. 
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).


 
 
   
 
 
 
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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 earlier.
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 and 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. 


 
 
   
 
 
 
 
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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.
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.
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 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, atezolizumab, or paclitaxel, the
consent form must be reviewed and updated. All patients currently enrolled in the study 


 
 
   
 
 
 
 
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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.
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
14 November 2019
1.0
–
17 December 2019
2.0
Changes to address comments from the US FDA.
Corrections and updates to ensure consistency throughout the 
protocol.
13 March 2020
3.0
Changes to address Health Authority comments.
7 April 2020
3.1
Correction of typographical errors.
3 July 2020
4.0
Changes made before study commencement to ensure 
consistency with the updated Investigator’s Brochure, and 
pursuant to Investigator feedback. 
21 May 2021
5.0
Modification of the designs of Substudies 1 and 2, 
implementation of a new dose regimen.


 
 
   
 
 
 
 
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APPENDICES
Appendix 1
Eligible FGFR genetic aberrations
FGFR2 gene fusions and other rearrangements (‘FGFR2fus’)

FGFR2 gene fusions with breakpoints upstream or downstream of the kinase 
domain which are in-strand and in-frame with the partner gene

FGFR2 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  

FGFR2 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 

FGFR2 small variants (insertions, deletions, substitutions) introducing a premature 
stop codon or a frame-shift downstream of the kinase domain  
High-level FGFR2 gene amplification (FGFR2high-amp)
The quantitative correlate of >10 FGFR2 gene copy numbers called by the NGS algorithm 
of the central diagnostic test.
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), and 
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.
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 ctDNA analysis from plasma, the resulting FGFRfus/am/mt status 
will be, for the purpose of this clinical study protocol, defined as molecularly eligible for 
considering conduct of clinical study screening procedures.
FGFR2fus or FGFR2high-amp concurrent to FGFR1–3mt
Patients with FGFR2fus or FGFR2high-amp concurrent to any FGFR1–3 mutation will be 
allocated to Cohort 1.1.


 
 
   
 
 
 
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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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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. In all substudies, the first 
on-study tumor imaging assessments will be performed at C3D1 ±7 days, and subsequently 
every 8 weeks (i.e., C5D1 and C7D1 ±7 days) for 6 months, then every 12 weeks (C10D1, 
C13D1 etc., ±7 days) thereafter (or more frequently if clinically indicated), until 
progression of disease, withdrawal of consent, or death.
In Cohort 3.3 and with regard to the 3-week cycle interval, the first on-study tumor 
assessments will be performed on C3D15, and subsequently every 8 weeks (i.e., C6D8 and 
C9D1, ±7 days) for 6 months, and then every 12 weeks (C13D1, C17D1 etc., ±7 days) 
thereafter (with additional scans 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 standard of care for imaging of lesions in the respective organ(s). 
All target and non-target sites are evaluated at each time point of tumor assessment. 
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. 


 
 
   
 
 
 
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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 5.3.5.3 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 clinical study DZB-CS-202 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. If additional blood specimens are collected 
specifically for future biomedical research, these should be obtained at a time when the 
patient is having blood drawn for other study purposes.
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 pecific 
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 speciments 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 the 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
A search was conducted in June–September 2019 to identify relevant substrates of 
CYP isoforms potentially inhibited by derazantinib which should be best avoided as co-
medications.
Methodology to identify relevant substrates
Major interactions for typical inhibitors of the iso-enzymes of interest were searched in the 
interaction checker tool from drugs.com (https://www.drugs.com/drug_interactions.html), 
a free tool with good performance for DDI evaluation (Marcath 2018). The major 
interactions were selected and reviewed looking at the information in the ‘Professional’
tab. The drugs for which interaction is clearly assigned to the inhibition of the respective
iso-enzyme are listed as substrates in the tables within this appendix; the drugs for which 
interaction is clearly assigned to other mechanisms (e.g., pharmacodynamic, other enzyme) 
are not listed in the tables. In cases of unclear assignment, the interaction was further 
evaluated by consultation of Stockley’s Drug Interactions (Eighth edition (Baxter 2008), 
drug labels (e.g., EMA SPCs, USPIs), or reviews (e.g., EPARs).
Substrates for the specifc iso-enzyme listed in the University of Indiana Flockhart Table™ 
(https://drug-interactions.medicine.iu.edu/MainTable.aspx ).were also checked.
Limitations and recommendations
Note that this list is not intended to be exhaustive. Interactions that are not present as 
‘major’ in drugs.com (e.g. moderate interactions, interactions not captured in the tool) or 
in the Flockhart Table ™ are not listed. 
To check for potential interactions, the combination of a drug with the reference inhibitors 
listed in the tables in drugs.com or in the labels can be checked for.
For additional information, consult a pharmacist or the Sponsor.
Identification and classification of inhibitors
Iso-enzyme inhibitors were identified as those listed as clinically relevant inhibitors by the 
FDA1, or those that are given a specific classification in the Flockhart Table™. Note that 
this list is not exhaustive, and only provides examples of reference inhibitors.
Inhibitors can be classified by their potency:

Strong inhibitor: 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: causes at least a 2-fold increase in the plasma AUC values, 
or 
50–80% decrease in clearance.

