Clinical trial NCT02895360
Conditions: Neoplasms
Sponsor: Basilea Pharmaceutica
Start date: 2016-08-24; Completion date: 2020-08-07
Enrollment: 43 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Single-agent, open-label, multi-center sequential dose escalation and expansion study of BAL101553, administered as an intravenous (IV) infusion over 48 hours to adults with advanced or recurrent solid tumors or recurrent glioblastoma.

Detailed description:
This is the first study of prolonged intravenous infusion of BAL101553 (lisavanbulin). BAL101553 will be administered as an intravenous infusion over 48 hours, to adults with advanced or recurrent solid tumors or recurrent glioblastoma who have failed standard therapy, or for whom no effective standard therapy is available.

The primary goal of the study is to find the highest dose of BAL101553 that can safely be given to humans and to assess what side effects occur. The study will start by treating patients with a low dose. Once it has been shown that this low dose is well tolerated, new patients will be treated at higher dose levels ("dose escalation"). Once the highest, well tolerated dose is identified, up to 20 new patients with platinum-resistant/refractory ovarian cancer and up to 20 new patients with recurrent glioblastoma will be treated at that dose (this part is called "dose expansion") to further assess as secondary goal the tolerability and potential anticancer activity of BAL101553. A further secondary goal of this study is to assess the pharmacokinetics of BAL101553.

Arms: arm 1: Fixed 3+3 dose escalation of BAL101553 in patients with advanced solid tumors arm 2: BAL101553 at MTD in patients with platinum-resistant/refractory ovarian cancer or recurrent glioblastoma
Interventions: intervention 1: BAL101553 intervention 2: BAL101553 at MTD
Intervention descriptions: intervention 1: BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle; oral capsule daily for one week during Cycle 2 (study days 15-21) intervention 2: BAL101553 48-hour infusion on day 1, 8, and 15 of each 28-day cycle; treatment with maximum tolerated dose (MTD)

Protocol documents:
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NCT02895360


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 2 of 109
SIGNATURE PAGE
An open-label Phase 1/2a study of BAL101553 administered as intravenous 48-hour 
infusions in adult patients with advanced solid tumors or recurrent glioblastoma
Protocol Number/Version
CDI-CS-003 (SAKK number: SAKK 67/15) / 7.0
Study title
An open-label Phase 1/2a study of BAL101553 administered as 
intravenous 48-hour infusions in adult patients with advanced 
solid tumors or recurrent glioblastoma 
SNCTP number:
SNCTP000001954
Compound:
BAL101553
Phase of development:
Phase 1/2a
Date:
8 October 2018
Function:
Name:
Date/Signature:


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 3 of 109
PROTOCOL SYNOPSIS
TITLE
An open-label Phase 1/2a study of BAL101553 administered as intravenous 48-hour infusions in adult 
patients with advanced solid tumors or recurrent glioblastoma
SPONSOR
Basilea Pharmaceutica International Ltd, Switzerland
STUDY PHASE
Phase 1/2a
OBJECTIVES 
The primary objectives of this study are to determine the maximum tolerated dose (MTD) and to 
characterize dose-limiting toxicities (DLTs) of BAL101553, administered as an intravenous (IV) infusion 
over 48 hours on study Days 1, 8 and 15 of a 28-day treatment cycle, to adults with advanced or recurrent 
solid tumors who have failed standard therapy or for whom no effective standard therapy is available.
Secondary objectives:

To evaluate the safety and tolerability of BAL101553 administered as a 48-hour continuous IV 
infusion.

To assess the antitumor activity of BAL101553 administered as a 48-hour continuous IV infusion. 

To assess the pharmacokinetics (PK) of BAL101553 and BAL27862 after 48-hour IV infusion; and 
after daily oral administration on study Days 15–21 of Cycle 2 (Phase 1 only). 
Exploratory objectives:

To assess the use of biomarkers to characterize the pharmacodynamic (PD) effects of BAL101553, 
administered as a 48-hour continuous IV infusion.

To explore the potential utility of biomarkers in blood and/or tumor tissue as predictive biomarkers.
STUDY DESIGN 
Single-agent, open-label, multi-center, Phase 1/2a study in two parts: 
1. a Phase 1 dose-escalation portion using a 3+3 titration design to determine the MTD in solid-tumor 
patients; and 
2. a Phase 2a expansion portion to further characterize safety and tolerability of BAL101553 at the MTD
(70 mg/m2) and obtain efficacy data in patients with platinum-resistant/refractory ovarian cancer or
recurrent glioblastoma (GBM).
PLANNED NUMBER OF PATIENTS

Dose-escalation portion: planned up to 42 evaluable patients, completed with 16 patients evaluable for 
MTD assessment (20 patients dosed).

Expansion portion: up to 40 evaluable patients.
NUMBER OF CENTERS/LOCATIONS

Dose-escalation portion: three study centers

Expansion portion: approximately ten study centers


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 4 of 109
INCLUSION CRITERIA
Patients meeting all of the following inclusion criteria at screening will be eligible for enrollment in the 
study. Informed consent must be obtained within the 28 days prior to the start of treatment. Screening 
evaluations will be performed within the 15 days prior to the start of treatment (within 21 to 28 days for 
radiology assessments). 
Patients meeting all of the following:  
1. Age 18 years or older.
2. Patients who have:
a. Phase 1: Histologically- or cytologically-confirmed advanced or recurrent solid tumor, who failed 
standard therapy or for whom no effective standard therapy is available.

Patients with brain metastases must have undergone definitive treatment (surgery and/or 
radiation) at least 3 months prior to starting study drug and be documented as having stable 
disease by imaging.
b. Phase 2a:
i. Histologically-confirmed ovarian, fallopian tube or primary peritoneal cancer (collectively 
referred to herein as ‘ovarian cancer’) that is either platinum-resistant (disease progression 
within 6 months of the last receipt of platinum-based chemotherapy) or refractory (lack of 
response or disease progression while receiving the most recent platinum-based therapy).

Patients may have received up to four lines of prior cytotoxic chemotherapy, but none of 
them in the platinum-resistant/refractory setting. Confirmed high-grade serous, endometrioid, 
or carcinosarcoma histotypes are permitted.

An archived fixed-frozen paraffin-embedded tumor tissue block, or a minimum of 15 slides 
from such a block, must be available, otherwise a new tumor biopsy should be obtained in 
accordance with local institutional practices.

Patients must have at least one site of measurable disease as defined by RECIST criteria, and 
no clinical or radiological evidence of bowel obstruction.

Patients with brain metastases must have undergone definitive treatment (surgery and/or 
radiation) at least 3 months prior to starting study drug and be documented as having stable 
disease by imaging.
ii. Histologically-confirmed glioblastoma (GBM) in first relapse, defined as: progression following 
initial therapy, i.e., radiation, chemotherapy, or radiation + chemotherapy, with or without prior 
surgery.

Patients being treated with steroids must be on a stable or decreasing dose.
3. Patients with advanced solid tumors (excluding GBM) must have measurable disease (according to 
Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), documented within the 28 days prior to 
study-drug administration. 
Patients with GBM must have measurable disease, defined by contrast-enhancing magnetic resonance 
imaging (MRI), performed within 21 days prior to study-drug administration.
4. Life expectancy of ≥ 12 weeks.
5. Acceptable organ and marrow function documented within 15 days prior to starting study drug, defined 
as follows: 

Absolute neutrophil count ≥ 1.5 × 109/L.

Platelets ≥ 100 × 109/L. 

Hemoglobin ≥ 9 g/dL.

Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN), unless the patient has known 
Gilbert’s syndrome. 

Aspartate amino transferase (AST) and alanine amino transferase (ALT) ≤ 2.5 × institutional ULN 
or ≤ 5 × ULN in presence of liver metastasis.

Serum creatinine ≤ 1.5 × institutional ULN, or creatinine clearance ≥60 mL/min by Cockcroft-
Gault formula.

Serum sodium ≥ the institutional lower limit of normal (LLN).


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 5 of 109
6. Patients (excluding those with GBM) must have an Eastern Cooperative Oncology Group (ECOG) 
performance status ≤ 1, and those with GBM must have an ECOG performance status ≤ 2.
7. Female patients who are not pregnant or breast-feeding and meet one of the following conditions:

Postmenopausal for at least 1 year.

Post-hysterectomy and/or post-bilateral ovariectomy.

Women of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) 
pregnancy test result and must use highly effective contraceptive methods for the duration of the 
study and for an additional 90 days after the last dose of study drug. Highly effective contraceptive 
methods include male or female sterilization (bilateral tubal occlusion or vasectomy); intrauterine 
device (IUD); or combined (estrogen and progesterone containing) hormonal contraception (oral, 
vaginal ring or transdermal patch) with an ethinylestradiol dose of at least 30 µg, plus use of male 
condoms (preferably with spermicides), female condoms, a female diaphragm or a cervical cap.
8. Male patients must agree not to donate sperm from the first dose of study drug until 90 days after the 
last dose of study drug. Male patients, without a vasectomy and with a partner of childbearing potential, 
must agree to use condoms during the study and for at least 90 days after the last dose of study drug. 
The patient should be instructed that their female partner should use another form of contraception for 
the duration of the study and continue this use for at least 90 days after the last dose of study drug.
9. Signed, written informed consent must be obtained and documented according to the International 
Conference on Harmonization’s Guideline for Good Clinical Practice E6 (ICH-GCP) [1], the local 
regulatory requirements, and the permission to use private health information in accordance with the 
Health Insurance Portability and Accountability Act (HIPAA), where required, before performing any 
study-specific screening procedures.
10. Patients must have an implantable venous access system (‘PORT’) at the time of screening or must be 
willing to have a venous access system implanted for the purpose of the study. Patients with an existing 
PORT will be eligible for the study if the PORT chamber is made of titanium and the cathether is made 
of either silicon or polyurethane. If a patient has an exisiting PORT made of any other material, their 
eligibility may be approved by the Sponsor, based on the availability of compatibility data.
EXCLUSION CRITERIA
Patients meeting any of the following exclusion criteria at screening must not be enrolled in the study:  
1. Patients with advanced or recurrent solid tumors (excluding GBM) who: 

Have received chemotherapy, radiotherapy, immunotherapy, or investigational agents within the 4 
weeks (2 weeks for single fraction of palliative radiotherapy, 6 weeks for nitrosoureas or mitomycin 
C) prior to starting study drug; or 

Have not recovered to ≤Common Terminology Criteria for Adverse Events version 4.03 (CTCAE) 
grade 1 from all side effects of prior therapies, except for residual toxicities such as alopecia, which 
do not pose an ongoing medical risk. 
Patients with prostate cancer must have discontinued anti-androgens (e.g., bicalutamide, nilutamide) for 
at least 6 weeks prior to starting study drug; chemical castration with luteinizing hormone-releasing 
hormone analogues can be continued.
Patients with GBM who: 

Have received radiotherapy within 12 weeks prior to starting study drug, unless there is a new area 
of enhancement consistent with recurrent disease outside of the radiation field, or there is 
histological confirmation of unequivocal tumor progression; or

Have received administration of prior antitumor chemotherapy within the 4 weeks prior to starting 
study drug, or within the 6 weeks prior to starting study drug in the case of nitrosoureas; or

Have undergone surgical resection within 4 weeks prior to starting study drug, or a stereotactic 
biopsy/core biopsy within 1 week prior to starting study drug; or

Have been treated previously with bevacizumab.
2. Patients who have had prior exposure to BAL101553.
3. Inability to swallow oral medication (Phase 1).


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 6 of 109
4. Patients with gastrointestinal disease or those who have had a procedure that is expected to interfere 
with the oral absorption or tolerance of BAL101553 (e.g., functionally relevant gastrointestinal 
obstruction, or frequent vomiting) (Phase 1).
5. Symptomatic brain metastases or metastatic leptomeningeal disease, indicative of active disease 
6. Peripheral neuropathy ≥ CTCAE grade 2.
7. Known human immunodeficiency virus (HIV) infection. 
8. Known acute or chronic hepatitis B or hepatitis C infection.
9. Average triple systolic blood pressure (SBP) ≥ 140 mmHg or average triple diastolic blood pressure 
(DBP) ≥ 90 mmHg at the Screening visit. Patients with an initial BP ≥ 140/90 mmHg may be included 
if SBP < 140 mmHg and DBP < 90 mmHg is confirmed in two subsequent BP measurements on the 
same day.
10. Blood pressure (BP) combination treatment with more than two antihypertensive medications.
11. Any history of cerebral hemorrhage, cerebral aneurysm, or ischemic stroke; or a history of transient 
ischemic attack within 24 months prior to screening.
Acute or subacute intratumoral hemorrhage in patients with GBM, considered by the Investigator to be 
clinically significant. 

Patients with MRI or computed tomography (CT) demonstrating old hemorrhage, or a subacute 
bleed after a neurosurgical procedure (biopsy or resection), will be eligible.
12. Significant cardiac disease or abnormality, including any one of the following:

Left ventricular ejection fraction < 50% at screening (assessed by echocardiography).

QTcF > 470 ms on screening electrocardiogram (ECG) or a clinically relevant ECG abnormality.

Congenital long QT syndrome.

History of sustained ventricular tachycardia, ventricular fibrillation or torsades de pointes.

Presence of atrial fibrillation with tachyarrhythmia (ventricular response rate > 100 bpm).

Bradycardia (heart rate < 50 bpm).

Complete left bundle branch block.

Bifascicular block (complete right bundle branch block and anterior or posterior left hemiblock).

Myocardial infarction, acute coronary syndrome (including unstable angina), coronary 
revascularization procedures, or coronary arterial bypass grafting within 6 months prior to starting 
study drug.

Cardiac troponin (either troponin T or troponin I) above the institutional ULN.

Congestive heart failure of New York Heart Association class III or IV.
13. Uncontrolled intercurrent illness that would unduly increase the risk of toxicity or limit compliance with 
study requirements in the opinion of the Investigator; including but not limited to: ongoing or active 
symptomatic infection, uncontrolled diabetes mellitus, unstable or uncompensated cardiac, hepatic, 
renal, respiratory, or psychiatric illness. 
14. Current anticoagulation with warfarin potassium or other coumarin derivates. Heparin/low-molecular 
weight heparin (at prophylaxis or treatment doses), aspirin or other oral platelet inhibitors are permitted.
15. Women who are pregnant or breast-feeding. Men or women of reproductive potential who are not 
willing to apply effective birth control during the study and for at least 90 days after the last dose of 
study drug in both sexes.
INVESTIGATIONAL PRODUCT 
BAL101553 as a powder for concentrate for solution for infusion.
BAL101553 hard capsules for daily oral administration. 
DOSE / ROUTE / REGIMEN
BAL101553 will be given as a 48-hour continuous infusion using a Baxter elastomeric pump (pump 
models 2C4711K or 2C1009KP/2C4009K) that will be connected to an implantable venous access system 
(‘PORT’) on study Days 1, 8 and 15 of each 28-day treatment cycle until disease progression, unacceptable 
toxicity, or another reason for withdrawal from study drug occurs (see Section 4.4). In Phase 1, during 
Cycle 2 only, the Day 15 IV dose will be replaced by 7 days of oral BAL101553 capsules. There will be no 
oral dosing in Phase 2a.


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 7 of 109
Administration
Intravenous infusion on study Days 1, 8 and 15 of each 28-day treatment cycle, with the exception of study 
Days 15–21 of Cycle 2, during which time patients will be administered daily oral BAL101553 (Phase 1 
only).
Starting dose
In Cohort 1, the starting dose for IV BAL101553, administered as a 48-hour continuous infusion on study 
Days 1, 8 and 15 of each 28-day treatment cycle, is 30 mg/m2; the starting dose for oral BAL101553, 
administered as daily capsules on study Days 15–21 of Cycle 2, is 8 mg per day. The cumulative weekly-
oral dose for subsequent dose levels will be calculated based on PK modeling to approximate the weekly-
IV dose or exposure.
Dose-escalation portion (Phase 1) of the study:
Dose escalation will be performed using a 3+3 titration design (see Table 1 and Section 3.1.2). The starting 
doses of 30 mg/m2 IV and 8 mg/day oral BAL101553 are based on the clinical experience and safety data 
from study CDI-CS-001 in patients with advanced solid tumors administered BAL101553 via a 2-hour 
infusion and from study CDI-CS-002 in patients with advanced solid tumors administered BAL101553 as 
daily oral capsules.
Dose cohorts will comprise three patients. If a DLT is observed in any of these patients, the dose level will 
be expanded to include a second cohort of [up to] three patients. Dose increments between dose levels, 
ranging from approximately 33–50%, will be based on the extent and severity of observed drug toxicity.
On study Days 15–21 of Cycle 2, patients will receive oral BAL101553 capsules in place of the Day 15 
infusion to assess the bioavailability of daily oral BAL101553.
DLT will be defined as any one of the following events, assessed by the Investigator as being BAL101553 
study-treatment-related and graded according to CTCAE, during the first 28-day treatment cycle:

Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) lasting for ≥5 consecutive days.

Febrile neutropenia (ANC < 1.0 × 109/L and single temperature of > 38.3°C, or a sustained temperature 
of ≥38.0°C for > 1 h).

Grade 4 thrombocytopenia (platelet count < 25 × 109/L), or grade 3 thrombocytopenia (platelet count 
< 50 × 109/L) with bleeding.

Any other ≥ grade 4 hematological AE.

≥Grade 3 nausea, vomiting, or diarrhea despite appropriate pre-medication and/or management.

Grade 3 AST or ALT elevations (> 5–20 × ULN) for > 7 days, or grade 4 (> 20 × ULN) for any 
duration. 

Grade 3 QTc interval prolongation (QTcF > 500 ms or > 60 ms change from baseline).

Hypertension-related DLT:
o
Grade 4 hypertension (CTCAE).
o
Any recording of SBP > 220 mmHg or DBP > 110 mmHg.
o
At least one observation of SBP ≥ 160 mmHg or DBP ≥ 100 mmHg that does not resolve to SBP 
< 160 mmHg and DBP < 100 mmHg within 24 hours, despite antihypertensive treatment.    
Note: The need for administration of new antihypertensive medication or modification to more 
intensive antihypertensive medication will not be considered a DLT.  

Any study-treatment-related AE which leads to missing both the Day 8 and Day 15 doses in Cycle 1, or 
that causes a delay in the start of Cycle 2 by more than 14 days. 

Any other study-treatment-related AEs which, in the view of the Investigator and/or Sponsor, represent 
a clinically significant hazard to the patient.

Any other ≥ grade 3 non-hematological study-treatment-related AE.
Note: The following study-treatment-related AEs will not be considered DLT unless considered to present 
a clinically significant hazard to the patient:
o
Grade 3 fatigue. 
o
Grade 3 or 4 elevations in alkaline phosphatase.
o
Grade 3 or 4 hypophosphatemia.
o
Grade 4 lymphopenia. 


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 8 of 109
There will be a minimum period of observation of 28 days between the first dose of the last patient treated 
at that dose level, to the first dose of the first patient treated at the next dose level. Additionally, a delay of 
at least 7 days must be implemented between the first dose of the first and second patients at the same dose 
level. No delay is required between the second patient and any subsequent patient enrolled at the same dose 
level. As a delay in the start of the second cycle by more than 14 days due to a drug-related AE is 
considered a DLT, no patient will be permitted to be enrolled at a new dose level until all patients in the 
current dose group have initiated treatment Cycle 2, or have discontinued the study for reasons other than 
drug-related toxicity.
Decisions to escalate dose levels and determination of the MTD will be made by a Dose-Cohort Escalation 
Committee, as summarized below:

If no DLTs are observed during Cycle 1 at a given dose level, escalation to the next dose level will 
proceed. If one DLT is observed during Cycle 1 at a given dose level, that dose level will be expanded 
to include a second cohort of [up to] three patients; escalation to the next dose level will proceed only if 
DLTs are observed in < 33% of patients (i.e., one of six patients). If DLTs are observed in ≥33% of 
patients (i.e., ≥two patients) at a given dose level, that dose will be defined as the maximum 
administered dose (MAD) and dose escalation will be stopped. Additional, intermediate dose levels 
between the MAD and the next lower dose level may be explored, at the discretion of the Dose-Cohort 
Escalation Committee (see Section 3.2.1). 

The MTD is defined as the highest dose level below the MAD with an acceptable tolerability profile.
Dose escalation and MTD determination will be primarily based on the occurrence of DLTs during 
Cycle 1, however, will also include a clinical review of all relevant available data from the current and 
previous dose levels. At least six patients must be treated at the MTD dose level in the dose-escalation 
portion of this study.

Dosing of any new patient may only be started after approval by the Sponsor. All study centers must 
notify the Sponsor when a patient is screened, is scheduled for dosing and after administration of the 
first dose. 
Recommendations for dose delays or dose modifications in patients experiencing BAL101553 related 
toxicities are summarized below:

In patients who experience a DLT, dosing may only be resumed after recovery to ≤CTCAE grade 1, or 
baseline, and subsequent doses of BAL101553 will be reduced by one dose level, or by half if this 
occurs at the starting dose level (i.e. to 15 mg/m2). A maximum of two dose reductions per patient will 
be allowed and the dose may not be re-escalated. Non-DLT events may also require dose delay or dose 
reduction (see Section 3.2.3 and Table 4).

Patients who experience a drug-related AE which leads to missing both the Day 8 and 15 doses within 
any 28-day cycle, or which delays the start of the subsequent cycle by more than 14 days, should be 
discontinued from the study. Such events will be considered a DLT if they occur during Cycle 1. 
Intra-patient dose escalation, including multiple subsequent increases of dose levels, may be allowed in 
patients who have stable disease or response and did not experience drug-related AEs ≥ CTCAE grade 2 
during their most recent treatment cycle; if all patients in the next-higher dose level have completed their 
first treatment cycle with acceptable tolerability; and if a decision has been taken to start dosing at the 
subsequent higher dose level. Dose increases will be at the discretion of the Investigator, after discussion 
with the Sponsor and review of available safety data for all patients. Dose increases will only occur at the 
start of a subsequent cycle (i.e., Day 1 of the next treatment cycle) for an eligible patient. Any DLTs 
experienced by patients after intra-patient dose escalation will not count in the calculation of DLT 
incidence for the corresponding dose level. 
Expansion portion (Phase 2a) of the study:
In December 2017, the MTD was defined as 70 mg/m2; up to 40 additional evaluable patients will be 
enrolled at this dose to further evaluate the safety and tolerability, pharmacodynamic effects and antitumor 
activity of BAL101553. There will be two separate target populations, each with up to 20 evaluable 
patients: the first will comprise ovarian cancer patients; and the second will comprise GBM patients. For 
each target population, a separate cumulative safety evaluation will be performed after six patients have 
completed their first 28-day cycle or have discontinued treatment, and after completion of the first cycle, or 
discontinuation, by each subsequent group of six patients.


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 9 of 109
DURATION OF PATIENT PARTICIPATION
Patients with an objective response or stable disease may continue to receive BAL101553 until disease 
progression, unacceptable toxicity, or another discontinuation criterion is met. 
Discontinuation of treatment will be recorded and reasons may include:

Disease progression.

Adverse event (AE).

Abnormal laboratory value.

Abnormal test procedure result.

Missing both the Day 8 and Day 15 doses within any 28-day cycle, or causing a delay of more than 
14 days in the start of a subsequent cycle, due to toxicity.

Requirement for more than two dose level reductions in a patient due to AEs.

Intercurrent illness that prevents further administration of treatment.

Withdrawal of consent.

Withdrawn from the study at Investigator discretion.

Protocol violation

Protocol non-compliance.

Lost to follow-up.

New cancer treatment/therapy.

Administrative reasons.

Death
ASSESSMENTS 
A detailed study visit and assessment schedule is provided in Table 5 (Phase 1) and Table 6 (Phase 2a) (Section 
5.1).
Patients who provide informed consent will undergo screening evaluations to determine eligibility. 
Informed consent must be obtained within the 28 days prior to the first administration of study drug. 
Screening assessments will be initiated and completed within the 15 days prior to the first dose of study 
drug (except for radiology assessments, which may be obtained within 28 days [excluding GBM patients] 
or 21 days [GBM patients] prior to the first dose of study-drug administration).
Safety / tolerability
The severity of AEs will be described using the CTCAE criteria. Safety evaluations will include analysis of 
AEs, laboratory assessments (hematology, biochemistry, cardiac troponin, coagulation, urinalysis), 
pregnancy testing in women of childbearing potential, ECG, transthoracic echocardiography, chest X-
ray/CT/MRI, vital signs, ECOG performance status, physical examination, and evaluation of concomitant 
medications.
Pharmacokinetics
Phase 1: PK variables calculated from rich plasma concentration data using noncompartmental analysis for 
BAL101553 (if applicable) and for BAL27862 will comprise: Cmax, Tmax, AUC0–τ, AUC0–last, AUC0–∞, t½, 
systemic clearance and volume of distribution.
Phase 2a: Plasma concentrations will be presented as tabulated lists according to the PK schedule.
Efficacy
In patients with advanced or recurrent solid tumors (excluding GBM), evaluation of disease progression 
and response in patients with measurable disease will be assessed clinically and/or by RECIST v1.1 
criteria. For GBM patients, evaluation of disease progression and response will be assessed based on the 
Response Assessment in Neuro-Oncology (RANO) criteria.
Biomarker analysis
• Filter cards for dried-blood-spot analysis of single nucleotide polymorphisms, genes involved in drug 
transport or drug metabolism, and/or potential biomarkers.
• Archival tumor blocks (collected from all patients when available).
• Tumor biopsies (if patient is willing to undergo biopsy; excluding GBM patients).


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 10 of 109
• Circulating tumor cells [CTCs] from blood.
o
Collection of CTCs will be performed in at least two study centers with a goal to obtain samples 
from at least 50% of patients in Phase 1 and 50% of ovarian-cancer patients in Phase 2a.
• Malignant pleurocentesis or paracentesis fluid (when available during routine clinical course) will be 
analyzed.
STATISTICAL ANALYSIS 
Analysis populations

The full analysis population (FAP) will include patients who receive at least one partial or complete 
dose of BAL101553. 

Safety population: FAP with at least one post-baseline safety assessment.

PK population: FAP with at least one post-baseline PK assessment.

The MTD-determining population will consist of Phase 1 patients who have: received at least one 
partial or complete dose of BAL101553 and experienced a DLT; or received all scheduled doses of 
BAL101553 on study Days 1, 8 and 15 in Cycle 1 without a DLT, have been observed for ≥ 28 days 
following the first dose, and have been evaluated for safety.

The efficacy-evaluable populations (EEPs) will include all Phase 2a patients:
o
With progressive disease who complete at least Cycle 1 dosing (i.e. received study drug on Days 1, 
8 and 15) and who undergo at least one on-study clinical tumor assessment, or radiological 
assessment by RECIST v1.1 guidelines, or RANO criteria. 
o
With stable disease, partial response, or complete response, based on a radiological assessment by 
RECIST v1.1 guidelines or RANO criteria at the end of Cycle 2, who receive at least four doses of 
study drug in the first two cycles. 
For the Phase 2a portion of the study, separate analyses will be performed for the ovarian-cancer and GBM 
target populations. 
DLT, MAD, and MTD recommendation 
The number of patients experiencing DLT and the types of DLTs will be listed by dose level. The MAD is 
defined as the dose level at which DLTs are observed in ≥two of [up to] six evaluable patients during 
treatment Cycle 1 (i.e., in a regular or expanded dose level). The MTD is defined as the highest dose level 
below the MAD with an acceptable tolerability profile. 
Adverse events 
Adverse events (AEs) and serious adverse events (SAEs) will be described by body system, in individual 
listings and frequency tables, for each dose level and cycle as appropriate. 
Laboratory evaluations 
The frequency of laboratory abnormalities will be displayed by worst CTCAE grade and by dose level and 
cycle as appropriate. Newly-occurring laboratory abnormalities will be displayed in a separate listing. Shift 
tables will be provided for laboratory parameters classified according to worst CTCAE grade. 
Efficacy analysis
The objective response rate and disease control rate will be presented by dose level and by disease 
subgroups, as appropriate. Progression-free survival (until end of study and at 6 months after first study-
drug administration) will be listed by dose level. 
Pharmacokinetic analysis
Listings and descriptive analysis of PK variables will be presented by dose level, including arithmetic and 
geometric means, coefficient of variations, standard deviations, minimum, maximum, and median. 
Bioavailability will be determined as the ratio of the AUCs after oral and IV administration.
Biomarker analysis
Listings and descriptive analysis of biomarkers will be presented by dose level, scheduled time point/cycle, and by 
disease subgroup, as appropriate. Analyses of biomarkers and their association to clinical response or PK will be 
exploratory.


B
C
C
T
L
L
L
L
1
BAL101553 
Clinical Study
Confidential –
TABLE OF 
LIST OF TA
LIST OF FIG
LIST OF AP
LIST OF AB
1. BACKG
1.1
Mi
1.2
BA
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No
1.3.1
1.3.2
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1.3.3
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1.4.1
1.4.1
1.4.1
1.4.2
1.4.2
1.4.2
1.4.2
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1.4.3
1.4.3
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ABLES ......
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GROUND A
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Version 7.0
October 2018
age 11 of 109
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B
C
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2
3
4
BAL101553 
Clinical Study
Confidential –
1.5.2
1.5.3
1.5.3
1.5.3
2. OBJECT
2.1
Pri
2.2
Sec
2.3
Ex
3. STUDY 
3.1
Ov
3.1.1
3.1.2
3.1.2
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3.1.3
3.1.4
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3.2.2
3.2.2
3.2.3
3.2.3
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Nu
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4. STUDY 
4.1
Ta
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Purpose of 
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Version 7.0
October 2018
age 12 of 109
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B
C
C
5
BAL101553 
Clinical Study
Confidential –
4.2
Inc
4.3
Ex
4.4
Cri
4.5
Ev
4.5.1
4.5.2
5. STUDY 
5.1
Sch
5.2
Stu
5.2.1
5.2.2
5.2.3
5.2.4
5.2.5
5.2.6
5.2.7
5.2.8
5.2.9
5.2.9
5.2.9
5.2.10
5.2.1
5.2.1
5.2.11
5.2.12
5.2.13
5.2.14
5.2.15
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Day 1 of C
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Version 7.0
October 2018
age 13 of 109
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B
C
C
6
BAL101553 
Clinical Study
Confidential –
5.3
Stu
red
5.3.1
5.3.2
5.4
Stu
5.4.1
5.4.1
5.4.1
5.4.1
5.4.1
5.4.2
5.4.2
5.4.2
5.4.2
5.4.2
5.4.2
5.4.2
5.4.2
5.4.2
5.4.3
5.4.3
5.4.3
5.4.3
5.4.4
5.4.5
5.4.5
5.4.5
5.4.5
6. STUDY 
6.1
Bli
6.2
Pac
6.3
Sh
y Protocol CD
Proprietary in
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Version 7.0
October 2018
age 14 of 109
dose 
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B
C
C
7
BAL101553 
Clinical Study
Confidential –
6.4
Pre
6.4.1
6.4.2
6.5
Ad
6.6
Co
6.6.1
6.6.1
6.6.1
6.6.2
6.6.3
7. SAFETY
7.1
De
7.1.1
7.1.2
7.1.2
7.1.3
7.1.3
7.2
Ev
7.2.1
7.2.2
7.3
Ha
7.3.1
7.3.2
7.3.2
7.3.2
7.3.3
7.3.4
7.3.4
7.3.4
7.4
Pre
7.4.1
y Protocol CD
Proprietary in
esentation o
BAL10155
BAL10155
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Phase 2
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BAL101553 
Clinical Study
Confidential –
7.4.2
8. STATIS
8.1
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8.2.1
8.2.1
8.2.1
8.2.1
8.2.1
8.2.2
8.2.2
8.2.2
8.2.2
8.2.2
8.2.2
8.2.2
8.2.2
8.2.2
8.2.2
8.2.2
8.2.3
8.2.4
9. STUDY 
9.1
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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 17 of 109
9.4
Protocol amendments .......................................................................................102
9.5
Premature termination of the study..................................................................102
9.6
Publication policy.............................................................................................102
10. ETHICS AND GOOD CLINICAL PRACTICE .......................................................103
10.1 Good Clinical Practice .....................................................................................103
10.2 Informed consent..............................................................................................103
10.3 Patient confidentiality and data protection.......................................................104
10.4 Independent Ethics Committees/Institutional Review Boards.........................104
11. REFERENCES ..........................................................................................................104
12. APPENDICES ...........................................................................................................105
LIST OF TABLES
Table 1
Cohorts 1–4: Planned intravenous dose-escalation levels ........................37
Table 2 
Overview of dose-limiting toxicities ........................................................38
Table 3
Dose-escalation criteria.............................................................................40
Table 4
General guidelines for treatment continuation criteria and 
recommendations for dose modification...................................................43
Table 5
Phase 1 - Schedule of assessments ...........................................................52
Table 6
Phase 2a - Schedule of assessments..........................................................56
Table 7 
ECOG performance status ........................................................................76
LIST OF FIGURES
Figure 1
Schematic overview of study design .......................................................33
LIST OF APPENDICES
Appendix 1 
Response evaluation and criteria in solid tumors (RECIST) 
guidelines, version 1.1 ............................................................................105
Appendix 2
RANO criteria for glioblastoma and high-grade gliomas.......................106
Appendix 3
Criteria for evaluating relationship between adverse events and 
study treatment........................................................................................107
Appendix 4
Investigator’s protocol signature page....................................................109


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 18 of 109
LIST OF ABBREVIATIONS
ADR
Adverse drug reaction
AE
Adverse event
ALT
Alanine amino transferase
ANC
Absolute neutrophil count
AST
Aspartate amino transferase
AUC0-∞
Area under the concentration-time curve from time zero to infinity; calculated 
as AUC0-last + Clast/λz
AUC0-last
Area under the concentration-time curve from time zero to the last quantifiable 
concentration
AUC0-τ
Area under the concentration-time curve from time zero to time (τ); where tau 
is the length of the dosing interval
BP
Blood pressure
BRCA1/2
Breast cancer susceptibility gene 1/2
BSA
Body surface area
CA-125
Cancer antigen 125
CDI
Cell death inducer
CEC(s)
Circulating endothelial cell(s)
CEP(s)
Circulating endothelial progenitor cell(s) 
Cmax
Maximum observed plasma concentration
CRA
Clinical research associate
CRF
Case report form
CT
Computed tomography
CTC(s)
Circulating tumor cell(s)
CTCAE 
Common Terminology Criteria for Adverse Events version 4.03
CYP
Cytochrome P450
D
Day (of a treatment cycle)
DBP
Diastolic blood pressure
DCEC
Dose-Escalation Cohort Committee
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleaic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case repot form
EEP
Efficacy-evaluable population
FAP
Full analysis population
GBM
Glioblastoma
GCP
Good Clinical Practice


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 19 of 109
GLP
Good Laboratory Practice
hCG
Human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
ICH
International Conference on Harmonisation
IDH
Isocitrate dehydrogenase gene
IEC/IRB
Independent Ethics Committee / Institutional Review Board
ISF
Investigator site file
IUD
Intrauterine device
IV
Intravenous
LLN
Lower limit of normal
MAD
Maximum administered dose
MGMT
O6-methylguanin-DNA-methyltransferase gene
MRI
Magnetic resonance imaging
MTA
Microtubule targeting agent
MTD
Maximum tolerated dose
N
Number
PD
Pharmacodynamic(s)
PET
Positron emission tomography 
Pgp
P-glycoprotein
PK
Pharmacokinetic(s)
QTcF
QT interval corrected for heart rate (Fridericia correction)
RANO
Response Assessment in Neuro-Oncology
RECIST v1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose
RT
Radiotherapy 
SAE
Serious adverse event
SBP
Systolic blood pressure
SUSAR
Suspected unexpected serious adverse reaction
t½
Terminal elimination half-life
Tmax
Time to maximum plasma concentration
TB
Total bilirubin
TMZ 
Temozolomide 
ULN
Upper limit of normal
URL
Uniform resource locator


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 20 of 109
1. BACKGROUND AND RATIONALE
1.1
Microtubule targeting agents in cancer chemotherapy
Microtubule targeting agents (MTAs) are among the most active cytotoxic anticancer 
drugs currently in use, and have a broad spectrum of activity. Microtubule destabilizers 
(e.g., Vinca alkaloids) are used in the treatment of several types of hematologic 
malignancies, and solid tumors such as lung cancer; microtubule stabilizers 
(e.g., taxanes) are used in the treatment of a variety of solid tumors. 
Despite a high initial sensitivity of many malignancies to MTAs, resistance can arise 
through several potential mechanisms, including tumor overexpression of P-glycoprotein 
(Pgp), elevated levels of β-tubulin subtype III, reduced levels of the cancer susceptibility 
gene BRCA1, elevated levels of the cell cycle inhibitory protein p21, and acquired 
mutations in β-tubulin. Accordingly, it is important to identify improved tubulin-
inhibiting agents that may overcome these resistance factors and improve the 
effectiveness of treatment. 
1.2
BAL101553 as a microtubule targeting agent
BAL101553 is a water-soluble, lysine pro-drug of the synthetic small molecule 
BAL27862. The active drug BAL27862 (a furazano-benzimidazole derivative), 
reversibly binds tubulin heterodimers at the colchicine site, inhibiting microtubule 
formation and disrupting microtubule organization [2].
The active compound BAL27862 (molecular weight = 387.4 g/mol) is lipophilic (LogD = 
2.49 at pH 7.4), highly permeable (permeability = 135×10-6 cm/s in a Caco-2 model), and 
demonstrated excellent drug penetration into tissues including the brain, in mice [3]. 
BAL27862 displays a novel microtubule fragmentation activity, generating mobile, short 
microtubule fragments in interphase cells. BAL27862 destabilizes the mitotic spindle 
leading to the formation of tiny microtubule asters. The microtubule phenotype 
associated with BAL27862 treatment is distinct from that observed with conventional 
MTAs, including taxanes and Vinca alkaloids. 
1.3
Nonclinical studies with BAL101553
1.3.1
Nonclinical pharmacodynamics and activity 
BAL27862 induces apoptosis, and shows marked antiproliferative activity against cancer 
cell lines and patient-derived tumor cells from several solid-tumor histotypes. 
Antiproliferative activity is retained in tumor cells that over-express the drug efflux pump 
Pgp, as well as diverse tumor models that are refractory to Vinca alkaloids, taxanes, and 
epothilone B through non-Pgp-related resistance mechanisms. BAL27862 is also active 
against temozolomide-sensitive and -resistant glioblastoma (GBM) cell lines and 
paclitaxel-resistant ovarian cell lines. Importantly, patient-derived tumor cells exhibiting 
intrinsic resistance to paclitaxel have been demonstrated to be sensitive to BAL27862 
using clonogenic assays. Normal human stem cells and peripheral blood 
mononucleocytes are relatively insensitive to BAL27862. 
BAL27862 and BAL101553 exhibit antitumor activity with intravenous (IV) 
administration in human xenograft mouse models derived from several chemo-sensitive 
tumor histotypes, where activity is comparable to standard antineoplastic drugs. 


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 21 of 109
Immunohistochemical examination of treated tumors indicates profound effects on tumor 
cell proliferation and viability, together with a potent disruption of the tumor vasculature; 
supporting in vitro analyses indicating a dual mechanism of action on refractory tumor 
cells and vascular cells. Moreover, a single BAL101553 administration has dose-
dependent effects on tumor vascularization, with more profound antivascular effects at 
higher drug doses resulting in less efficient drug distribution to tumor. Hence, higher 
doses may not necessarily result in proportionally higher tumor drug levels. Fractionation 
of the IV dose does not decrease antitumor activity, indicating that AUC rather than Cmax
is the main factor in antitumor response. BAL27862 and BAL101553 also exhibit 
antitumor activity after oral administration in a number of xenograft models, with 
equivalent antitumor responses observed with both daily and weekly oral BAL101553 
dosing in a Pgp-overexpressing colorectal cancer model. 
Significant antitumor activity has also been observed with both BAL27862 (oral and IV) 
and BAL101553 (IV) in a Pgp-overexpressing mammary tumor xenograft model. These 
Pgp models are known to be refractory to standard MTAs, such as paclitaxel and 
vincristine. 
Moreover, BAL101553 (IV) exhibits antitumor activity in an epothilone- and taxane-
resistant non-small cell lung cancer xenograft model associated with mutation of class I 
-tubulin and in a serous ovarian xenograft model that is partially refractory to cisplatin. 
In mice bearing orthotopic GBM tumors, daily-oral administration of BAL101553 as a 
single agent led to survival advantages in both MGMT-methylated (e.g. GBM39) and -
unmethylated (e.g. GBM26) models.
Co-administration of capecitabine or cisplatin results in a trend towards increased 
antitumor activity, suggesting a potential for combination with cytotoxic agents. More 
profound antitumor effects have also been shown in combination with ionizing radiation 
and trastuzumab as compared to single agent treatment.
In GBM models, BAL101553 has shown anticancer activity as a single agent, as well as 
in combination with radiotherapy (RT) and with radiochemotherapy. In an orthotopic 
GBM model (GBM6) with reduced sensitivity to temozolomide (TMZ) and RT, more 
profound survival effects were observed when oral BAL101553 was combined with RT 
or RT/TMZ as compared to the single agents or RT and TMZ combined. These results 
indicate a potential to combine BAL101553 with radiotherapy, other chemotherapies and 
therapeutic antibodies.
Correlative studies suggest that high expression of stathmin, MAP4, phospho-AKT 
(Serine 473) and detyrosinated-(Glu-) and acetylated-tubulin may be associated with 
resistance to BAL27862. Moreover, reduced expression of the mitotic spindle checkpoint 
kinase BubR1 confers resistance on sensitive tumor cell lines. Monitoring of tumor p21 
expression levels, as well as proliferation, viability and vascularization, may also be 
useful to show treatment-related pharmacodynamic (PD) effects. Validated tumor 
immunohistochemical assays are available for all the selected biomarkers and initial 
tumor epidemiology studies have been performed in a bank of human non-small-cell lung 
cancer, small-cell lung cancer, GBM and breast, colorectal, prostate, ovarian, pancreatic, 
hepatobiliary and gastric cancer specimens.


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Version 7.0
October 2018
age 22 of 109
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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 23 of 109
permeable. A dedicated pharmacokinetic (PK) study performed in dogs, using the capsule 
formulation intended for clinical use, confirmed the excellent oral bioavailability of 
BAL101553. 
1.3.3
Nonclinical toxicology
BAL101553 was investigated in 4-week oral toxicity studies in rats and dogs, with once 
daily administration. The patterns of clinical, functional, laboratory and post-mortem 
findings were consistent with the expected adverse events (AEs) of anticancer drugs, and 
was comparable to previous studies with once-weekly IV administration. The main 
targets of toxicity were the gastrointestinal tract, blood, immune and lymphatic systems, 
and the testes. With the exception of testicular degeneration, changes were generally 
reversible after a 4-week recovery period. Considering weekly exposure (AUC), daily 
oral administration was better tolerated than weekly IV
administration. The 
no-adverse-effect-level after once-daily oral dosing was < 2.5 mg/kg/day in rats and 
0.5 mg/kg/day in dogs; the maximum tolerated dose (MTD) was 10 and 5 mg/kg/day in 
male and female rats, respectively, and 2 mg/kg/day in dogs. 
There were no indications of central nervous system or peripheral neurotoxicity, or drug-
related effects on the QTc-interval, in IV- or oral-administration animal studies.
1.3.4
Correlative studies
Several possible prognostic factors or surrogate markers for BAL101553 activity have 
been proposed. These include the number of circulating tumor cells (CTCs), circulating
endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and expression 
of specific proteins detectable in blood or in tumor tissue including stathmin, MAP4, 
BubR1, phospho-AKT (Serine 473), detyrosinated-(Glu)-
and acetylated-tubulin. 
BAL101553 activity does not appear to be associated with β-tubulin variant III 
expression levels, a biomarker heavily implicated in resistance to standard MTAs. 
However, based on the prognostic importance of this marker, analysis of β-tubulin variant 
III is proposed. Antitumor activity may also be correlated to the basal proliferation index
(as measured by expression of Ki67), apoptosis levels (as measured by caspase 
activation), vascular density (as measured by a vascular marker such as CD34), and 
expression of cell cycle regulators (such as p21CIP1). These biomarkers also provide value 
as PD markers of tumor response, providing important information to aid dose evaluation 
during the study. It is therefore appropriate to investigate these potential biomarkers of 
BAL101553 activity. Early evaluation of the practicality of the assays for use in 
enrollment criteria, patient stratification, or for monitoring efficacy, will provide a basis 
for future clinical studies.
Accordingly, blood samples, and tumor biopsies obtained where possible, obtained from 
patients before, during, and after treatment will be analyzed to identify possible 
biomarkers of therapeutic response or resistance. Additional protein expression or genetic 
and epigenetic analyses (e.g., gene expression and mutation, DNA methylation, 
microRNA analysis) may be performed on remaining blood and tumor biopsy samples to 
further explore potential relevant biomarkers of disease and/or drug response. Filter cards 
for dried-blood-spot analysis will be used for exploratory analysis. This may include the 


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 24 of 109
correlation of PK exposure variables of BAL101553/BAL27862 with
genetic 
variations/haplotypes of CYP450, other drug-metabolizing enzymes, or drug transporters.
1.4
Clinical studies with BAL101553
1.4.1
CDI-CS-001: Multiple-ascending-dose study of intravenous BAL101553 
administered as a 2-hour infusion in adult patients with advanced solid tumors
Study CDI-CS-001 was a single-agent, open-label first-in-human Phase 1/2a IV study 
carried out in patients with solid tumors who have failed standard anticancer therapy, or 
for whom no effective standard therapy is available. The Phase 1 dose-escalation portion 
of the study used a modified titration design to determine the MTD. The Phase 2a 
expansion portion of the study further characterized the safety and tolerability of 
BAL101553 at MTD and sub-MTD doses and aimed to obtain efficacy data in patients 
with advanced solid tumors. The study was completed in April 2016.
The primary objective of the Phase 1 portion of this study was to determine the MTD of 
BAL101553 when given as 2-h infusions on Days 1, 8, and 15 of each 28-day cycle. The 
MTD was defined as the highest dose administered in Cycle 1 without the occurrence of 
Dose-limiting toxicity (DLT) in two or more patients, in a dose cohort of at least six 
patients, and was determined to be 60 mg/m2. Dose escalation was performed using a 
modified titration design [4, 5]. The starting weekly dose of BAL101553 was 15 mg/m2,
based on Good Laboratory Practice (GLP) toxicology studies.
A total of 24 patients received BAL101553 at the following dose levels: 15 mg/m2 (n=1), 
30 mg/m2 (n=3), 45 mg/m2 (n=3), 60 mg/m2 (n=10), and 80 mg/m2 (n=7). Two patients 
were replaced in the 60 mg/m2 cohort, as they were considered to be non-evaluable for 
safety/MTD.
The objective of the Phase 2a portion of the study was to obtain further information 
related to the efficacy, safety, PK and pharmakodynamics of BAL101553. At the onset of 
this part of the study, patients were randomized to receive BAL101553 at 60 mg/m2 or at 
a lower dose level of 30 mg/m2, to define whether the MTD or a sub-MTD dose is more 
appropriate for further clinical development. After dosing of 23 patients (12 patients at 
30 mg/m2 and 11 patients at 60 mg/m2), the 60 mg/m2 dose level was discontinued due to 
safety concerns following observation of myocardial injury (troponin release and 
electrocardiogram [ECG] changes) in two patients. Patients were then randomized to dose 
levels of 45 mg/m2 or 30 mg/m2. Subsequently, one patient at the 45 mg/m2 dose level 
experienced a small, asymptomatic  myocardial infarction. In response to this, 30 mg/m2
was declared to be the highest dose to be administered in the Phase 2a portion of the trial;
this is now considered to be the highest-tested safe dose of IV BAL101553, administered
as a 2-hour infusion on study Days 1, 8 and 15 of each 28-day cycle. A total of 49 
patients were administered BAL101553 during this phase of the study, 40 of whom were 
evaluable for efficacy.


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age 25 of 109
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Version 7.0
October 2018
age 27 of 109
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n Cohort 7,
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Version 7.0
October 2018
age 28 of 109
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P
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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 30 of 109
capsules on study Days 15–21 of Cycle 2, i.e. after completion of the MTD-relevant 
safety assessments in Cycle 1. 
A 48-hour infusion was chosen for this study, as PK modelling has suggested that 
administration of BAL101553 over this timeframe would result in Cmax levels which are 
25% of those observed when the drug is given as a 2-hour infusion.
Dose level sizes of three patients (without DLT) and six patients (if DLT is observed) 
have been utilized in numerous dose-escalation studies of anticancer drugs, and can be 
considered as a standard approach [6, 7]. The proposed study design is intended to limit 
patient exposure to low and likely inefficacious dose levels, while allowing identification 
of adequately tolerated doses with the greatest likelihood of efficacy. 
A minimum period of observation of 28 days, between the administration of the first dose 
to the last patient at the current dose level and the administration of the first dose to the 
first patient at the next higher dose level, was chosen as it provides a reasonable time 
window for the assessment of safety findings prior to the treatment of new patients. This 
observation period is also practical to maintain a consistent 28-day schedule for patient 
clinic visits. The 7-day delay in the initiation of treatment between the first and second 
patient in a dose level is intended to allow for further identification of untoward toxicity 
when starting a new dose level.
The continuation of therapy for patients who may benefit from treatment is also in line 
with current standards in anticancer studies. The provision to permit intra-patient dose 
increases as higher doses are tested and found to be well tolerated provides patients 
entered in the study an opportunity to be treated at a potentially therapeutic dose.
The Phase 2a expansion portion of the study is intended to confirm the tolerability of 
BAL101553 at the MTD (70 mg/m2), and to provide additional information about its 
safety and tolerability profile, PK, PD and antitumor efficacy in patients with platinum-
resistant/refractory ovarian cancer and in patients with recurrent GBM. 
An expansion in the target population of patients with platinum-resistant/refractory 
ovarian cancer is justified by a clinical signal, with a response seen in one patient dosed 
at 70 mg/m2, supported by: non-clinical data in a serous-ovarian xenograft model 
partially refractory to cisplatin; other taxane-resistant cellular models in which 
BAL101553 has demonstrated activity; and based on the utility of other microtubule-
targeting drugs (e.g. taxanes) in the indication of ovarian cancer.
An expansion in the target population of patients with recurrent GBM is justified by 
extensive non-clinical data using BAL101553 as a single agent, as well as in combination 
with radiotherapy (RT) and radiochemotherapy, and considering the excellent brain 
penetration of BAL27862 (a small, lipophilic molecule), which was demonstrated in a 
mouse model.
Treatment in both study phases (Phase 1 dose-escalation and Phase 2a expansion) will be 
extended for patients who may benefit from therapy. 


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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 32 of 109
Subsequent oral dose levels will be calculated to approximate the weekly IV dose or 
exposure. The oral-dose calculation may be modified based on observed PK during the 
study.
There will be no oral dosing in Phase 2a.
2. OBJECTIVES OF THE STUDY
2.1
Primary objectives
Dosing strategies which limit Cmax-related BAL101553 toxicities provide the potential to 
administer higher dose levels of the drug in order to enhance its antiproliferative effects. 
The primary objectives of this study are to determine the MTD and to characterize dose-
limiting toxicities (DLTs) of BAL101553, administered as an IV infusion over 48 hours 
on study Days 1, 8 and 15 of a 28-day treatment cycle, to adults with advanced or 
recurrent solid tumors who have failed standard therapy, or for whom no effective 
standard therapy is available.
2.2
Secondary objectives 
The secondary objectives are:
To evaluate the safety and tolerability of BAL101553 administered as a 48-hour 
continuous IV infusion.
To assess the antitumor activity of BAL101553 administered as a 48-hour continuous 
IV infusion. 
To assess the PK of BAL101553 and BAL27862 after 48-hour IV infusion; and after 
daily oral administration on study Days 15–21 of Cycle 2 (Phase 1 only). 
2.3
Exploratory objectives
To assess the use of biomarkers to characterize the PD effects of BAL101553, 
administered as a 48-hour continuous IV infusion.
To explore the potential utility of biomarkers in blood and/or tumor tissue as 
predictive biomarkers.
3. STUDY DESIGN
3.1
Overview of study design and dosing regimen
This is a single-agent, open-label, multi-center, Phase 1/2a study of BAL101553, 
administered IV over 48 hours on study Days 1, 8 and 15 of a 28-day treatment cycle.
Additionally, the Phase 1 part of this study aims to determine the bioavailability of oral 
BAL101553 by means of daily administration of BAL101553 capsules on study Days 
15–21 of Cycle 2, i.e., after completion of the MTD-relevant safety assessments in 
Cycle 1. 
The study will be conducted in two parts: a Phase 1 multiple-ascending-dose-escalation 
portion using a 3+3 titration design to determine the MTD, to be carried out in up to 
42 evaluable patients (completed with 16 patients evaluable); and a Phase 2a expansion 
portion to further characterize safety and tolerability of BAL101553 at the MTD (70 
mg/m2) and to obtain efficacy data. The Phase 2a part of the trial will include two target 


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 33 of 109
populations, each with up to 20 evaluable patients: the first will comprise platinum-
resistant/refractory ovarian, fallopian tube or primary peritoneal cancer (collectively 
referred to herein as 'ovarian cancer') patients; and the second will comprise GBM 
patients in first relapse. For each target population, a separate cumulative safety 
evaluation will be performed after six patients have completed their first 28-day cycle or 
have discontinued treatment (see Section 3.2.2.1), and after completion of the first cycle, 
or discontinuation, by each subsequent group of six patients. An overview of the study 
protocol design is presented in Figure 1.
Figure 1
Schematic overview of study design
3.1.1
Treatment cycles
For the Phase 1 part of this study, each treatment cycle will comprise 28 days, during 
which IV BAL101553 will be given as a 48-hour IV infusion on study Days 1, 8 and 15, 
using an elastomeric Baxter pump (pump models 2C4711K or 2C1009KP/2C4009K). 
On study Days 15–21 of Cycle 2, oral BAL101553 capsules will be given daily, instead 
of the Day15 IV infusion (see Section 3.1.2.2). In this phase of the study, patients will be 
replaced if the minimum safety evaluation requirements for assessment of the MTD in 
Cycle 1 have not been met (see Sections 4.5 and 6.6.1.1).
For the Phase 2a part of the study, each treatment cycle will comprise 28 days, during 
which IV BAL101553 will be given as a 48-hour IV infusion starting on study Days 1, 8 
and 15. In this phase of the study, patients will be replaced if they could not complete 
Cycle 1 and Cycle 2, for reasons other than progressive tumor disease (see Sections 3.1.3, 
4.5 and 6.6.1.2).
Section 3.2.4 describes the planned treatment duration. Patients will be allowed to receive 
repeated 28-day treatment cycles until the occurrence of progressive disease, or 
unacceptable toxicity. 
Phase 1 
Dose escalation, 3+3 titration design
Phase 2a 
Treatment at the MTD
Up to 42 evaluable patients
(completed with 16 patients evaluable for MTD 
assessment; 20 patients dosed)
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• Day 8
• Day 15*
*Cycle 2 only: 
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on Days 15–21.
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Target populations:
• Platinum-resistant/refractory ovarian, fallopian tube or 
primary peritoneal cancer patients
• GBM patients in first relapse
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Version 7.0
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age 34 of 109
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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 35 of 109
3.1.3
Expansion portion (Phase 2a)
In December 2017, the MTD was defined as 70 mg/m2; up to 40 additional evaluable 
patients (see Section 4.5.2) will be treated at this dose and evaluated for safety, PK, PD
effects, and for antitumor activity (see Table 6).
The Phase 2a part of the study will include two separate target populations, each with up 
to 20 evaluable patients: the first will comprise platinum-resistant/refractory-ovarian 
cancer patients; and the second will comprise GBM patients in first relapse. 
For each target population, a separate cumulative safety evaluation will be performed 
after six patients have completed their first 28-day cycle or have discontinued treatment 
(see Section 3.2.2.1), and after completion of the first cycle, or discontinuation, by each
subsequent group of six patients. 
BAL101553 treatment will be continued in patients enrolled in the dose-expansion 
portion until disease progression, occurrence of unacceptable toxicity, or until the patient 
withdraws from the study (see Section 4.4). Efficacy assessments to assess objective 
response to treatment must be scheduled at the end of at least each even-numbered 
treatment cycle (e.g., end of Cycle 2, 4, 6, etc.) and subsequent treatment cycles may not 
be initiated if disease progression is observed. Section 5.4.3 provides criteria for 
assessing response, stable disease, and disease progression.
3.1.4
End of study
The end of the study is defined as the completion of the last study-related contact with 
any patient.
3.2
Treatment plan
3.2.1
Phase 1 - intravenous dose-escalation scheme
The planned IV dose-escalation scheme to determine the maximum administered dose 
(MAD) and MTD of IV BAL101553, including the percent increases between the 
planned IV doses and the planned number of patients to be enrolled at each dose level, is 
presented in Table 1. 
Each dose level will utilize a 3+3 dose-escalation design. The number of patients required 
to evaluate a dose level refers to patients who are considered evaluable for MTD
assessment (see definition in Section 4.5). Cohorts of patients will receive increasing 
dose levels of BAL101553 until the MAD is reached. For each cohort, new patients will 
be recruited. The MAD will be defined as the dose level at which DLTs are observed 
during treatment Cycle 1 in two or more of [up to] six patients (i.e., > 33%). The MTD 
will be  defined as the highest tested dose below the MAD with an acceptable tolerability 
profile. A minimum of six patients must be treated at a dose level for it to be declared the 
MTD.
After the planned number of patients have completed at least one cycle of BAL101553 at 
a given dose level and have been evaluated for safety, the members of the Dose-Cohort 
Escalation Committee (DCEC) will decide whether to proceed to the next higher dose 
level (see Section 3.2.1.2). Dose escalation will be primarily based on whether DLTs are 
observed during Cycle 1 at each dose level. However, the dose-escalation decisions must 
also include a clinical review of all relevant available data (including unmonitored data)


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 36 of 109
from the current and previous dose cohorts, and will not be solely based on Cycle 1 DLT 
information. The process for dose-escalation decisions is described in Section 3.2.1.2; a 
summary of the rules governing escalation decisions is presented in Table 3.
Dose increments of approximately 50% are planned from 30 mg/m2 onwards, until 
observation of a DLT. Once a BAL101553-related DLT is observed, the dose level at 
which the toxicity occurred will be expanded [up] to six patients. If no other patients (i.e., 
only one of the six patients) experience a DLT at this level, three patients will be enrolled 
at the next dose level, the increment of which will be approximately 33% (see Table 1). If 
any further patients (i.e., ≥ two of the [up to] six patients) experience a DLT, dose 
escalation must be stopped and this dose will be declared the MAD. Furthermore, at least 
three additional patients must be enrolled at the next lowest dose level, if only three 
patients were previously treated at that dose. Lower and intermediate dose levels may be 
explored to determine the MTD.
If a DLT is observed in any patient in  Cohort 1 (i.e., at a dose of 30 mg/m2), that dose 
level will be expanded [up] to six patients. If ≥ two of these [up to] six patients 
experience a DLT, the dose for the subsequent cohort will be decreased to 15 mg/m2 and 
all subsequent dose levels will be increased by approximately 33%.
There will be a minimum period of observation of 28 days from the first dose of the last 
patient treated at that dose level, to the first dose of the first patient treated at the next 
dose level. There will be a minimum period of observation of 7 days between the first 
doses given to the first and second patients in the cohort. No delay is required between 
the second patient and any subsequent patient enrolled at the same dose level. A delay in 
the start of the second cycle by more than 14 days due to a drug-related AE is considered 
a DLT. Therefore, no patients will be permitted to enroll at a new dose level until all 
patients in the current dose cohort have started treatment in Cycle 2, or have discontinued 
the study for reasons other than drug-related toxicity.
Recommendations for dose delays or dose modifications in patients experiencing 
BAL101553-related toxicities, are described in Section 3.2.3.2. 
The IV dose levels listed in Table 1 are to be considered provisional. Possible changes 
include: 
administration of dose levels below the planned starting dose for the study
expansion of the current dose group
termination of further dose escalation
administration of intermediate dose levels (e.g., between the current and previous dose 
levels, or between the current and the next planned dose level)


BAL101553 
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Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 37 of 109
Table 1
Cohorts 1–4: Planned intravenous dose-escalation levels
Dose 
level 1
Starting dose: 30 mg/m2
NRT
1×DLT*
>1×DLT
Dose 
level 2
45 mg/m2
(50% increase)
40 mg/m2
(33% increase)
MAD
NRT
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>1×DLT
NRT
1×DLT
>1×DLT
Dose 
level 3#
70 mg/m2
(50% increase)
60 mg/m2
(33% increase)
MAD
53 mg/m2
(33% increase)
MAD
NRT
1×DLT
>1×DLT
NRT
1×DLT
>1×DLT
NRT
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Dose 
level 4
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90 mg/m2
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MAD
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MAD
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MAD
NRT = no relevant toxicity; DLT = dose-limiting toxicity; MAD = maximum administered dose.
*Observation of a DLT in any patient will trigger an expansion of the dose level to [up to] six patients.
# The change from dose level 2 (45 mg/m2) to dose level 3 (70 mg/m2) corresponds to a 55% increase.


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age 38 of 109
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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 39 of 109
Further internal or external experts may be included in the DCEC as necessary. Detailed 
information regarding composition, processes, and dose-escalation decisions will be 
provided in the Dose-Escalation Charter.
3.2.1.2.2
Consultation
At scheduled intervals, and ad hoc as needed, DCEC will confer to review and discuss all 
safety information. In particular, a discussion will be held prior to each dose escalation. 
In this conference, safety information including DLT and all ≥CTCAE grade 2 AEs 
during Cycle 1 from the current dose level, will be reviewed. Data collection for this 
review will be coordinated by the Sponsor. Safety information from patients in later 
cycles, updated safety data from ongoing/completed patients from previous levels 
(including intra-patient dose escalation), PK data and efficacy information must also be 
considered. DLT which occurred in Cycle 1 at the current dose level must be considered 
in the dose-escalation decision, however, the dose-escalation decisions will be based on a 
clinical review of all relevant available data from the current and previous dose cohorts. 
Minutes of the conference will be prepared by the Sponsor and approved by the entire 
DCEC. 
After reaching consensus the DCEC will select the actual IV dose for the next cohort of 
patients, based on the planned dose-escalation levels (see Table 1) or intermediate levels 
as a guide. The corresponding cumulative-weekly oral dose will also be selected as 
described in Section 3.1.2.1.
3.2.1.2.3
Dose-escalation criteria
Dose-level expansion and escalation will mainly depend on the occurrence of DLTs 
(Table 2). The process and rules for dose-escalation decisions are presented in Table 3. 
Dose escalation and enrollment of a new cohort will require consultation and agreement 
within the DCEC, after all patients in the previous cohort have completed one cycle of 
dosing and observation, and after a review of all available safety and PK data. The 
magnitude of a dose increment will depend on the observation of drug-related grade 3 
toxicities at the previous dose level (see Section 3.2.1). If toxicities occur that warrant 
inclusion of additional patients to assess the safety profile at a given dose level, the 
DCEC may decide to include a second cohort of [up to] three patients in the absence of a 
DLT. The DCEC may also decide to modify the dose-escalation plan, i.e. reduce the 
increment to the next dose level, in the absence of a DLT or grade 3 toxicity.
Dose escalation must not occur before completion of the first treatment cycle by all 
patients at the preceding dose level, where completion means either occurrence of DLT, 
or administration of the planned dose of BAL101553 on study Days 1, 8 and 15 in 
treatment Cycle 1 and observation for ≥ 28 days of the cycle with safety evaluation. 
Section 4.5 describes the replacement of patients who do not complete at least one 
treatment cycle for reasons other than occurrence of DLT. 
Recommendations for dose delays or dose modifications in patients experiencing 
BAL101553-related toxicities, are described in Section 3.2.3.


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 40 of 109
Table 3
Dose-escalation criteria
Number of patients with DLT in the 
first 3 patients of a dose cohort 1
Escalation decision
0 of 3 patients with DLT
Enroll 3 patients at the next dose level2.
1 of 3 patients with DLT
Enter 3 additional patients at this dose level.
-If only 1 of the 6 patients experiences a DLT, enter 3 
patients at the next-higher dose level2.
-If ≥ 2 of the [up to] 6 patients experience DLT, then dose 
escalation is stopped; this dose is declared the MAD. If only 
3 patients were treated at the previous dose level, at least 3 
additional patients must be enrolled at that dose to 
determine the MTD2.
≥ 2 of 3 patients with DLT
Dose escalation must be stopped. This dose level will be 
declared the MAD. If only 3 patients were treated at the 
previous dose level, at least 3 additional patients must be 
enrolled at that dose to determine the MTD2.
Maximum administered dose (MAD):
The MAD is the dose level with a rate of DLT in ≥ 33% of patients during treatment Cycle 1, i.e.: 
≥ 2 of [up to] 3 patients with DLT in the first 3 patients of a dose level.
≥ 2 of [up to] 6 patients with DLT in a dose level that was expanded to 6 patients.
Maximum tolerated dose (MTD):
The MTD is the highest dose level below the MAD with an acceptable tolerability profile, i.e.:
Not more than 1 of 6 patients with DLT at the highest dose level below the MAD.
At least 6 patients must be treated at the MTD level during the dose-escalation phase.
Intermediate dose levels may be assessed, e.g., if one dose is well tolerated without DLT and the 
subsequent dose level is defined as the MAD.
The number of patients refers to patients evaluable for DLT assessment. DLT=dose-limiting toxicity.
1 Treatment related means causal relationship of the event to BAL101553 is considered to be at least ‘possible’.
2 Refer to Table 1 for descriptions of provisional dose levels.
3.2.1.2.4
Enrollment
Following each consultation and dose-escalation decision, the Principal Investigators of 
all study centers must be notified by the Sponsor of both the IV dose (in mg/m2) and the 
oral dose (in mg) to be given to patients in the new dose cohort. The dose levels will be 
documented in the dose-escalation meeting minutes. Investigators must not enroll 
patients at a new dose level until they have received notification of the consensus 
decision, the agreed new dose level and the start date for enrollment into the new cohort. 
All study centers must notify the Sponsor when a patient is screened (within 24 hours of 
informed consent); when a patient is scheduled for their first dosing (at least 24 hours
prior to the scheduled dosing), after administration of the first dose (within the 24 hours 
after dosing), and when a patient discontinues treatment (within the 24 hours after 
discontinuation, for any reason). 
Dosing of any new patient may only be started after approval by the Sponsor. Approval 
of dosing for new patients must conform to planned dose-level size and the post-dose 
observation periods as described in Section 3.2.1.2. 
The Sponsor must notify all centers when dosing for a new patient has been approved, 
and in addition, must provide a screening/enrollment log for the entire study which will 


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age 42 of 109
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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 43 of 109
Table 4
General guidelines for treatment continuation criteria and recommendations for dose modification
Type of event
(CTCAE grading)
Criteria to start a new 
treatment cycle
Criteria to withhold dose 
within a cycle
Criteria to reduce dose by 
one level
Criteria to resume treatment 
within a cycle
Criteria to withdraw a patient 
from the study
General aspects
Laboratory results consistent 
with enrollment criteria 
(Section 4.2)
See criteria below
Any DLT1 or criterion below
Resolution of DLT1 to 
≤CTCAE grade 1 (or baseline) 
and any criterion below
Any drug-related event which 
delays new cycle by > 14 days
Specific events
Absolute neutrophil 
count (ANC)
≥ 1.5 per 109/L
< 1.0 per 109/L
< 1.0 per 109/L
≥ 1.0 per 109/L
≥ 1.5 per 109/L after DLT
(No specific criteria)
Febrile Neutropenia
None/fully resolved
Any occurrence
Any occurrence
Fully resolved
(No specific criteria)
Thrombocytopenia
≥ 100 per 109/L
< 50 per 109/L
< 50 per 109/L
≥ 75 per 109/L
≥ 100 per 109/L after DLT
(No specific criteria)
Hemoglobin
≥ 9 g/dL
< 6.5 g/dL
< 6.5 g/dL
≥ 8 g/dL
Grade 4 anemia
S-Creatinine (S-Cr)
≤ 1.5 × ULN
> 2.0 × ULN
> 2.5 × ULN
≤ 1.5 × ULN
≥ Grade 3 (S-Cr > 3.0 × ULN)
ALT/AST
≤ 2.5 (5.0)2 × ULN
> 5.0 × ULN (any duration)
> 5.0 × ULN for > 7 days
≤ 3.0 (5.0)2 × ULN
(No specific criteria)
Total bilirubin (TB)
≤ 1.5 (2.0)2 × ULN
> 2.0 (2.5)2 × ULN
>  2.0 (2.5)2 × ULN
≤ 1.5  (2.0)2 × ULN
Grade 4 (TB > 10 × ULN)
Neurotoxicity3
Grade 0 or 1
≥ Grade 2
≥ Grade 2
Grade 0 or 1
≥ Grade 3
Diarrhea4
Grade 0 or 1
≥ Grade 3
≥ Grade 3
Grade 0 or 1
Grade 4
QTcF
≤ 470 ms
> 500 ms or > 60 ms change 
vs baseline4
> 500 ms or > 60 ms change 
vs baseline5
≤ 470 ms
Recurrent QTcF > 500 ms or 
> 60 ms change vs baseline
Other toxicity6,7
≤ Grade 1 (or baseline)
≥ Grade 3
Grade 3
≤ Grade 1 (or baseline)
Grade 4
Abnormal laboratory values must be monitored at least twice per week until resolution to ≤ CTCAE grade 1, or stabilization.
1DLT during Cycle 1, or event of equivalent severity occurring in any subsequent cycle.
2 Refers to patients with tumor involvement of the liver or liver metastases.
3 Consider neurology consultation if neurotoxicity occurs.
4 Despite appropriate medication/management.
5 See Section 5.4.2.6: requires ECG monitoring, clinical assessment, blood sampling for PK assessment and increased ECG monitoring at next dosing.
6 Grade 3 fatigue; grade 3/4 alkaline phosphatase elevations, asymptomatic hypophosphatemia, or lymphopenia; do not require dose delays/modifications unless considered clinically significant.SBP must be 
7 Blood Pressure: BP must be < 140 mmHg and DBP < 90 mmHg prior to dosing on Day 1 of Cycle 1 and Cycle 2. From Cycle 3 onwards SBP must be < 160 mmHg and DBP < 100 mmHg prior to dosing 
on Day 1. If a patient’s systolic BP exceeded 180 mmHg or diastolic BP exceeded 110 mmHg on any dosing day, then systolic BP must be < 140 mmHg and diastolic BP must be < 90 mmHg prior to any 
subsequent dosing.


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 44 of 109
3.2.4
Duration of treatment
All patients will be scheduled to receive two 28-day treatment cycles. 
BAL101553 treatment may be continued after the second 28-day cycle until disease 
progression, occurrence of unacceptable toxicity, or other criteria for discontinuation are 
met (see Section 4.4). To continue treatment beyond two 28-day treatment cycles, 
efficacy assessments scheduled at the end of at least each even-numbered cycle must be 
completed. Subsequent treatment cycles may not be initiated if disease progression is 
observed. In Phase 1, from Cycle 6 onwards, the interval between CT/MRI scans may be 
extended from 8 weeks to 12 weeks. 
Unless treatment is stopped due to occurrence of DLT, patients in the dose-escalation 
portion of the study (Section 3.1.2) will be replaced if they could not complete at least 
one 28-day treatment cycle (see Sections 4.5.1 and 6.6.1.1), and patients in the expansion 
portion of the study (Section 3.1.3) will be replaced if they could not complete at least 
two 28-day treatment cycles (see Sections 4.5.2 and 6.6.1.2), for reasons other than 
progressive disease. 
3.3
Number of patients
A total of up to 56 evaluable patients will be enrolled in the study.
The dose-escalation portion of the study to determine and characterize the MTD of 
BAL101553 administered as a 48-hour infusion has been completed with 20 patients 
dosed and 16 patients evaluable for MTD assessment. Up to 20 evaluable ovarian cancer 
and 20 evaluable GBM patients are expected to be treated in the expansion portion of the 
study, to further characterize the safety and tolerability profile of IV BAL101553 at the 
MTD (70 mg/m2) and to obtain efficacy data in patients with these solid-tumor types.
Assuming approximately 25% drop-out rate, up to 70 patients may be enrolled in total. 
3.4
Study centers
Up to three investigational centers will participate in the dose-escalation portion designed 
to characterize the MTD, and approximately ten investigational centers will participate in 
the expansion portion in patients treated at the MTD. 


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4. STUDY POPULATIONS
4.1
Target populations
4.1.1
Phase 1
Those eligible for enrollment into the study include consenting patients who meet the 
inclusion/exclusion criteria and have:
A histologically- or cytologically-confirmed advanced or recurrent solid tumor, who 
have failed standard therapy, or for whom no effective standard therapy is available,
and who meet the inclusion/exclusion criteria, will be eligible for enrollment into the 
study.
4.1.2
Phase 2a
Those eligible for enrollment into the study include consenting patients who meet the 
inclusion/exclusion criteria and have:
A histologically-confirmed ovarian, fallopian-tube or primary-peritoneal cancer that is 
either platinum-resistant or refractory; or 
A histologically-confirmed GBM in first relapse.
4.2
Inclusion criteria
Patients meeting all of the following inclusion criteria at screening will be eligible for 
enrollment in the study. Informed consent must be obtained within the 28 days prior to 
the start of treatment. Screening evaluations will be performed within the 15 days prior to 
the start of treatment (within 21 to 28 days for radiology assessments). 
Patients meeting all of the following:  
1.
Age 18 years or older.
2.
Patients who have:
a. Phase 1: Histologically- or cytologically-confirmed advanced or recurrent solid 
tumor, who failed standard therapy or for whom no effective standard therapy is 
available.
Patients with brain metastases must have undergone definitive treatment 
(surgery and/or radiation) at least 3 months prior to starting study drug and be 
documented as having stable disease by imaging.
b. Phase 2a: either
i.
Histologically-confirmed ovarian, fallopian tube or primary peritoneal cancer 
(collectively referred to herein as ‘ovarian cancer’) that is either platinum-
resistant (disease progression within 6 months of the last receipt of platinum-
based chemotherapy) or refractory (lack of response or disease progression 
while receiving the most recent platinum-based therapy).
Patients may have received up to four
lines of prior cytotoxic 
chemotherapy, but none of them in the platinum-resistant/refractory setting. 
Confirmed high-grade serous, endometrioid, or carcinosarcoma histotypes 
are permitted. 


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An archived fixed-frozen paraffin-embedded tumor tissue block, or a 
minimum of 15 slides from such a block, must be available, otherwise a 
new tumor biopsy should be obtained in accordance with local institutional 
practices.
Patients must have at least one site of measurable disease as defined by 
RECIST criteria, and no clinical or radiological evidence of bowel 
obstruction.
Patients with brain metastases must have undergone definitive treatment 
(surgery and/or radiation) at least 3 months prior to starting study drug and 
be documented as having stable disease by imaging; or
ii. Histologically-confirmed glioblastoma (GBM) in first relapse, defined as:
progression following initial therapy, i.e., radiation, chemotherapy, or radiation 
+ chemotherapy, with or without prior surgery. 
Patients being treated with steroids must be on a stable or decreasing dose.
3.
Patients with advanced solid tumors (excluding GBM) must have measurable disease 
(according to RECIST v1.1), documented within the 28 days prior to study-drug 
administration. 
Patients with GBM must have measurable disease, defined by contrast-enhancing 
MRI, within the 21 days prior to study-drug administration.
4.
Life expectancy of ≥ 12 weeks.
5.
Acceptable organ and marrow function documented within 15 days prior to starting 
study drug, defined as follows: 
  Absolute neutrophil count ≥ 1.5 × 109/L.
  Platelets ≥ 100 × 109/L. 
  Hemoglobin ≥ 9 g/dL.
  Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN), unless the 
patient has known Gilbert’s syndrome. 
  Aspartate amino transferase (AST) and alanine amino transferase (ALT) ≤ 2.5 × 
institutional ULN or ≤ 5 × ULN in presence of liver metastasis.
  Serum creatinine ≤ 1.5 × institutional ULN, or creatinine clearance ≥60 mL/min 
by Cockcroft-Gault formula.
  Serum sodium ≥ the institutional lower limit of normal (LLN).
6.
Patients (excluding those with GBM) must have an Eastern Cooperative Oncology 
Group (ECOG) performance status ≤ 1, and and those with GBM must have an 
ECOG performance status ≤ 2.
7.
Female patients who are not pregnant or breast-feeding and meet one of the following 
conditions:
  Postmenopausal for at least 1 year.


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  Post-hysterectomy and/or post-bilateral ovariectomy.
  Women of childbearing potential must have a negative serum human chorionic 
gonadotropin (hCG) pregnancy test result and must use highly effective 
contraceptive methods for the duration of the study and for an additional 90 days 
after the last dose of study drug. Highly effective contraceptive methods include 
male or female sterilization (bilateral tubal occlusion or vasectomy); intrauterine 
device (IUD); or combined (estrogen and progesterone containing) hormonal 
contraception (oral, vaginal ring or transdermal patch) with an ethinylestradiol 
dose of at least 30 µg, plus use of male condoms (preferably with spermicides), 
female condoms, a female diaphragm or a cervical cap.
8.
Male patients must agree not to donate sperm from the first dose of study drug until 
90 days after the last dose of study drug. Male patients, without a vasectomy and 
with a partner of childbearing potential, must agree to use condoms during the study 
and for at least 90 days after the last dose of study drug. The patient should be 
instructed that their female partner should use another form of contraception for the 
duration of the study and continue this use for at least 90 days after the last dose of 
study drug.
9.
Signed, written informed consent must be obtained and documented according to the 
International Conference on Harmonization’s Guideline for Good Clinical Practice 
E6 (ICH-GCP) [1], the local regulatory requirements, and the permission to use 
private health information in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA), where required, before performing any study-specific 
screening procedures.
10. Patients must have an implantable venous access system (‘PORT’) at the time of 
screening or must be willing to have a venous access system implanted for the 
purpose of the study. Patients with an existing PORT will be eligible for the study if 
the PORT chamber is made of titanium and the cathether is made of either silicon or 
polyurethane. If a patient has an exisiting PORT made of any other material, their 
eligibility may be approved by the Sponsor, based on the availability of compatibility 
data.
4.3
Exclusion criteria
Patients meeting any of the following exclusion criteria at screening must not be enrolled 
in the study:  
1.
Patients with advanced or recurrent solid tumors (excluding GBM) who: 
Have received chemotherapy, radiotherapy, immunotherapy, or investigational 
agents within the 4 weeks (2 weeks for single fraction of palliative radiotherapy, 
6 weeks for nitrosoureas or mitomycin C) prior to starting study drug; or 
  Have not recovered to ≤Common Terminology Criteria for Adverse Events 
version 4.03 (CTCAE) grade 1 from all side effects of prior therapies, except for 
residual toxicities such as alopecia, which do not pose an ongoing medical risk. 


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Patients 
with 
prostate 
cancer 
must 
have 
discontinued 
anti-androgens 
(e.g., bicalutamide, nilutamide) for at least 6 weeks prior to starting study drug; 
chemical castration with luteinizing hormone-releasing hormone analogues can be 
continued.
Patients with GBM who: 
Have received radiotherapy within the 12 weeks prior to starting study drug, 
unless there is a new area of enhancement consistent with recurrent disease 
outside of the radiation field, or there is histological confirmation of unequivocal 
tumor progression; or
Have received administration of prior antitumor chemotherapy within the 4 weeks 
prior to starting study drug, or within the 6 weeks prior to starting study drug in 
the case of nitrosoureas; or
Have undergone surgical resection within the 4 weeks prior to starting study drug, 
or a stereotactic biopsy/core biopsy within 1 week prior to starting study drug; or
Have been treated previously with bevacizumab.
2.
Patients who have had prior exposure to BAL101553.
3.
Inability to swallow oral medication (Phase 1).
4.
Patients with gastrointestinal disease or those who have had a procedure that is 
expected to interfere with the oral absorption or tolerance of BAL101553 
(e.g., functionally relevant gastrointestinal obstruction, or frequent vomiting) (Phase 
1).
5.
Symptomatic brain metastases or metastatic leptomeningeal disease, indicative of 
active disease. 
6.
Peripheral neuropathy ≥ CTCAE grade 2.
7.
Known human immunodeficiency virus (HIV) infection. 
8.
Known acute or chronic hepatitis B or hepatitis C infection.
9.
Average triple systolic blood pressure (SBP) ≥ 140 mmHg or average triple diastolic 
blood pressure (DBP) ≥ 90 mmHg at the Screening visit. Patients with an initial BP ≥ 
140/90 mmHg may be included if SBP < 140 mmHg and DBP < 90 mmHg is 
confirmed in two subsequent BP measurements on the same day.
10. Blood pressure (BP) combination treatment with more than two antihypertensive 
medications.
11. Any history of cerebral hemorrhage, cerebral aneurysm, or ischemic stroke; or a 
history of transient ischemic attack within 24 months prior to screening.
Acute or subacute intratumoral hemorrhage in patients with GBM, considered by the 
Investigator to be clinically significant. 
Patients with MRI/CT demonstrating old hemorrhage, or a subacute bleed after a 
neurosurgical procedure (biopsy or resection), will be eligible.


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12.Significant cardiac disease or abnormality, including any one of the following:
Left ventricular ejection fraction < 50% at screening (assessed by 
echocardiography).
QTcF > 470 ms on screening ECG or a clinically relevant ECG abnormality.
Congenital long QT syndrome.
History of sustained ventricular tachycardia, ventricular fibrillation or torsades de 
pointes.
Presence of atrial fibrillation with tachyarrhythmia (ventricular response rate > 
100 bpm).
Bradycardia (heart rate < 50 bpm).
Complete left bundle branch block.
Bifascicular block (complete right bundle branch block and anterior or posterior 
left hemiblock).
Myocardial infarction, acute coronary syndrome (including unstable angina), 
coronary revascularization procedures, or coronary arterial bypass grafting within 
6 months prior to starting study drug.
Cardiac troponin (either troponin T or troponin I) above the institutional ULN.
Congestive heart failure of New York Heart Association class III or IV.
13. Uncontrolled intercurrent illness that would unduly increase the risk of toxicity or 
limit compliance with study requirements in the opinion of the Investigator; 
including but not limited to: ongoing or active symptomatic infection, uncontrolled 
diabetes mellitus, unstable or uncompensated cardiac, hepatic, renal, respiratory, or 
psychiatric illness. 
14. Current anticoagulation with warfarin potassium or other coumarin derivates. 
Heparin/low-molecular weight heparin (at prophylaxis or treatment doses), aspirin or 
other oral platelet inhibitors are permitted.
15. Women who are pregnant or breast-feeding. Men or women of reproductive potential 
who are not willing to apply effective birth control during the study and for at least 
90 days after the last dose of study drug in both sexes.
4.4
Criteria for discontinuation of treatment
Patients may continue to receive treatment until disease progression, unacceptable 
toxicity, or another discontinuation criterion is met.
Patients may voluntarily withdraw from the study at any time for any reason. The 
Investigator may also withdraw a patient from the study. If a patient who has received at 
least one partial or complete dose of study drug discontinues at any time, every effort 
must be made to complete the End-of-Study visit. 


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Reasons for discontinuation of treatment must be recorded and may include:

Disease progression.

Adverse event.

Abnormal laboratory value.

Abnormal test procedure result.

Missing both the Day 8 and Day 15 IV doses within a cycle, or a delay of more than 
14 days in the start of a subsequent cycle, due to toxicity.

Requirement for more than two dose-level reductions in a patient due to AEs.

Intercurrent illness that prevents further administration of treatment.

Withdrawal of consent.

Withdrawn from the study at Investigator discretion.

Protocol violation.

Protocol non-compliance.

Lost to follow-up.

New cancer treatment/therapy.

Administrative reasons.

Death.
For all patients who discontinue the study, AE monitoring must be continued for at least 
28 days after the last dose of study drug (see Sections see Sections 7.3.2 and 7.4.2). 
Patients will also be contacted to record antineoplastic therapies received within 28 days 
after discontinuation of study drug (see Section 5.2.18).
For patients who fail to return for the End-of-Study visit, the Investigator must make 
every effort to contact the patient (by telephone or mail correspondence). The outcome of 
this contact must be documented by the Investigator and filed in the Investigator’s study 
file. The reasons for discontinuation of treatment must be recorded in the case report 
form (CRF).
4.5
Evaluability and replacement of patients
4.5.1
Phase 1
Patients in the dose-escalation portion of the study (Section 3.1.2) must meet the 
following minimum evaluation requirements in Cycle 1 to be eligible for MTD 
determination:
Received the correct dose as described in Sections 6.5 and 6.6.1.1.
Received at least one partial or complete dose of BAL101553 and experienced a DLT.
Received all three scheduled doses of BAL101553 (see Section 6.6.1.1) without 
experiencing a DLT (including the ability to initiate treatment Cycle 2), have been 
observed for ≥28 days following the first dose, and have been evaluated for safety.
Patients who do not meet these minimum requirements in the dose-escalation portion of 
the study will be replaced by recruitment of new patients.


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4.5.2
Phase 2a 
For patients to be considered eligible for efficacy analysis in the Phase 2a dose-expansion 
portion of the study (see Section 3.1.3):
The correct dose must be given as described in Sections 6.5 and 6.6.1.2.
Patients with progressive disease must have completed at least Cycle 1 dosing (i.e.,
received study drug on Days 1, 8 and 15), have undergone at least one on-study 
clinical tumor assessment or radiological assessment by RECIST v1.1 guidelines
(ovarian cancer patients) or RANO criteria (GBM patients), and have been evaluated 
for safety.
Patients with stable disease, partial response, or complete response, based on a 
radiological assessment by RECIST v1.1 guidelines (ovarian cancer patients) or 
RANO criteria (GBM patients) at the end of Cycle 2, must have received at least four 
doses of study drug in the first two cycles and have been evaluated for safety. 
Patients who do not fulfill these requirements will be replaced by recruitment of new 
patients.
5. STUDY VISITS, ASSESSMENTS AND PROCEDURES
5.1
Schedule of assessments
A summary of the schedule of assessments to be performed from Screening through to 
the End-of-Study visit is presented in Table 5 for Phase 1 and in Table 6 for Phase 2a.


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Table 5
Phase 1 - Schedule of assessments
Screening
Cycle 1
Cycle 2
Cycle 3 and subsequent cycles
End of 
Study
Day (D) of cycle1
−15 to −1
D1
D8
D15
D22
D28
D1
D8
D15
D21/22†
D28
D1
D8
D15
D22*
D28
Informed consent2
X
Inclusion/exclusion criteria
X
Diagnosis and extent of cancer/prior anticancer therapy
X
Demographics/medical history/baseline medical conditions and 
medications
X
Physical examination/ECOG performance status3
X
X
X
X
X
Vital signs4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood pressure5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG6
X
X
X
X
X
X
X
X
X
X
Echocardiography7
X
X
Chest X-ray8
X
Hematology9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation11
X
X
X
X
X
Urinalysis11
X
X
X
X
X
Cardiac troponin12
X
X
X
X
X
X
X
X
Pregnancy test13
X
X
X
X
X
Radiological assessment of tumor8,14 (RECIST v1.1 criteria)
X
X
X(ENC)
X
Implantable venous access system (PORT system)15
X
BAL101553 administration16
X
X
X
X
X
X
X
X
X
X
Drug dispensing and accountability
X
X
X
X
X
X
X
X
X
X
Adverse events/ Serious adverse events 17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/treatments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for pharmacokinetics18
X
X
X
X
X
X
X
X
Dried-blood-spot analysis (Centogene cards)19
X
Blood for CTC analysis20
X
X
X
X
Tumor biopsy21
X
X
X
X
Archival tumor specimen collection (when available)
X
ENC = even-numbered cycles (Note that from Cycle 6 onwards, the interval between CT/MRI scans may be extended from 8 weeks to 12 weeks).
†Note: Assessments normally scheduled for D22 visits should be performed on D21 of Cycle 2.
*Note: D22 visits are optional from Cycle 3 onwards


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1.
Deviations from the visit schedule by ± 2 days are permitted for reasons other than toxicity, e.g., for administrative reasons or to accommodate travel logistics. D28 assessments of a 
given cycle may be performed on D29 of that cycle, i.e., pre-dose on D1 of the subsequent cycle. 
2.
Informed consent must be obtained within the 28 days prior to D1 of Cycle 1. Screening assessments must be performed and completed within the 15 days prior to D1/Cycle 1, with 
the exception of radiology assessments, which if conducted within the 28 days prior to D1 of Cycle 1, do not need to be repeated during Screening.
3.
For D1 of all cycles, the physical exam and ECOG status must be performed within the 3 days prior to dosing; if the Screening exam was performed ≤ 3 days prior to D1, these do not 
need to be repeated on D1/Cycle 1 (see Sections 5.4.2.3 and 5.4.2.1).
4.
Complete vital signs (see Section 5.4.2.4) will be obtained at Screening, at any D22 in-clinic visit, at the End-of-Study visit, and:
Cycle 1: 
On D1, pre-dose and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 24 h 30 h, 48 h, 52 h, 54 h and 72 h after the start of study-drug infusion. 
On D8 and D15, pre-dose, and 0.5 h and 1 h after the start of study-drug infusion, and at the end of the 48-hour study-drug infusion. 
Cycle 2: 
On D1, pre-dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 24 h, 30 h, 48 h and 72 h after the start of study-drug infusion. 
On D8, pre-dose, and 0.5 h and 1 h after the start of study-drug infusion, and at the end of the 48-hour study-drug infusion.
On D15, pre-dose, and 1 h, 2 h, 4 h and 6 h after the first intake of oral BAL101553.
On D21, pre-dose, and 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 30 h and 48 h after the last intake of oral BAL101553. 
Cycle 3 onwards: Pre-dose, 1 h after the start of study-drug infusion and at the end of the 48-hour study-drug infusion, on all dosing days.
The body weight measurement must be obtained within the 3 days prior to dosing on D1 of all cycles.
5.
Triple BP measurements should be taken at Screening, pre-dose on all dosing days, at any D22 in-clinic visit, and at the End-of-Study visit. Single BP measurements will be obtained:
Cycle 1: 
On D1, every 30 min after the start of the study-drug infusion, until 4 h after the start of the study-drug infusion; and then at 6 h, 8 h, 24 h, 30 h, 48 h, 52 h, 54 h, and 72 h 
after the start of study-drug infusion.
On D8 and D15, 0.5 h and 1 h after the start of study-drug infusion; and at the end of the 48-hour study-drug infusion.
Cycle 2:
On D1, every 30 min after the start of the study-drug infusion, until 4 h after the start of the study-drug infusion; and then at 6 h, 8 h, 24 h, 30 h, 48 h and 72 h after the 
start of study-drug infusion.
On D8, 0.5 h and 1 h after the start of study-drug infusion; and at the end of the 48-hour study-drug infusion.
On D15, 1 h, 2 h, 4 h and 6 h after the first intake of oral BAL101553.
On D21, 0.5 h, 1 h, 2 h, 4 h, 8h, 24 h, 30 h and 48 h after the last intake of oral BAL101553. 
Cycle 3 onwards: 1 h after the start of study-drug infusion and at the end of the 48-hour study-drug infusion, on all dosing days. 
SBP must be < 140 mmHg and DBP < 90 mmHg prior to dosing on D1 of Cycle 1 and Cycle 2. Pre-dose on D8 or D15 of Cycles 1 and 2, and on all dosing days from Cycle 3 
onwards, a patient’s SBP must be < 160 mmHg and DBP < 100 mmHg. If a patient’s SBP is > 180 mmHg or DBP is > 110 mmHg on any dosing day, then their SBP must be 
< 140 mmHg and their DBP < 90 mmHg, prior to any subsequent dosing.
If post-dose SBP ≥ 160 mmHg or DBP ≥100 mmHg occur, triple BP measurements will be taken every 10–15 min until return to SBP/DBP < 160/90 mmHg. Patients should only be 
discharged home once BP levels have stabilized to SBP levels < 160 mmHg and DBP levels < 100 mmHg (see Section 5.4.2.5).


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6.
Three sequential (i.e., triplicate) 12-lead ECG are to be obtained, each separated by ~1 min and all taken within a 5-min time window, at Screening to determine study eligibility of 
patients, at the End-of-Study visit and as follows (see Section 5.4.2.6):
Cycle 1: 
On D1, pre-dose, and 1 h, 2 h, 4 h, 8 h, 24 h, 48 h and 72 h after start of study-drug infusion. 
On D8 and D15, pre-dose, 1 h after the start of study-drug infusion, and at the end of the 48-hour study-drug infusion.
Cycle 2:
On D1, pre-dose; and 1 h, 2 h, 4 h, 8 h, 24 h and 48 h after start of study-drug infusion.
On D8, pre-dose, 1 h after the start of study-drug infusion, and at the end of the 48-hour study-drug infusion.
On D15, pre-dose and 6 h after the first intake of oral BAL101553.
On D21, pre-dose, and 1 h, 2 h, 4 h, 8h, 24 h and 48 h after the last intake of oral BAL101553.
Cycle 3 onwards:
Pre-dose on D1 only.
In patients undergoing intra-patient dose escalation or dose reduction; on D1, D8 and D15 of the first two cycles at each new dose level: prior to and 1 h after the start of study-drug 
infusion, and at the end of the 48-hour study-drug infusion. 
Triplicate 12-lead ECG should also be obtained when patients experience SBP > 200 mmHg or DBP > 110 mmHg, or whenever clinical cardiovascular signs or symptoms occur.
Any abnormal on-study ECG must be transmitted to a central ECG laboratory for evaluation (including QTc assessment).
7.
A transthoracic echocardiography (M-Mode, 2D or 3D) must be performed at Screening and at the End-of-Study visit (see Section 5.4.2.7).
8.
Chest X-ray to establish a baseline for safety assessments, to be repeated as clinically indicated. For tumor assessments where a chest CT scan is performed, a chest X-ray is not 
required. Radiology assessments conducted within the 28 days prior to D1 of Cycle 1 do not need to be repeated during Screening.
9.
Hematology (see Section 5.4.2.8.1) must be performed at each study visit and reviewed:
Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1.
Within 1 day prior to administration of BAL101553 on any other dosing day.
10. Biochemistry (see Section 5.4.2.8.2) must be performed according to the same schedule as Hematology.
11. Coagulation and urinalysis (see Sections 5.4.2.8.4 and 5.4.2.8.5) must be performed and reviewed:
Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1.  
Within 1 day prior to administration of BAL101553 on D1 of all subsequent cycles.
12. Cardiac troponin (see Section 5.4.2.8.3) must be performed and reviewed:
Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1. 
At the end of the 48-hour study-drug infusion on D1 of Cycle 1.
Within 1 day prior to administration of BAL101553 on: Cycle 1 D8 and D15; and Cycle 2 D1, D8 and D15. 
The same test (cardiac troponin-I or troponin-T) must be used consistently for a given patient at Screening and throughout the study.   
13. Women of child-bearing potential must have a negative serum pregnancy test (hCG) at Screening; and a negative serum or urine pregnancy test (hCG) prior to BAL101553 dosing on 
D1 of every cycle and at the End-of-Study visit. Screening labs performed ≤3 days prior to first dosing, and labs performed within 1 day prior to all other in-clinic dosing days, do 
not need to be repeated (see Section 5.4.2.8.6).  


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14. Tumor assessment by radiological exam (CT/MRI scans) will be performed at Screening (or within the 28 days prior to D1) and within the 7 days prior to completion of every even-
numbered cycle, before administration of the next cycle of BAL101553. From Cycle 6 onwards, the interval between CT/MRI scans may be extended from 8 weeks to 12 weeks. The 
End-of-Study assessment does not need to be repeated if an assessment was done within the 28 days prior (see Section 5.4.3.1).
15. Patients who do not have an implantable venous access system (PORT) will undergo (ambulatory) surgery and will receive subsequent training by a qualified nursing team on the use 
and proper handling of the venous access system (see Section 5.4.1.4.6). Implantation of the PORT will be recorded in medical history (see Section 5.4.1.4).
16. On D1 of Cycle 1 and D21 of Cycle 2, patients will be hospitalized up to 3 days after the start of study-drug infusion or first oral-drug administration for serial PK sampling and 
safety monitoring. The pump should be inspected for functionality 1 h after the start of infusion, after the 30-h PK sample, and 2 h prior to the end of infusion. On all other IV dosing 
days, patients must stay in the study unit for at least 1 h after the start of the BAL101553 infusion, and must return to the unit at least 2 h before the end of the 48-hour infusion.
Seven consecutive days of BAL101553 oral dosing (Cycle 2 D15–21) will replace the Cycle 2 D15 IV administration of the drug.
17. Non-serious changes in, or worsening of, a patient’s condition that occur between informed consent and first study-drug administration will be collected as pre-dose medical history 
(see Section 5.4.1.1). If any such occurence is considered to be serious, it will additionally be reported following the procedures of an serious adverse event (SAE), to allow for an 
assessment of serious procedure-related events. All AEs occurring from the time of first study-drug administration to 28 days following the last dose of study drug will be collected
following the procedures outlined in Section 7.3.2.1. AEs occurring between D1 and D28 of Cycle 1 will be assessed against the DLT definitions outlined in Table 2. DLTs will 
additionally be recorded on the End-of-Cycle 1 assessment page of the CRF.
18. Blood PK samples will be collected from all patients at the End-of-Study visit, when a patient reports a DLT (if possible) and as follows (see Section 5.4.4):
Cycle 1: 
On D1, pre-dose, and 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 30 h, 48 h, 52 h, 54 h and 72 h after the start of study-drug infusion.
On D8 and D15, pre-dose, and 1 h and 48 h after the start of study-drug infusion.
Cycle 2:
On D1, pre-dose, and 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 30 h, 48 h and 72h after the start of study-drug infusion.
On D8, pre-dose, and 1 h and 48 h after the start of study-drug infusion.
On D15, pre-dose.
On D21, pre-dose, and 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 30 h and 48 h after oral administration of BAL101553.
The sampling schedule may be amended based on observed PK in humans. In patients undergoing intra-patient dose escalation or dose reduction, blood PK samples will be collected 
during one cycle at each new dose level for a given patient, according to the schedule for Cycle 1 above. 
19. One blood sample (approximately 4 mL) will be obtained in an EDTA-tube pre-dose on D1 of Cycle 1 and distributed onto Centogene filtercards for dried-blood-spot analysis of 
single nucleotide polymorphisms and/or genes involved in drug transport or drug metabolism or potential biomarkers (see Section 5.4.5.1.2).  
20. Samples for CTCs will be taken at at least two study sites, with the goal to obtain samples from at least 50% of patients at each dose level. Samples will be obtained pre-dose on: D1
and D15 of Cycle 1; and D22 of Cycles 1 and 2. Samples for CTCs will also be obtained using the same schedule in patients undergoing intra-patient dose escalation or dose 
reduction, at each new dose level (see Section ). 
21. Where possible, a tumor biopsy will be obtained during Screening if it is agreed to by the patient, is easily accessible, and is deemed safe for the patient. Also, if possible, a post-
treatment biopsy can be obtained on D22 of Cycle 1 and/or Cycle 2. Additional post-treatment biopsies may be obtained on D22 of one subsequent cycle after Cycle 2, or at 
progressive disease (see Section 5.4.5.2).


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Table 6
Phase 2a - Schedule of assessments
Screening
Cycle 1
Cycle 2
Cycle 3 and subsequent cycles
End of 
Study
**
Day (D) of cycle1
−15 to −1
D1
D8
D15
D22
D28
D1
D8
D15
D22
D28
D1
D8
D15
D22*
D28
Informed consent2
X
Inclusion/exclusion criteria
X
Diagnosis and extent of cancer/prior anticancer therapy3
X
Demographics/medical history/baseline medical conditions and medications
X
Physical examination/ECOG performance status4
X
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood pressure6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG7
X
X
X
X
X
X
X
X
X
Echocardiography8
X
X
Chest X-ray9
X
Hematology10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation12
X
X
X
X
X
Urinalysis12
X
X
X
X
X
Cardiac troponin13
X
X
X
X
X
X
X
X
Pregnancy test14
X
X
X
X
X
Radiological assessment of tumor9,15 (RECIST v1.1/RANO criteria)
X
X
X(ENC)
X
CA-125 monitoring (ovarian cancer patients only)
X
X
X(ENC)
X
Implantable venous access system (PORT system)16
X
BAL101553 administration17
X
X
X
X
X
X
X
X
X
Drug dispensing and accountability
X
X
X
X
X
X
X
X
X
Adverse events/ Serious adverse events 18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/treatments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for pharmacokinetics19
X
X
X
X
X
Dried-blood-spot analysis (Centogene cards)20
X
Blood for CTC analysis (ovarian cancer patients only)21
X
X
X
X
Tumor biopsy (ovarian cancer patients only)22
X
X
X
X
Archival tumor specimen collection (when available)
X
ENC = even-numbered cycles.
*Note: D22 visits are optional from Cycle 3 onwards
**Note: For patients in the Phase 2a portion of the study  who did not have disease progression at the end of the 28-day safety follow-up period, the patient and/or their treating physicians will also be contacted 
at 4 months and 6 months after the date of their first study-drug administration for the purpose of assessing progression-free survival.


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1.
Deviations from the visit schedule by ± 2 days are permitted for reasons other than toxicity, e.g., for administrative reasons or to accommodate travel logistics. D28 assessments of a 
given cycle may be performed on D29 of that cycle, i.e., pre-dose on D1 of the subsequent cycle. 
2.
Informed consent must be obtained within the 28 days prior to D1 of Cycle 1. Screening assessments must be performed and completed within the 15 days prior to D1/Cycle 1, with 
the exception of radiology assessments, which if conducted within 21 days (GBM patients) or 28 days (ovarian cancer patients) prior to D1 of Cycle 1, do not need to be repeated 
during Screening.
3.
This includes results available regarding BRCA1/BRCA2 mutation status in patients with ovarian cancer and IDH mutation status in GBM patients.
4.
For D1 of all cycles, the physical exam and ECOG status must be performed within the 3 days prior to dosing; if the Screening exam was performed ≤ 3 days prior to D1, these do not 
need to be repeated on D1/Cycle 1 (see Sections 5.4.2.3 and 5.4.2.1).
5.
Complete vital signs (see Section 5.4.2.4) will be obtained at Screening, at any D22 in-clinic visit, at the End-of-Study visit, and:
Cycle 1: 
On D1, pre-dose; 0.5 h, 1 h, 2 h, 4 h and 24–30 h after the start of study-drug infusion; at the end of infusion; and 6 h and 24–48* h after the end of infusion. 
*Patients treated prior to the first Safety Evaluation only.
All other dosing days: pre-dose, 1 h after the start of study-drug infusion, and at the end of infusion.
The body weight measurement must be obtained within the 3 days prior to dosing on D1 of all cycles.
6.
Triple BP measurements should be taken at Screening, pre-dose on all dosing days, at any D22 in-clinic visit, and at the End-of-Study visit. Single BP measurements will be obtained:
Cycle 1: 
On D1, 0.5 h, 1 h, 2 h, 4 h and 24–30 h after the start of study-drug infusion; at the end of infusion; and 6 h and 24–48* h after the end of infusion.
*Patients treated prior to the first Safety Evaluation only.
All other dosing days: 1 h after the start of study-drug infusion, and at the end of infusion.
SBP must be < 140 mmHg and DBP < 90 mmHg prior to dosing on D1 of Cycle 1 and Cycle 2. Pre-dose on D8 or D15 of Cycles 1 and 2, and on all dosing days from Cycle 3 
onwards, a patient’s SBP must be < 160 mmHg and DBP < 100 mmHg. If a patient’s SBP is > 180 mmHg or DBP is > 110 mmHg on any dosing day, then their SBP must be 
< 140 mmHg and their DBP < 90 mmHg, prior to any subsequent dosing.
If post-dose SBP ≥ 160 mmHg or DBP ≥100 mmHg occur, triple BP measurements will be taken every 10–15 min until return to SBP/DBP < 160/90 mmHg. Patients should only be 
discharged home once BP levels have stabilized to SBP levels < 160 mmHg and DBP levels < 100 mmHg (see Section 5.4.2.5).
7.
Three sequential (i.e., triplicate) 12-lead ECG are to be obtained, each separated by ~1 min and all taken within a 10-min time window, at Screening to determine study eligibility of 
patients, at the End-of-Study visit and as follows (see Section 5.4.2.6):
Cycle 1: 
On D1, pre-dose; 1 h, 2 h, 4 h and 24–30 h after the start of study-drug infusion; at the end of infusion; and 6 h and 24–48* h after the end of infusion. 
*Patients treated prior to the first Safety Evaluation only.
All other dosing days in Cycles 1 and 2:
pre-dose, 1 h after start of study-drug infusion, and at the end of infusion.
Cycle 3 onwards:
Pre-dose on D1 only.
Triplicate 12-lead ECG should also be obtained when patients experience SBP > 200 mmHg or DBP > 110 mmHg, or whenever clinical cardiovascular signs or symptoms occur.
Any abnormal on-study ECG must be transmitted to a central ECG laboratory for evaluation (including QTc assessment).