Weak inhibitor: causes at least a 1.25-fold but less than 2-fold increase in the 
plasma AUC values, or 20–50% decrease in clearance.
                                                          
1 https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-
inhibitors-and-inducers#table2-2


 
 
   
 
 
 
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CYP1A2 relevant substrates and inhibitors
Substrates
Inhibitors

Agomelatine 1

Alosetron 1

Aminophylline

Amitriptylline

Amoxapine

Caffeine

Clomipramine

Clozapine

Desipramine

Doluxetine

Doxepin

Haloperidol

Imipramine

Nortiptyline

Ondansetron

Oxtriphylline

Pirfenidone

Propranolol

Protriptyline

Ramelteon 1

Tacrine

Tasimelteon

Theophylline

Tizanidine 1

Trimipramine

Warfarin
Strong

Ciprofloxacin 

Many other fluoroquinolones 

Fluvoxamine 4

Verapamil 
Weak

Cimetidine 
1 CONTRAINDICATED with an inhibitor of the iso-enzyme, with evidence that the interaction is mainly driven by 
this iso-enzyme.
2 CONTRAINDICATED with an inhibitor of the iso-enzyme, with limited evidence that the interaction is mainly 
driven by this iso-enzyme.
3 DOSE ADJUSTMENT advised with an inhibitor of the iso-enzyme, with evidence that the interaction is mainly 
driven by this iso-enzyme.
4 Inhibitor with which search was conducted in www.drugs.com.


 
 
   
 
 
 
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CYP2C8 relevant substrates and inhibitors
Substrates
Inhibitors

Atorvastatin

Bexarotene

Cerivastatin

Fluvastatin

Loperamide

Lovastatin

Pioglitazone 3

Pitavastatin

Pravastatin

Read yeast rice

Repaglinide 1

Simvastatin 2

Paclitaxel

Torsemide
Strong

Clopidogrel

Gemfibrozil 4
Moderate

Teriflunomide

Trimethoprim
1 CONTRAINDICATED with an inhibitor of the iso-enzyme, with evidence that the interaction is mainly driven by 
this iso-enzyme.
2 CONTRAINDICATED with an inhibitor of the iso-enzyme, with limited evidence that the interaction is mainly 
driven by this iso-enzyme.
3 DOSE ADJUSTMENT advised with an inhibitor of the iso-enzyme, with evidence that the interaction is mainly 
driven by this iso-enzyme.
4 Inhibitor with which search was conducted in www.drugs.com.


 
 
   
 
 
 
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CYP2D6 relevant substrates and inhibitors
Substrates

Alprenolol

Amitriptyline

Amoxapine

Amphetamine

Antipsychotics

Aripiprazole 3

Atomoxetine 3

benzphetamine 3

brexpiprazole

Bufuralol

Carvedilol

Chlorpromazine

Clomipramine

Codeine

Debrisoquine

Desipramine

Desvenlafaxine

Deutetrabenazine 3

Dextroamphetamine

Dextromethorphan

Dolasetron

Donepezil

Doxepin

Duloxetine

Eliglustat 1

Encainide

Flecainide

Fluoxetine 

Furazolidone 2

Granisetron

Haloperidol

Iloperidone 3

Imipramine

Isocarboxazid 2

Levopromazine

Methoxyamphetamine

Metoclopramide

Metoprolol

Mexiletine

Mianserin

Nebivolol

Nortryptiline

Ondansetron

Oxycodone

Palonosetron

Paroxetine 3

Perhexiline

Perphenazine

Pimozide 1

Promethazine

Propafenone

Propranolol

Protriptyline

Risperidone

Selegiline 2

SSRIs

Tamoxifen

Tetrabenazine 3

Thioridazine 1

Timolol

Tramadol

Tricyclic anti-depressants

Trimipramine

Tropisetron

Valbenazine 3

Vortioxetine 3

Zuclopenthixol
Inhibitors
Strong: 

Bupropion 4

Cinacalcet

Fluoxetine

Paroxetine 4

quinidine 4
Moderate

duloxertine

erythromycin

fluconazole

rolapitant

sertraline

terbinafine

verapamil
Weak:

amiodarone

cimetidine

escitalopram
1 CONTRAINDICATED with an inhibitor of the iso-enzyme, with evidence that the interaction is mainly driven by 
this iso-enzyme. 2 CONTRAINDICATED with an inhibitor of the iso-enzyme, with limited evidence that the 
interaction is mainly driven by this iso-enzyme.
3 DOSE ADJUSTMENT advised with an inhibitor of the iso-enzyme, with evidence that the interaction is mainly 
driven by this iso-enzyme. 
4 Inhibitor with which search was conducted in www.drugs.com.
Underlined indicates caution is advised for an entire class, some of the individual drugs in the list are members of 
the classes; the use of class IA and III antiarrhythmics is not advised with quinidine but this is for 
pharmacodynamics reasons not specifically due to 2D6 inhibition.