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8.
A transthoracic echocardiography (M-Mode, 2D or 3D) must be performed at Screening and at the End-of-Study visit (see Section 5.4.2.7).
9.
Chest X-ray to establish a baseline for safety assessments, to be repeated as clinically indicated. For tumor assessments where a chest CT scan is performed, a chest X-ray is not 
required. Radiology assessments conducted within 21 days (GBM patients)  or 28 days (ovarian cancer patients) prior to D1 of Cycle 1 do not need to be repeated during Screening.
10. Hematology (see Section 5.4.2.8.1) must be performed at each study visit and reviewed:
Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1.
Within 1 day prior to administration of BAL101553 on any other dosing day.
11. Biochemistry (see Section 5.4.2.8.2) must be performed according to the same schedule as Hematology.
12. Coagulation and urinalysis (see Sections 5.4.2.8.4 and 5.4.2.8.5) must be performed and reviewed:
At Screening and at the End-of-Study visit
Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1.  
Within 1 day prior to administration of BAL101553 on D1 of all subsequent cycles.
13. Cardiac troponin (see Section 5.4.2.8.3) must be performed and reviewed:
At Screening and at the End-of-Study visit
Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1. 
At the end of the 48-hour study-drug infusion on D1 of Cycle 1.
Within 1 day prior to administration of BAL101553 on: Cycle 1 D8 and D15; and Cycle 2 D1, D8 and D15. 
The same test (cardiac troponin-I or troponin-T) must be used consistently for a given patient at Screening and throughout the study.   
14. Women of child-bearing potential must have a negative serum pregnancy test (hCG) at Screening; and a negative serum or urine pregnancy test (hCG) prior to BAL101553 dosing on 
D1 of every cycle and at the End-of-Study visit. Screening labs performed ≤3 days prior to first dosing, and labs performed within 1 day prior to all other in-clinic dosing days, do 
not need to be repeated (see Section 5.4.2.8.6).  
15. Tumor assessment by radiological exam (CT/MRI scans) and CA-125 monitoring (only in ovarian cancer patients) will be performed at Screening, or within the 28 days prior to D1 
(within the 21 days prior to D1 for GBM patients); and within the 7 days prior to completion of every even-numbered cycle, before administration of the next cycle of BAL101553. 
The End-of-Study assessment does not need to be repeated if an assessment was done within the 28 days prior (see Section 5.4.3.1).
16. Patients who do not have an implantable venous access system (PORT) will undergo (ambulatory) surgery and will receive subsequent training by a qualified nursing team on the use 
and proper handling of the venous access system (see Section 5.4.1.4.6). Implantation of the PORT will be recorded in medical history (see Section 5.4.1.4).
17. On D1 of Cycle 1, patients may be hospitalized up to 3 days after the start of study-drug infusion for serial PK sampling and safety monitoring (see Section 6.5). The pump should be 
inspected for functionality 1 h after the start of infusion, after the 24–30-h PK sample, and 2 h prior to the end of infusion. On all other IV dosing days, patients must stay in the study 
center for at least 1 h after the start of the BAL101553 infusion, and must return to the unit at least 2 h before the end of the 48-hour infusion. 
18. Non-serious changes in, or worsening of, a patient’s condition that occur between informed consent and first study-drug administration will be collected as pre-dose medical history 
(see Section 5.4.1.1). If any such occurence is considered to be serious, it will additionally be reported following the procedures of an serious adverse event (SAE), to allow for an 
assessment of serious procedure-related events. All AEs occurring from the time of first study-drug administration to 28 days following the last dose of study drug will be collected 
following the procedures outlined in Section 7.3.2.1. 


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19. Blood PK samples will be collected from all patients at the End-of-Study visit and as follows (see Section 5.4.4): 
Cycle 1: 
On D1, pre-dose; 1 h, 4 h and 24–30 h after the start of study-drug infusion; at the end of infusion; and 6 h and 24–48* h after the end of infusion.
On D8, pre-dose and at the end of infusion.
*Patients treated prior to the first Safety Evaluation only.
Cycle 2:
on D1 and D8, pre-dose and at the end of infusion.
In patients undergoing intra-patient dose reduction: at each new dose level, D1 and D8 of the first cycle: pre-dose and at the end of infusion.
The sampling schedule may be amended based on observed PK in humans. 
20. One blood sample (approximately 4 mL) will be obtained in an EDTA-tube pre-dose on D1 of Cycle 1 and distributed onto Centogene filtercards for dried-blood-spot analysis of 
single nucleotide polymorphisms and/or genes involved in drug transport or drug metabolism or potential biomarkers (see Section 5.4.5.1.2).  
21. Samples for CTCs will be taken at at least two study centers, with the goal to obtain samples from at least 50% of ovarian cancer patients. Samples will be obtained pre-dose on: D1 
and D15 of Cycle 1; and D22 of Cycles 1 and 2 (see Section 5.4.5.1). Samples for CTC analysis will not be obtained from GBM patients.
22. Where possible, a tumor biopsy will be obtained from ovarian cancer patients during Screening if it is agreed to by the patient, is easily accessible, and is deemed safe for the patient. 
Also, if possible, a post-treatment biopsy can be obtained on D22 of Cycle 1 and/or Cycle 2. Additional post-treatment biopsies may be obtained on D22 of one subsequent cycle after 
Cycle 2, or at progressive disease (see Section 5.4.5.2). Tumor biopsies will not be obtained from GBM patients.


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5.2
Study visits
Informed consent must be obtained within the 28 days prior to Cycle 1, Day 1. Patients 
must provide written informed consent before any study-specific screening assessments 
are performed. Study centers must maintain a log of all consenting patients, which must 
include date of consent.
AEs must be monitored on an ongoing basis and at each study visit. AE monitoring must 
be continued for at least 28 days following the last dose of study drug (see Section 5.2.17
and Section 7.3.2).
Deviations from the visit schedule by ± 2 days are permitted for reasons other than 
toxicity, e.g., for administrative reasons or to accommodate travel logistics. Day 28 
assessments of a given cycle may be performed on Day 29 of that cycle, i.e., pre-dose on 
Day 1 of the subsequent cycle. 
5.2.1
Screening visit
Patients will be assigned a subject number once they have provided consent. Patients are 
considered to be enrolled in the study once it is confirmed that they meet all of the 
eligibility criteria for the study, as confirmed by the Sponsor.
Screening assessments must be performed in accordance with Table 5 (Phase 1) and 
Table 6 (Phase 2a) and completed within the 15 days prior to Day 1 of Cycle 1, with the 
exception of radiology assessments (see below).
The following assessments and procedures are to be performed at the Screening visit:
Patient demographics.
Medical history, baseline medical conditions, and prior and concomitant current 
medications/treatments, as described in Section 5.4.1.
Available results of BRCA1/BRCA2 mutation status in patients with ovarian cancer
and IDH mutation status in GBM patients.
Physical examination, as described in Section 5.4.2.3. 
Complete vital signs, as described in Section 5.4.2.4.
BP measurements, as described in Section 5.4.2.5.
Triplicate 12-lead ECGs, according to Section 5.4.2.6.
Transthoracic echocardiography, as described in Section 5.4.2.7.
A chest X-ray to establish a baseline for safety assessments, to be repeated as 
clinically indicated.
o For tumor assessments where a chest CT scan is performed, a chest X-ray is not 
required. 
o Radiology assessments conducted within 28 days (excluding GBM patients) or 21 
days (GBM patients) prior to Day 1 of Cycle 1 do not need to be repeated during 
Screening.
Tumor assessment by radiological exam (CT/MRI scans), as described in Section 
5.4.3.1.
CA-125 in ovarian cancer patients.
Laboratory safety tests (hematology, biochemistry, coagulation, cardiac troponin and 
urinalysis), as described in Section 5.4.2.8. 


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Women of child-bearing potential must have a negative serum pregnancy test (hCG), 
as described in Section 5.4.2.8.6 (see also Section 7.3).
ECOG performance status, as described in 5.4.2.1.
PORT sytem implantation, as described in Section 5.4.1.4.6.
Tumor biopsy, if easily accessible, agreed to by the patient, and deemed safe for the 
patient, as described in Sections 5.4.5 and 5.4.5.2 (excluding GBM patients).
Collection of archival tumor specimen, as described in Section 5.4.5.3.
5.2.2
Day 1 of Cycle 1 
Eligible patients enrolled in the study will return to clinic on study Day 1. Assessments 
must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 2a).
Screening labs, physical exams, and ECOG assessments performed within the 3 days
prior to first dosing do not need to be repeated.
The following assessments and procedures are to be performed at the Cycle 1/Day 1 visit:
Study-drug dispensing, administration and accountability.
Concomitant medications/treatments, as described in Section 5.4.1.
Physical examination, as described in Section 5.4.2.3. 
Complete vital signs, as described in Section 5.4.2.4:
o Phase 1: pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 24, 30, 48, 52, 54 and 72 hours after the 
start of study-drug infusion.
o Phase 2a: pre-dose; 0.5, 1, 2, 4 and 24–30 hours after the start of study-drug 
infusion; at the end of infusion; and 6 and 24–48* hours after the end of infusion.
BP measurements as described in Section 5.4.2.5:
o Phase 1: pre-dose, every 30 min, until 4 hours after the start of the study-drug 
infusion, and then at 6, 8, 24, 30, 48, 52, 54 and 72 hours after the start of study-
drug infusion.
o Phase 2a: pre-dose; 0.5, 1, 2, 4 and 24–30 hours after the start of study-drug 
infusion; at the end of infusion; and 6 and 24–48* hours after the end of infusion.
o If post-dose SBP ≥ 160 mmHg or DBP ≥100 mmHg occur, BP should be monitored 
every 10–15 min until return to SBP/DBP < 160/90 mmHg. 
Triplicate 12-lead ECGs, according to Section 5.4.2.6:
o Phase 1: pre-dose, and 1, 2, 4, 8, 24, 48 and 72 hours after the start of study-drug 
infusion.
o Phase 2a: pre-dose; 1, 2, 4 and 24–30 hours after the start of study-drug infusion; at 
the end of infusion; and 6 and 24–48* hours after the end of infusion.
o Triplicate 12-lead ECG should also be obtained when patients experience SBP 
> 200 mmHg or DBP > 110 mmHg, or whenever clinical cardiovascular signs or 
symptoms occur.
Laboratory safety tests (hematology, biochemistry, coagulation, cardiac troponin and 
urinalysis), as described in Section 5.4.2.8:
o Analyses must be performed and reviewed within the 3 days prior to BAL101553 
administration.
o One additional troponin assessment needs to be performed at the end of the study-
drug infusion.


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Women of child-bearing potential must have a negative pregnancy test (hCG), prior to 
dosing, as described in Section 5.4.2.8.6 (see also Section 7.3):
o Analyses must be performed and reviewed within the 3 days prior to BAL101553 
administration.
Blood samples for PK analysis, as described in Section 5.4.4:
o Phase 1: Pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48, 52, 54 and 72 hours after the start 
of study-drug infusion.
o Phase 2a: Pre-dose; 1, 4 and 24–30 hours after the start of study-drug infusion; at 
the end of infusion; and 6 and 24–48* hours after the end of infusion.
Blood sample collection for biomarker analysis, as described in Section 5.4.5.1:
o Dried-blood-spot analysis: pre-dose.
o CTC analysis: pre-dose (excluding GBM patients).
ECOG performance status, as described in 5.4.2.1.
Recording of changes in, or worsening of, a patient’s condition and AE monitoring, as 
described in Section 7.3.2.
*Patients treated prior to the first Safety Evaluation only.
5.2.3
Day 8 of Cycle 1
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the Cycle 1/Day 8 visit:
Study-drug dispensing, administration and accountability.
Concomitant medications/treatments, as described in Section 5.4.1.
Complete vital signs, as described in Section 5.4.2.4:
o Phase 1: pre-dose, 0.5 hours and 1 hour after the start of study-drug infusion, and at 
the end of the 48-hour study-drug infusion.
o Phase 2a: pre-dose, 1 hour after the start of study-drug infusion, and at the end of 
infusion.
BP measurements as described in Section 5.4.2.5: 
o Phase 1: pre-dose, 0.5 hours and 1 hour after the start of the study-drug infusion, 
and at the end of the 48-hour study-drug infusion.
o Phase 2a: pre-dose, 1 hour after the start of study-drug infusion, and at the end of 
infusion.
o If post-dose SBP ≥ 160 mmHg or DBP ≥100 mmHg occur, BP should be monitored 
every 10–15 min until return to SBP/DBP < 160/90 mmHg. 
Triplicate 12-lead ECGs, according to Section 5.4.2.6:
o Pre-dose, 1 hour after the start of the study-drug infusion, and at the end of infusion
(Phase 1 and Phase 2a). 
o Triplicate 12-lead ECG should also be obtained when patients experience SBP 
> 200 mmHg or DBP > 110 mmHg, or whenever clinical cardiovascular signs or 
symptoms occur.
Laboratory safety tests (hematology, biochemistry and cardiac troponin), as described 
in Section 5.4.2.8:


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o Analyses must be performed and reviewed within 1 day prior to BAL101553 
administration.
Blood samples for PK analysis, as described in Section 5.4.4:
o Phase 1: pre-dose, 1 hour and 48 hours after the start of study-drug infusion.
o Phase 2a: pre-dose and at the end of infusion.
AE monitoring, as described in Section 7.3.2.
5.2.4
Day 15 of Cycle 1
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the Cycle 1/Day 15 
visit:
Study-drug dispensing, administration and accountability.
Concomitant medications/treatments, as described in Section 5.4.1.
Complete vital signs, as described in Section 5.4.2.4:
o Phase 1: pre-dose, 0.5 hours and 1 hour after the start of study-drug infusion, and at 
the end of the 48-hour study-drug infusion.
o Phase 2a: pre-dose, 1 hour after the start of study-drug infusion, and at the end of 
infusion.
BP measurements as described in Section 5.4.2.5: 
o Phase 1: pre-dose, 0.5 hours and 1 hour after the start of the study-drug infusion, 
and at the end of the 48-hour study-drug infusion.
o Phase 2a: pre-dose, 1 hour after the start of study-drug infusion, and at the end of 
infusion.
o If post-dose SBP ≥ 160 mmHg or DBP ≥100 mmHg occur, BP should be monitored 
every 10–15 min until return to SBP/DBP < 160/90 mmHg. 
Triplicate 12-lead ECGs, according to Section 5.4.2.6:
o Pre-dose, 1 hour after the start of the study-drug infusion, and at the end of infusion
(Phase 1 and Phase 2a).
o Triplicate 12-lead ECG should also be obtained when patients experience SBP 
> 200 mmHg or DBP > 110 mmHg, or whenever clinical cardiovascular signs or 
symptoms occur.
Laboratory safety tests (hematology, biochemistry and cardiac troponin), as described 
in Section 5.4.2.8:
o Analyses must be performed and reviewed within 1 day prior to BAL101553 
administration.
Blood samples for PK analysis, as described in Section 5.4.4 (Phase 1 only):
o Pre-dose, 1 hour and 48 hours after the start of study-drug infusion.
Blood sample collection for biomarker analysis, as described in Section 5.4.5.1:
o CTC analysis: pre-dose (excluding GBM patients).
AE monitoring, as described in Section 7.3.2.
5.2.5
Day 22 of Cycle 1
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 


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Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 64 of 109
The following assessments and procedures are to be performed at the Cycle 1/Day 22
visit:
Concomitant medications/treatments, as described in Section 5.4.1.
Complete vital signs, as described in Section 5.4.2.4.
BP measurements as described in Section 5.4.2.5.
Laboratory safety tests (hematology and biochemistry), as described in Section 
5.4.2.8. 
Blood sample collection for biomarker analysis, as described in Section 5.4.5.1:
o CTC analysis (excluding GBM patients).
Tumor biopsy, if easily accessible, agreed to by the patient, and deemed safe for the 
patient, as described in Section 5.4.5.2 (excluding GBM patients).
o Note: the blood sample for biomarker analysis should be obtained prior to tumor 
biopsy.
AE monitoring, as described in Section 7.3.2.
5.2.6
Day 28 of Cycle 1
Day 28 assessments of a given cycle may be performed on Day 29 of that cycle, i.e., pre-
dose on Day 1 of the subsequent cycle.
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the Cycle 1/Day 28
visit:
Concomitant medications/treatments, as described in Section 5.4.1.
AE monitoring, as described in Section 7.3.2.
5.2.7
Day 1 of Cycle 2
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the Cycle 2/Day 1 visit:
Study-drug dispensing, administration and accountability.
Concomitant medications/treatments, as described in Section 5.4.1.
Physical examination, as described in Section 5.4.2.3. 
Complete vital signs, as described in Section 5.4.2.4:
o Phase 1: pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 24, 30, 48 and 72 hours after the start of 
study-drug infusion.
o Phase 2a: pre-dose, 1 hour after the start of study-drug infusion, and at the end of 
infusion.
BP measurements as described in Section 5.4.2.5: 
o Phase 1: pre-dose, every 30 min until 4 h after the start of the study-drug infusion, 
and then at 6, 8, 24, 30, 48 and 72 hours after the start of study-drug infusion.
o Phase 2a: pre-dose, 1 hour after the start of study-drug infusion, and at the end of
infusion.


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 65 of 109
o If post-dose SBP ≥ 160 mmHg or DBP ≥100 mmHg occur, BP should be monitored 
every 10–15 min until return to SBP/DBP < 160/90 mmHg. 
Triplicate 12-lead ECGs, according to Section 5.4.2.6:
o Phase 1: pre-dose, and 1, 2, 4, 8, 24 and 48 hours after the start of study-drug 
infusion.
o Phase 2a: pre-dose, 1 hour after the start of the study-drug infusion, and at the end 
of infusion.
o Triplicate 12-lead ECG should also be obtained when patients experience SBP 
> 200 mmHg or DBP > 110 mmHg, or whenever clinical cardiovascular signs or 
symptoms occur.
Laboratory safety tests (hematology, biochemistry, coagulation, cardiac troponin and 
urinalysis), as described in Section 5.4.2.8:
o Analyses must be performed and reviewed within 1 day prior to BAL101553 
administration.
Women of child-bearing potential must have a negative pregnancy test (hCG), prior to 
dosing, as described in Section 5.4.2.8.6 (see also Section 7.3):
o Analyses must be performed and reviewed within 1 day prior to BAL101553 
administration.
Blood samples for PK analysis, as described in Section 5.4.4:
o Phase 1: Pre-dose, and 0.5, 1, 2, 4, 8, 24, 30, 48 and 72 hours after the start of 
study-drug infusion.
o Phase 2a: pre-dose and at the end of infusion.
ECOG performance status, as described in 5.4.2.1.
AE monitoring, as described in Section 7.3.2.
5.2.8
Day 8 of Cycle 2
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the Cycle 2/Day 8 visit:
Study-drug dispensing, administration and accountability.
Concomitant medications/treatments, as described in Section 5.4.1.
Complete vital signs, as described in Section 5.4.2.4:
o Phase 1: pre-dose, 0.5 hours and 1 hour after the start of study-drug infusion, and at 
the end of the 48-hour study-drug infusion.
o Phase 2a: pre-dose, 1 hour after the start of study-drug infusion, and at the end of 
infusion.
BP measurements as described in Section 5.4.2.5: 
o Phase 1: pre-dose, 0.5 hours and 1 hour after the start of the study-drug infusion, 
and at the end of the 48-hour study-drug infusion.
o Phase 2a: pre-dose, 1 hour after the start of study-drug infusion, and at the end of 
infusion.
o If post-dose SBP ≥ 160 mmHg or DBP ≥100 mmHg occur, BP should be monitored 
every 10–15 min until return to SBP/DBP < 160/90 mmHg. 
Triplicate 12-lead ECGs, according to Section 5.4.2.6:


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age 66 of 109
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BAL101553 
Clinical Study
Confidential –
AE moni
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Assessments
The followi
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Study-dru
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October 2018
age 67 of 109
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BAL101553 
Clinical Study
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The followi
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5.4.2.8. 
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October 2018
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or to tumor 


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 69 of 109
5.2.11
Day 28 of Cycle 2
Day 28 assessments of a given cycle may be performed on Day 29 of that cycle, i.e., pre-
dose on Day 1 of the subsequent cycle.
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the Cycle 2/Day 28 
visit:
Concomitant medications/treatments, as described in Section 5.4.1.
Tumor assessment by radiological exam (CT/MRI scans) and CA-125 assessment:
o May be performed at any time within the 7 days prior to completion of every even-
numbered cycle, before administration of the next cycle of BAL101553. 
AE monitoring, as described in Section 7.3.2.
5.2.12
Day 1 of Cycle 3 onwards
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the Cycle 3 onwards/
Day 1 visit:
Study-drug dispensing, administration and accountability.
Concomitant medications/treatments, as described in Section 5.4.1.
Physical examination, as described in Section 5.4.2.3. 
Complete vital signs, as described in Section 5.4.2.4:
o Pre-dose, 1 hour after the start of study-drug infusion, and at the end of the 48-hour 
study-drug infusion.
BP measurements as described in Section 5.4.2.5:
o Pre-dose, 1 hour after the start of study-drug infusion, and at the end of the 48-hour 
study-drug infusion.
Triplicate 12-lead ECGs, according to Section 5.4.2.6:
o Prior to the start of study-drug infusion.
o Triplicate 12-lead ECG should also be obtained when patients experience SBP 
> 200 mmHg or DBP > 110 mmHg, or whenever clinical cardiovascular signs or 
symptoms occur.
Laboratory safety tests (hematology, biochemistry, coagulation, and urinalysis), as 
described in Section 5.4.2.8:
o Analyses must be performed and reviewed within 1 day prior to BAL101553 
administration.
Women of child-bearing potential must have a negative pregnancy test (hCG), prior to 
dosing, as described in Section 5.4.2.8.6 (see also Section 7.3):
o Analyses must be performed and reviewed within 1 day prior to BAL101553 
administration.
ECOG performance status, as described in 5.4.2.1.
AE monitoring, as described in Section 7.3.2.


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 70 of 109
5.2.13
Day 8 of Cycle 3 onwards
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the Cycle 3 onwards/
Day 8 visit:
Study-drug dispensing, administration and accountability.
Concomitant medications/treatments, as described in Section 5.4.1.
Complete vital signs, as described in Section 5.4.2.4:
o Pre-dose, 1 hour after the start of study-drug infusion, and at the end of the 48-hour 
study-drug infusion.
BP measurements as described in Section 5.4.2.5:
o Pre-dose, 1 hour after the start of study-drug infusion, and at the end of the 48-hour 
study-drug infusion.
Laboratory safety tests (hematology and biochemistry), as described in Section 
5.4.2.8:
o Analyses must be performed and reviewed within 1 day prior to BAL101553 
administration.
AE monitoring, as described in Section 7.3.2.
5.2.14
Day 15 of Cycle 3 onwards
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the Cycle 3 onwards/
Day 15 visit:
Study-drug dispensing, administration and accountability.
Concomitant medications/treatments, as described in Section 5.4.1.
Complete vital signs, as described in Section 5.4.2.4:
o Pre-dose, 1 hour after the start of study-drug infusion, and at the end of the 48-hour 
study-drug infusion.
BP measurements as described in Section 5.4.2.5:
o Pre-dose, 1 hour after the start of study-drug infusion, and at the end of the 48-hour 
study-drug infusion.
Laboratory safety tests (hematology and biochemistry), as described in Section 
5.4.2.8:
o Analyses must be performed and reviewed within 1 day prior to BAL101553 
administration.
AE monitoring, as described in Section 7.3.2.
5.2.15
Day 22 of Cycle 3 onwards 
Day 22 visits are optional from Cycle 3 onwards. However, if a Day 22 visit is scheduled,
the following assessments should be performed:
Concomitant medications/treatments, as described in Section 5.4.1.
Complete vital signs, as described in Section 5.4.2.4.


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 71 of 109
BP measurements as described in Section 5.4.2.5. 
Laboratory 
safety 
tests 
(hematology 
and 
biochemistry), 
as 
described 
in 
Section 5.4.2.8.
Tumor biopsy, if easily accessible, agreed to by the patient, and deemed safe for the 
patient, as described in Section 5.4.5.2 (excluding GBM patients).
AE monitoring, as described in Section 7.3.2.
5.2.16
Day 28 of Cycle 3 onwards
Day 28 assessments of a given cycle may be performed on Day 29 of that cycle, i.e., pre-
dose on Day 1 of the subsequent cycle.
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the Cycle 3 
onwards/Day 28 visit:
Concomitant medications/treatments, as described in Section 5.4.1.
Tumor assessment by radiological exam (CT/MRI scans) and CA-125 assessment:
o Even-numbered cycles only.
o May be performed at any time within the 7 days prior to completion of every even-
numbered cycle, before administration of the next cycle of BAL101553. 
o In Phase 1, from Cycle 6 onwards, the interval between CT/MRI scans may be 
extended from 8 weeks to 12 weeks.
AE monitoring, as described in Section 7.3.2.
5.2.17
End-of-Study visit
End-of-Study assessments are to be performed in patients who no longer receive 
BAL101553 treatment, and should take place within 7 days after the decision to 
discontinue treatment. 
Assessments must be performed in accordance with Table 5 (Phase 1) and Table 6 (Phase 
2a). 
The following assessments and procedures are to be performed at the End-of-Study visit:
Concomitant medications/treatments, as described in Section 5.4.1.
Physical examination, as described in Section 5.4.2.3. 
Complete vital signs, as described in Section 5.4.2.4.
BP measurements, as described in Section 5.4.2.5.
Triplicate 12-lead ECGs, according to Section 5.4.2.6.
Transthoracic echocardiography, as described in Section 5.4.2.7.
Laboratory safety tests (hematology, biochemistry, coagulation, cardiac troponin and 
urinalysis), as described in Section 5.4.2.8. 
Women of child-bearing potential must have a negative serum pregnancy test (hCG), 
as described in Section 5.4.2.8.6 (see also Section 7.3).
ECOG performance status, as described in 5.4.2.1.


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 72 of 109
Tumor assessment by radiological exam (CT/MRI scans), and CA-125 assessment, if 
this has not been performed within the 28 days prior to this visit, as described in 
Section 5.4.3.1.
Blood samples for PK analysis, as described in Section 5.4.4.
AE monitoring, as described in Section 7.3.2.
5.2.18
Follow-up contact
All AEs must be followed up until they have returned to baseline status or have 
stabilized, until 28 days after the last study-drug administration, or as described in 
Sections 7.3.2.1.2 and 7.4.2. Patients must also be contacted to record antineoplastic 
therapies received after discontinuation of study drug. Any AEs that occur in, and all 
cancer medications/therapies given to, a patient up to 28 days after the last dose of study 
drug must be recorded in the CRF.
In addition, patients with GBM and patients with ovarian cancer (in the Phase 2a portion 
of the study) who did not have disease progression at the end of the 28-day safety follow-
up period, and/or their treating physicians, will be contacted 4 months and 6 months after 
the date of first study-drug administration for the purpose of assessing progression-free 
survival (see Section 8.2.2.7).
Follow-up information can be obtained during an in-clinic visit, or by telephone if no 
physical assessments are required. 
5.3
Study assessments for patients undergoing dose escalation or dose reduction
5.3.1
Phase 1
Intra-patient dose increases or reductions are permitted, in accordance with Section 3.2.3. 
Dose increases, including multiple dose increases, may only occur after a patient has 
completed two full cycles without experiencing significant drug-related toxicities and 
only at the start of a subsequent cycle (i.e., Day 1 of the next treatment cycle).
For each patient, a maximum of two dose reductions by one dose level each will be 
allowed. 
For the first cycle at each new dose level, assessments should be performed as described 
for Cycle 1 (see Table 5), all subsequent cycles should follow the Cycle 3 onwards
schedule, with the following exceptions:
Triplicate 12-lead ECGs, according to Section 5.4.2.6:
o Day 1 and Day 8 of the first two cycles at each new dose level: pre-dose, 1 hour 
and 48 hours after the start of study-drug infusion.
Blood sample collection for CTC analysis will follow the Cycle 1 and Cycle 2 
schedules, as described in Section 5.4.5.1:
o During the first cycle at each new dose level: pre-dose on Day 1, Day 15 and 
Day 22.
o During the second cycle at each new dose level: pre-dose on Day 22.


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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 75 of 109
5.4.1.4.5
Blood-pressure elevations
BAL101553 has been associated with asymptomatic BP elevations that appear to be 
transient. General recommendations on the clinical management of BP elevations are 
summarized below (see also 5.4.2.5).
The general applicable BP criteria to initiate treatment are as follows:
Blood pressure should be recorded at Screening. Patients with resting BPs consistently 
above 140/90 mmHg should receive anti-hypertensive medication according to 
applicable guidelines. A patient should not be enrolled into the study until BP is 
consistently controlled to <140/90 mmHg.
SBP ≥ 180 mmHg and/or DBP ≥ 110 mmHg (asymptomatic): treatment with 
antihypertensive medication should be administered (“mandatory”) unless another 
treatment course is warranted by the clinical situation. The recommended treatment is 
oral labetalol 100 mg (50 mg in patients over 80 years of age or <50 kg). If this is 
contraindicated or the patient is already taking a beta-blocker, oral captopril 12.5 mg 
(6.25 mg in patients over 80 years of age or <50 kg) may be given. If this is 
contraindicated or the patient is already taking an ACE-inhibitor or adrenoreceptor 
blocker (ARB), oral clonidine 50 μg may be given. If this is contraindicated, specialist 
advice should be sought.
Patients who experienced BP elevations of SBP ≥ 180 mmHg or DBP ≥ 110 mmHg 
during one or more previous BAL101553 administrations should be managed by pre-
treatment with amlodipine 5 mg daily starting the night before BAL101553 infusion. 
Additional medication may be given as indicated above.
Patients who experience BP elevations requiring additional medication despite pre-
treatment with amlodipine 5 mg, should receive amlodipine 10 mg the night before 
BAL101553 infusion.
5.4.1.4.6
Implantable central venous access system
Patients who do not already have an implantable venous access system (‘PORT’) will 
undergo (ambulatory) surgery to have one inserted, according to the hospital’s guidelines. 
Patients will receive subsequent training by a qualified nursing team on the use and 
proper handling of the PORT.
Implantation should be done at least 3 days prior to BAL101553 administration. 
Study-approved devices include:
Baxter pump model 2C4711K, or 
Baxter pump model 2C1009KP/2C4009K.
If a patient receives a PORT as part of the study, this will be recorded in the eCRF as part 
of the patient’s medical history. Any insertion-related medications administered to the 
patient (e.g. anesthesia, analgesics, or antibiotics) will be captured in the concomitant 
medications page of the eCRF.  Any serious adverse events (SAEs) that occur due to the 
insertion will be captured on the SAE form as a study procedure-related SAE.   
Patients with an existing PORT will be eligible for the study if the PORT chamber is 
made of titanium and the cathether is either made of silicon or polyurethane. If a patient 


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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 80 of 109
Analyses must be performed and reviewed within the 3 days prior to administration of 
BAL101553 on Day 1 of Cycle 1, and within 1 day prior to study drug administration on 
any other dosing day.
General guidance regarding dose modifications for toxicities related to hematological 
laboratory assessments is provided in Table 4 (Section 3.2.3.2).
5.4.2.8.2
Biochemistry
The schedules for biochemistry blood samples are described in Table 5 (Phase 1) and 
Table 6 (Phase 2a). Biochemistry must be performed according to the same schedule as 
Hematology (see Section 5.4.2.8.1).
Biochemistry analyses include serum creatinine, blood urea nitrogen, uric acid, sodium, 
potassium, chloride, calcium, inorganic phosphorus, glucose, albumin, total protein, AST, 
ALT, total bilirubin, alkaline phosphatase, lipase, lactate dehydrogenase, and creatine 
phosphokinase.
Analyses must be performed and reviewed within the 3 days prior to administration of 
BAL101553 on Day 1 of Cycle 1, and within 1 day prior to study drug administration on 
any other dosing day.
General guidance regarding dose modifications for toxicities related to biochemical 
laboratory assessments is provided in Table 4 (Section 3.2.3.2).
5.4.2.8.3
Cardiac troponin
The schedules for cardiac troponin blood samples are described in Table 5 (Phase 1) and 
Table 6 (Phase 2a). The use of either cardiac troponin-I or troponin-T is permitted; 
however, the same troponin test must be used consistently for a given patient at 
Screening and throughout the study.
Analyses must be performed and reviewed within the 3 days prior to administration of 
BAL101553 on Day 1 of Cycle 1, and within 1 day prior to study drug administration on 
any other dosing day.
5.4.2.8.4
Coagulation
The schedules for coagulation blood samples are described in Table 5 (Phase 1) and 
Table 6 (Phase 2a). Coagulation analyses include International Normalized Ratio for 
reporting prothrombin time and Activated Partial Thromboplastin Time.
Analyses must be performed and reviewed within the 3 days prior to administration of 
BAL101553 on Day 1 of Cycle 1, and within 1 day prior to study drug administration on 
Day 1 of all subsequent cycles.
5.4.2.8.5
Urinalysis
The schedules for urinalyses are described in Table 5 (Phase 1) and Table 6 (Phase 2a). 
Urinalysis includes gross and microscopic exam. Dipstick analysis includes specific 
gravity, glucose, protein, and blood. Microscopic analysis includes white blood cells, red 
blood cells, and any additional findings (such as casts). 


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 81 of 109
Analyses must be performed and reviewed within the 3 days prior to administration of 
BAL101553 on Day 1 of Cycle 1, and within 1 day prior to study drug administration on 
Day 1 of all subsequent cycles.
5.4.2.8.6
Pregnancy testing
Women of child-bearing potential (i.e., who are not surgically sterile or < 12 months of 
amenorrhea post-menopause) must have a negative serum pregnancy (hCG) test during 
Screening, and a negative serum or urine pregnancy (hCG) test prior to BAL101553 
dosing on Day 1 of every cycle and at the End-of-Study visit.
Analyses must be performed and reviewed within the 3 days prior to administration of 
BAL101553 on Day 1 of Cycle 1, and within 1 day prior to study drug administration on 
any other dosing day.
5.4.2.8.7
Anticipated blood sample volumes 
In addition to laboratory safety assessments of hematology, biochemistry, cardiac 
troponin, coagulation and pregnancy status, blood must also be obtained for PK 
measurements and for biomarker assessments.
Phase 1
The anticipated volume of blood for laboratory assessments will be ~20 mL for the 
Screening investigation (safety laboratory).
The maximum anticipated volume of blood for the 28-day treatment in Cycle 1 
(including complete biomarker assessment and pregnancy testing) is ~124 mL (54 mL for 
safety laboratory, 36 mL for PK assessments, and 34 mL for biomarker assessments). For 
Cycle 2, the maximum anticipated volume of blood for the 28-day treatment cycle is 
110 mL (54 mL for safety laboratory, 46 mL for PK assessments and 10 mL for 
biomarker assessments). For all subsequent 28-day cycles, the anticipated volume of 
blood for each treatment cycle is 48 mL (safety laboratory). 
The anticipated volume of blood for laboratory assessments will be 22 mL for the End-
of-Study visit (20 mL for safety laboratory and 2 mL for PK assessment).
Phase 2a
The anticipated volume of blood for laboratory assessments will be ~20 mL for the 
Screening investigation (safety laboratory).
The maximum anticipated volume of blood for the 28-day treatment in Cycle 1 
(including complete biomarker assessment and pregnancy testing) for ovarian/GBM 
patients is ~108/78 mL (56 mL for safety laboratory, 18 mL for PK assessments, and 
34/4 mL for biomarker assessments). For Cycle 2, the maximum anticipated volume of 
blood for the 28-day treatment cycle ovarian/GBM patients is 72/62 mL (54 mL for 
safety laboratory, 8 mL for PK assessments, and 10/0 mL for biomarker assessments). 
For all subsequent 28-day cycles, the anticipated volume of blood for each treatment 
cycle is 48 mL (safety laboratory). 
The anticipated volume of blood for laboratory assessments will be 22 mL for the End-
of-Study visit (20 mL for safety laboratory and 2 mL for PK assessment).


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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 83 of 109
Detailed instructions and procedures for collecting and handling samples for PK analysis 
are provided in the ‘BAL101553 Pharmacokinetics Manual’ at the site. All samples for 
PK analysis will be shipped to and analyzed by 
:
Contact Information:
 
If needed, the PK sampling schedule may be amended based on observed PK in humans, 
however, no more than 12 PK samples will be obtained in order to establish a plasma 
concentration-time profile at Day 1 of Cycles 1 and 2. 
In the dose-escalation portion (Phase 1) of the study, concentration-over-time profiles
will be obtained on Day 1 of Cycles 1 and 2 (48-hour continuous IV infusion) and on 
Day 21 of Cycle 2 (oral BAL101553 administration), according to Table 5. For patients 
undergoing intra-patient dose escalation or dose reduction, blood PK samples will be 
collected during one cycle at each new dose level for a given patient, according to the 
schedule for Cycle 1 in Table 5.
In the dose expansion portion (Phase 2a) of the study, a concentration-over-time profile 
will be obtained on Day 1 of Cycle 1, according to Table 6. For patients undergoing intra-
patient dose reduction, blood PK samples will be collected pre-dose and at the end of 
infusion on Days 1 and 8 of the first cycle at each new dose level (see Section 5.3.2).
Based on the experience from the completed Phase 1 study CDI-CS-001, in which 
BAL101553 was administered as 2-hour infusions, urinary excretion of BAL101553/
BAL27862 is negligible. Therefore, no urinary excretion of BAL101553/BAL27862 will 
be measured in this study.
5.4.5
Biomarker assessments 
The schedules for biomarker sample collection are described in Table 5 (Phase 1) and 
Table 6 (Phase 2a).
Samples for biomarker assessments will be analyzed by the Sponsor or in specialized 
laboratories. The collection, storage, and shipping of CTCs and of other biomarker blood 
or tumor samples will be performed as described in the ‘BAL101553 Pharmacodynamics 
Manual’ provided to the study centers prior to study initiation.  
Exceptions to the schedule of Biomarker assessments can be made according to the 
Sponsor’s discretion. 
If available during the normal course of medical management, cells from malignant 
pleurocentesis or paracentesis fluid may also be analyzed for biomarkers. 


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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 86 of 109
All study drug must be kept under secure conditions, e.g., in the hospital pharmacy. 
Further information on the handling and stability of study drug will be provided in the 
‘BAL101553 Study Drug Administration Manual’.
6.4
Presentation of study drug
Any unused study drug will be kept at the study center for performance of drug 
accountability and for assessment of compliance (see Section 6.6).
6.4.1
BAL101553 for intravenous administration
BAL101553 for IV administration will be presented in vials containing 151.9 mg 
BAL101553 as powder for concentrate for solution for infusion. Complete and 
continuous daylight protection is mandatory during the handling, storage, transportation, 
and infusion of BAL101553 solutions. The following information applies to storage and 
handling of study-drug solutions prepared at room temperature:
Each vial is to be reconstituted with 7 mL of sterile Ringer Lactate. The reconstituted 
solution, after careful visual inspection for any precipitations, must be used within
1 hour to prepare the infusion solution. 
The reconstituted solution will be further diluted in Ringer Lactate to obtain the 
scheduled dose. The solution for infusion must be transferred into the pump within 
1 hour after dilution; thereafter, the infusion must start within 24 hours and will 
continue for up to an additional 72 hours.
Solutions must not be frozen at any time.
Note: Glucose-containing solutions must not be used.
Two Baxter elastomeric pump models are approved for use:
1. 2C4711K (120 mL pump) – setup can be used for infusion solutions within the  
concentration range of 0.19–4.17 mg/mL (22.5 – 500 mg BAL101553)
2. 2C1009KP/2C4009K (250 mL pump) – setup can be used for infusion solutions 
within the  concentration range of 0.15–2.00 mg/mL (37.5–500 mg BAL101553) 
6.4.2
BAL101553 for oral administration
BAL101553 for oral administration will be presented as hard capsules, each containing 
1 mg or 5 mg of study drug. The capsules also contain mannitol and magnesium stearate 
as excipients. The capsule shell is a white, opaque hydroxypropyl methylcellulose 
(HPMC) capsule, size 4.
6.5
Administration of study drug
Patients who do not have a PORT will undergo (ambulatory) surgery and will receive 
subsequent training by a qualified nursing team on the use and proper handling of the 
venous access system.
Intravenous administration
BAL101553 will be administered as a 48-hour IV infusion on Day 1, Day 8 and Day 15 
of each cycle, with the exception of Days 15–21 of Cycle 2 in Phase 1 (see below), via 
the PORT using an elastomeric pump (Baxter pump models 2C4711K or 


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 87 of 109
2C1009KP/2C4009K). Intravenous medication may only be administered by trained and 
qualified healthcare professionals in an appropriately supervised healthcare institution 
setting.
On Day 1 of Cycle 1, and on Day 1 of Cycle 2 (Phase 1 only), patients may be 
hospitalized for up to 72 hours for serial PK sampling and safety monitoring. Patients in 
Phase 1 can be discharged after the 30-hour PK sample. In Phase 2a, patients can be 
discharged after the 4-hour PK sample, but must return for the 24–30 hour PK sample. 
On all other intravenous BAL101553 dosing days, all patients must stay in the study 
center for at least 1 hour after the start of the BAL101553 infusion. Patients must always
return to the study center at least 2 hours before the end of the 48-hour infusion. 
Prolonged intravenous administration
If the infusion pump is not empty after 48 hours, the infusion may be prolonged by up to 
24 hours, particularly if the patient would otherwise receive less than 80% of the assigned 
dose for the visit in Cycle 1. In this event, the patient must return to the study center at 
least 1 hour before the predicted end of the infusion based on the pump weight at the end 
of the 48 hours. All assessments planned to take place 48 hours after the start of the 
infusion should be performed at the time of the actual end of the prolonged infusion. 
Assessments planned thereafter should also be shifted accordingly. 
Oral administration
Patients in Phase 1 will receive daily oral BAL101553 on Days 15–21 of Cycle 2 (i.e., for 
1 week). During the oral administration portion of Cycle 2, BAL101553 capsules are to 
be taken in the fasted state before breakfast each morning, with 250 mL of still water, for 
7 days. Patients must fast ≥ 4 h prior to and ≥ 1 h after dosing, but may eat normally
outside of these times. Water is allowed at all times during all parts of the study. On Day 
15 of Cycle 2, patients must stay in the study center for at least 6 hours after oral study-
drug intake for safety monitoring. Starting on study Day 21, patients will be hospitalized 
for serial PK sampling for up to 48 hours post-study-drug administration. 
Further details on dosage schedule and dose escalations/modifications are outlined in 
Section 3.2.1. Details on study drug administration are described in in the ‘BAL101553 
Study Drug Administration Manual’ at the sites.
The Sponsor must be notified at least 24 hours before, and within the 24 hours after, 
administration of the first dose (Cycle 1 Day 1) to any patient, and within 24 hours after 
any dose of study drug associated with drug administration errors. 
6.6
Compliance and drug supply accountability
6.6.1
Compliance
The Investigator or designee is responsible for drug accountability, reconciliation and 
record maintenance for used and unused study drug. The drug accountability records 
must be kept current and must be available for monitoring by the clinical research 
associate (CRA). The logs and all other forms or documents relating to overall drug 
accountability must be collected from study center by the CRA.


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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 92 of 109
All AEs must be recorded in the English language in the CRF and should include the 
following information:
1. Term. If possible, a diagnosis should be documented rather than signs and symptoms, 
using self-explanatory and concise medical terminology.
Note:Use of the AE term ‘disease progression’, ‘lack of efficacy’, or equivalent terms,
should be avoided. Instead, a diagnosis, signs, or symptoms should be used to describe 
the worsening of the disease under study.
2. Duration (start and end dates).
3. Toxicity grade (CTCAE grade 1–4), or severity grade (three-point scale, see Section 
7.2.1). 
4. Relationship to study treatment (see Section 7.2.2 and Appendix 3).
5. Action(s) taken with regards to the study treatment or additional treatments given for 
the event.
6. Whether the event is an SAE (see Section 7.1.3). 
7. Outcome.
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 changes in study-drug dosing or discontinuation of study participation
is considered clinically significant
Signs, symptoms or diagnosis associated with these abnormal results must be recorded on 
the AEs page of the CRF.
Adverse events must also be reported in the source document with at least the nature of 
the event, the start and end date, the relationship to the study drug, and the treatment (if 
applicable).
7.3.2.1.2
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.
All AEs must be followed up until they have returned to baseline status or have 
stabilized, or until 28 days after the last study-drug administration.
In addition, an AE which remains unresolved after completion of the study (including the 
last scheduled follow-up contact) and meets one or more of the criteria listed below,
requires detailed evaluation, follow-up and, if necessary, specific medical treatment until 
the AE is resolved or a reasonable explanation for its persistence is found:
an AE evaluated as related to the study drug
an AE that led to a patient withdrawal from the study
an SAE
These cases will be followed-up on the CRF unless otherwise agreed with the Sponsor.


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BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 94 of 109
7.4
Pregnancy 
7.4.1
Contraception for women of childbearing potential
As reproductive and fertility studies have not been performed with BAL101553 in 
animals, female patients of childbearing potential must not become pregnant while being 
treated with BAL101553.
The Investigator must make every effort to ensure that neither a clinical study patient, nor 
the partner of a male clinical study patient, becomes pregnant during the study, or within 
the 90 days after the last dose of study drug. This should be done and documented as part 
of the consent process, by explaining clearly to the patient the potential dangers of 
becoming pregnant/fathering a child, and also providing each patient with information 
about appropriate medically-approved effective contraception (see below).
Women of childbearing potential (i.e., who are not surgically sterile or < 12 months of 
amenorrhea post-menopause) must have a negative serum pregnancy test result during 
Screening. In addition, serum or urine pregnancy tests must be negative within the 3 days
prior to Day 1 of each cycle. If the serum pregnancy test performed during Screening was 
conducted within the 3 days prior to first dosing (Day 1/Cycle1), additional testing is not 
required for Day 1/Cycle 1. 
Women of childbearing potential must agree to use one of the following methods of 
contraception, to be strictly implemented during the study and for at least 90 days after 
the end of treatment:

Male or female sterilization (bilateral tubal occlusion or vasectomy).

Intrauterine device (IUD).

Combined (estrogen and progesterone containing) hormonal contraception (oral, 
vaginal ring or transdermal patch) with an ethinylestradiol dose of at least 30 µg, plus 
use of male condoms (preferably with spermicides), female condoms, a female 
diaphragm or a cervical cap.
7.4.2
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 center as soon as possible, but not later than 24 hours after the 
Investigator is informed.
Female patients must inform the Investigator if they become pregnant during the study or 
within the 90 days following the last study drug administration. The study drug must be 
discontinued immediately when a patient becomes pregnant. The patient must be 
monitored until conclusion of the pregnancy and infants must be followed-up at least for 
8 weeks after delivery.
Pregnancy outcomes should be collected, if possible, for the female partners of any males 
who took the study drug. Consent to collect information regarding these pregnancies and 
their outcomes must be obtained from the mother.


BAL101553 
Clinical Study Protocol CDI-CS-003
Version 7.0
8 October 2018
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd.
Page 95 of 109
The Investigator must immediately notify the Sponsor’s safety representative about any 
pregnancy by submitting a Pregnancy Report Form, in accordance with the requirements 
(timelines and contact details) of an SAE (see Section 7.3.2.2). In addition, pregnancy-
related adverse outcomes must also be reported as AEs or SAEs (see Sections 7.3.2.1 and 
7.3.2.2). Note that an induced abortion which is not required by an AE does not constitute 
an SAE.
It is the Investigator’s responsibility to notify the local IEC/IRB about any pregnancies 
resulting in an adverse outcome, in accordance with applicable laws and regulations.
8. STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN
PK 
parameters
will 
be 
derived 
using 
Phoenix 
WinNonLin 
6.3 
software 
(Pharsight Corporation a CertaraTM Company, Saint Louis, MO, US). All analyses and 
data presentations will be generated using SAS® Version 9.3 or higher software 
(SAS Institute, Cary, North Carolina, USA).
8.1
Study variables 
The primary study endpoint is the frequency and characteristics of DLT, or other
toxicities which are relevant for determination of the MTD of BAL101553.
Secondary endpoints:
Overall safety endpoints: 
- Type and frequency of AE, SAEs, laboratory, echocardiogram and ECG 
abnormalities; abnormalities in vital signs, physical examination results, chest 
X-ray/CT; frequency and causes of study withdrawals and dose modifications. 
Efficacy endpoints:
- Best objective response according to RECIST v1.1 (patients with solid tumors, 
excluding GBM) or RANO criteria (GBM patients), based on the change from 
baseline in tumor measurements as measured in patients with measurable disease.
- Progression-free survival.

Pharmacokinetic assessments (BAL101553 and BAL27862): 
Phase 1
- Cmax, Tmax, AUC0-τ, AUC0-last, AUC0-∞, t½, systemic clearance and volume of 
distribution.
- Bioavailability of oral BAL101553 (relative bioavailability of BAL27862).
Phase 2a
- Tabulated listing of BAL101553 and BAL27862 plasma concentrations.

Exploratory endpoints:
- PK samples may be used to investigate and identify metabolites; known metabolites 
for which standards are available may also be quantified in these samples. These 
investigations will not be reported in the Clinical Study Report, but will be the 
subject of (a) separate report(s).
- Change from baseline in biomarkers (including but not limited to number of CTCs).


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8.2.3
Sample size calculation
Up to 56 evaluable patients will be enrolled in the study in total. Of the 20 patients dosed
in the dose-escalation portion, 16  were MTD-evaluable; up to 20 evaluable ovarian 
tumor patients and up to 20 evaluable GBM patients will be included in the expansion 
portion. 
Assuming an ~25% drop-out rate, up to 70 patients may be enrolled. 
The 3+3 design does not require sample size specification; the escalation is continued 
until the MAD (i.e., a dose with an unacceptable number of DLT) is observed. The 
expansion portion is exploratory; therefore, no statistical sample size justification has 
been applied.
8.2.4
Handling of missing data and discontinuations
Patients whose clinical response is unknown or not reported will be treated as 
non-responders for summarizing the overall response rate.
Reasons for discontinuation and the Study Day 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 Study Day. Summary tables will be provided by dose group.
9. 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 Conference on 
Harmonisation (ICH) E6 [1] and applicable regulations, including the protocol and any 
subsequent amendments, CRFs, Query Forms, documented IEC/IRB approvals, 
documented regulatory approvals, sample informed consent forms, drug records, staff 
curriculum vitae, and other appropriate documents/correspondence.
9.1.2
Case report forms
For each patient enrolled, a CRF 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 CRFs and in all required reports.
If the CRF is to be the source document for certain data, this must be discussed and 
agreed with the Sponsor in advance, and clearly documented.


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9.1.3
Patient source documents
Patient source documents used to record key efficacy/safety parameters, independent of 
the CRFs may include, but are not limited to, patient hospital/clinic records, physicians’
and nurses’ notes, appointment books, original laboratory reports, ECG read-outs, X-ray, 
pathology and special assessment reports, signed informed consent/assent forms, 
consultant letters, and patient screening and enrollment logs. 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.
9.1.5
Sample retention 
Genetic filter cards, plasma samples collected for PK and tumor tissue material may be 
stored for up to 20 years for future medical and/or scientific research projects related to 
BAL101553. All patients will be asked to provide a separate informed consent for this 
purpose, authorizing the Sponsor to use their study information and samples for future 
research projects. 
After a maximum of 20 years, all stored samples will be safely destroyed.
9.2
Clinical monitoring
Before study initiation, at a site initiation visit or at an Investigator’s meeting, the 
Sponsor will review the protocol, CRFs 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 Good Clinical Practice (GCP) and the 
protocol, and the completeness, consistency and accuracy of the data being entered into 
the CRFs. 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 CRFs. 


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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 Clinical Monitoring Plan.
9.3
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.
9.4
Protocol amendments
Protocol amendments must be prepared by a representative of the Sponsor, and be 
reviewed and approved by the Project Physician and the Project Statistician.
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 changes necessary to eliminate an immediate hazard to study 
participants, or changes involving only logistical or administrative aspects of the study 
(e.g., changes to Monitors, changes to telephone numbers).
9.5
Premature termination of the study
The Sponsor reserves the right to terminate the study at any time. 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.
9.6
Publication policy
The Sponsor is committed to registering all therapeutic studies in a publicly accessible 
clinical trial registry (e.g., www.clinicaltrials.gov), and will ensure that results of these 
studies will be made available to the medical community, consistent with applicable laws 
and regulations.


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In accordance with standard editorial and ethical practice, the Sponsor will support 
publication of multicenter studies only in their entirety, and not as individual center data.  
Authorship is to be determined by mutual agreement.
The results of this study will be made available, e.g., submitted for publication and/or 
presentation at scientific meetings, in a timely manner. All manuscripts or abstracts must 
be submitted to the Sponsor prior to publication or presentation, allowing the Sponsor to 
protect proprietary information, and to provide comments based on information from 
other studies that may not yet be available to an Investigator.
10.
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, or, if incapable of doing so, after such consent has 
been provided by a legally acceptable representative of the patient. Written informed 
consent must be obtained 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. Appropriate forms for obtaining written informed consent will be 
provided to the Investigator by the Sponsor.
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 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 center. 
For patients not qualified to give legal consent, or incapable of doing so, written consent 
must be obtained from the patient’s legally acceptable representative. In the event that 
both the patient and his or her legally acceptable representative are unable to read the 
consent document, an impartial witness must be present during the entire informed 
consent discussion. After the patient and representative have 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 CRFs 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, the consent form must be reviewed and updated. 


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All patients currently enrolled in the study who have not yet completed the post-treatment 
phase 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 CRF, 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 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.
11.
REFERENCES
1. Integrated Addendum to ICH E6(R1): Guideline For Good Clinical Practice E6(R2).
ICH, 2016.
2. Prota, A.E., et al., The novel microtubule-destabilizing drug BAL27862 binds to the 
colchicine site of tubulin with distinct effects on microtubule organization. J Mol Biol, 
2014. 426(8): p. 1848-60.
3. Schmitt-Hoffmann, A., et al., Poster abstract C233: BAL27862: A unique 
microtubule-targeted agent with a potential for the treatment of human brain tumors, 
in AACR. 2009.
4. BasileaPharmaceutica. An Open-Label Study of BAL101553 in Adult Patients With 
Solid Tumors. 2014; Available from: http://clinicaltrials.gov/show/NCT01397929.
5. Molife, L.R., et al., Phase I/IIa trial of the novel microtubule inhibitor BAL101553 in 
advanced solid tumors: Phase I completed. Journal of Clinical Oncology, 2014. 
35(15s): p. suppl 2562.
6. Chen, Z., et al., Range and trend of expected toxicity level (ETL) in standard A + B 
designs: a report from the Children's Oncology Group. Contemp Clin Trials, 2009. 
30(2): p. 123-8.


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7. Ivy, S.P., et al., Approaches to phase 1 clinical trial design focused on safety, 
efficiency, and selected patient populations: a report from the clinical trial design task 
force of the national cancer institute investigational drug steering committee. Clin 
Cancer Res, 2010. 16(6): p. 1726-36.
8. Lopez, J., et al., Poster absrtact 2525: Phase 1/2a trial of intravenous BAL101553, a 
novel tumor checkpoint controller (TCC), in advanced solid tumors, in ASCO. 2016.
12.
APPENDICES
Appendix 1
Response evaluation and criteria in solid tumors (RECIST) guidelines, 
version 1.1
Source:
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J. New response evaluation criteria in solid tumors: revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009 ;45:228-47.
For specifics of RECIST v1.1 criteria and assessment, please refer to the following 
website: http://www.eortc.be/recist/documents/RECISTGuidelines.pdf.


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Appendix 2
RANO criteria for glioblastoma and high-grade gliomas
Source: Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick 
W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, 
Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade 
gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28(11):1963-72. 
http://jco.ascopubs.org/content/28/11/1963.full
Criteria for Response Assessment Incorporating MRI and Clinical Factors
Response
Criteria
Complete 
response
Requires all of the following: complete disappearance of all enhancing measurable and 
nonmeasurable disease sustained for at least 4 weeks; no new lesions; stable or improved 
nonenhancing (T2/FLAIR) lesions; patients must be off corticosteroids (or on physiologic 
replacement doses only); and stable or improved clinically. Note: Patients with nonmeasurable 
disease only cannot have a complete response; the best response possible is stable disease. 
Partial 
response
Requires all of the following: ≥ 50% decrease compared with baseline in the sum of products 
of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; 
no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing 
(T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; the
corticosteroid dose at the time of the scan evaluation should be no greater than the dose at time
of baseline scan; and stable or improved clinically. Note: Patients with nonmeasurable disease 
only cannot have a partial response; the best response possible is stable disease. 
Stable 
disease
Requires all of the following: does not qualify for complete response, partial response, or 
progression; stable nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. In the event that the corticosteroid dose was 
increased for new symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in corticosteroids 
was required because of disease progression, the last scan considered to show stable disease 
will be the scan obtained when the corticosteroid dose was equivalent to the baseline dose. 
Progression
Defined by any of the following: ≥ 25% increase in sum of the products of perpendicular 
diameters of enhancing lesions compared with the smallest tumor measurement obtained 
either at baseline (if no decrease) or best response, on stable or increasing doses of 
corticosteroids*; significant increase in T2/FLAIR nonenhancing lesion on stable or increasing
doses of corticosteroids compared with baseline scan or best response after initiation of 
therapy* not caused by comorbid events (eg, radiation therapy, demyelination, ischemic 
injury, infection, seizures, postoperative changes, or other treatment effects); any new lesion; 
clear clinical deterioration not attributable to other causes apart from the tumor (eg, seizures, 
medication adverse effects, complications of therapy, cerebrovascular events, infection, and so 
on) or changes in corticosteroid dose; failure to return for evaluation as a result of death or 
deteriorating condition; or clear progression of nonmeasurable disease. 
NOTE. All measurable and nonmeasurable lesions must be assessed using the same techniques as at 
baseline.
MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery.
* Stable doses of corticosteroids include patients not on corticosteroids. 


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Appendix 3
Criteria for evaluating relationship between adverse events and study 
treatment
NOT RELATED
This category is applicable to an AE that meets the following three criteria:
1. It does not follow a reasonable temporal sequence from administration of the drug, 
i.e., the time between the administration of study drug and occurrence of the event is 
not plausible. If the drug was interrupted or stopped the event did not improve or 
disappear. (There are important exceptions when an AE does not disappear upon 
discontinuation of the drug, yet drug-relatedness clearly exists; e.g., [i] bone marrow 
depression, [ii] tardive dyskinesias.). If the drug was re-administered it did not 
reappear.
2. It does not follow a known pattern of the response to the suspected drug or drugs of 
the same substance class.
3. It is judged to be clearly and incontrovertibly due only to extraneous causes such as 
the patient’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
UNLIKELY 
This category is applicable to an AE that meets the following three criteria:
1. It does not follow a reasonable temporal sequence from administration of the drug, 
i.e., the time between the administration of study drug and occurrence of the event is 
not plausible. If the drug was interrupted or stopped the event did not improve or 
disappear. If the drug was re-administered it did not re-appear.
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. 


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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.
A causal relationship is suspected for all AEs/SAEs reported with a relationship of 
‘possible’ or ‘probable’.


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Appendix 4
Investigator’s protocol signature page
BASILEA 
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE
Protocol 
CDI-CS-003 Version 7.0
(SAKK number: SAKK 67/15)
Basilea Product No:
BAL101553
Protocol Title:
An open-label Phase 1/2a study of BAL101553 administered as 
intravenous 48-hour infusions in adult patients with advanced solid 
tumors or recurrent glioblastoma 
Basilea Pharmaceutica International Ltd
Approval Date:
8 October 2018
By (Project Physician):
Name of Principal Investigator: 
Study Center: 
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 Ethics Committee 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 and Sub-Investigators (at minimum):
Please print names, qualifications, and dates next to the corresponding signatures
Signature
Name
Date
Principal Investigator
Sub-Investigator

SAP_001.pdf: 
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Page 1 of 32
BAL101553 
STATISTICAL ANALYSIS PLAN
CDI-CS-003 
An open-label Phase 1/2a study of BAL101553 administered as intravenous 48-hour 
infusions in adult patients with advanced solid tumors or recurrent glioblastoma
Document version: 
Version 1.0 
Date: 
15 November 2018 
Study protocol version / date: 
6.0 / 24 May 2018 
Number of pages: 
32
Confidentiality statement
The information contained in this document is