 
 
   
 
 
 
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Appendix 8
Examples of in vivo substrates, inhibitors, and inducers of 
P-glycoprotein
A search was conducted in June–September 2019 to identify relevant substrates of a 
transporter potentially inhibited by derazantinib and which should be best avoided as co-
medications.
Methodology to identify relevant substrates
Major interactions for typical inhibitors of the transporter of interest were searched in the 
interaction checker tool from drugs.com (https://www.drugs.com/drug_interactions.html), 
a free tool with good performance for DDI evaluation (Marcath 2018). The major 
interactions were selected and reviewed looking at the information in the ‘Professional’
tab. The drugs for which interaction is clearly assigned to the inhibition of the respective 
transporter are listed as substrates in the tables within this appendix; the drugs for which 
interaction is clearly assigned to other mechanisms (e.g., pharmacodynamic, enzyme) are 
not listed in the tables. In cases of unclear assignment, the interaction was further evaluated 
by consultation of Stockley’s Drug Interactions (Eighth edition (Baxter 2008), drug labels 
(e.g., EMA SPCs, USPIs), or reviews (e.g., EPARs).
Substrates for the specifc transporter listed in the October 2017 FDA Guidance for 
Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, 
and Labeling Recommendations are also listed.
Limitations and recommendations
Note that this list is not intended to be exhaustive. Interactions that are not present as 
‘major’ in drugs.com (e.g., moderate interactions, interactions not captured in the tool) or 
in the October 2017 FDA guidance do not appear in the list. 
To check for potential interactions for potential co-medications, the combination of the 
drug with the reference inhibitors listed in the tables in drugs.com or in the labels can be 
checked for.
For additional information, consult a pharmacist or the Sponsor.
Inhibitors
Iso-enzyme inhibitors were identified as those listed as clinically relevant inhibitors in the 
October 2017 FDA guidance.
Note that this list is not exhaustive, and only provides examples of reference inhibitors.


 
 
   
 
 
 
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P-glycoprotein relevant substrates and inhibitors
Substrates
Inhibitors

Aliskiren

Ambrisentan

Betrixaban

Colchicine 1

Dabigatran etexilate

Digoxin 1

Edoxaban 1

Everolimus

Fexofenadine

Imatinib

Lapatinib

Lefamulin

Loperamide

Maroviroc

Nilotinib

Ranolazine

Saxagliptin

Sirolimus

Talazoparib 1

Tolvaptan 1

Topotecan

Clarithromycin 

Itraconazole 

Quinidine

Verapamil 2
1 DOSE ADJUSTMENT advised with an inhibitor of the iso-enzyme, with evidence that the interaction is mainly 
driven by this iso-enzyme.
2 Inhibitor with which search was conducted in www.drugs.com.


 
 
   
 
 
 
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Appendix 9
Drugs with the potential to prolong QT and/or cause Torsades de 
Pointes
Known risk of Torsades de Pointes1
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
                                                          
1
Source: CredibleMeds® (https://www.crediblemeds.org).


 
 
   
 
 
 
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Version 5.0
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Page 201 of 206
Possible risk of Torsades de Pointes1
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)
                                                          
1
Source: CredibleMeds® (https://www.crediblemeds.org).


 
 
   
 
 
 
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Clinical Study Protocol
DZB-CS-202 (FIDES-03)
Version 5.0
21 May 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 202 of 206
Possible risk of Torsades de Pointes (continued)1
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
                                                          
1 Source: CredibleMeds® (https://www.crediblemeds.org).


 
 
   
 
 
 
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Clinical Study Protocol
DZB-CS-202 (FIDES-03)
Version 5.0
21 May 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 203 of 206
Conditional risk of Torsades de Pointes1
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
                                                          
1
Source: CredibleMeds® (https://www.crediblemeds.org).


 
 
   
 
 
 
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Clinical Study Protocol
DZB-CS-202 (FIDES-03)
Version 5.0
21 May 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 204 of 206
Appendix 10
Criteria for evaluating relationship between adverse events and 
study drug
The relationship between an adverse event (AE)/serious AE (SAE) and derazantinib and/or 
atezolizumab and/or ramucirumab and/or paclitaxel 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 and/or ramucirumab and/or paclitaxel.
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 and/or ramucirumab and/or paclitaxel.
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. 


 
 
   
 
 
 
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Version 5.0
21 May 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 205 of 206
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.
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.


 
 
   
 
 
 
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Clinical Study Protocol
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Version 5.0
21 May 2021
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 206 of 206
Appendix 11 Investigator’s protocol signature page
BASILEA 
INVESTIGATOR’S PROTOCOL SIGNATURE 
PAGE
Protocol / Version
DZB-CS-202 / Version 5.0
Basilea Product No:
Derazantinib
Protocol Title:
A Phase 1b/2 study of derazantinib as monotherapy and combination 
therapy with paclitaxel, ramucirumab or atezolizumab in patients with 
HER2-negative gastric adenocarcinoma harboring FGFR genetic
aberrations (FIDES-03)
Basilea Pharmaceutica International Ltd
Protocol date:
21 May 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 violation of the protocol, 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: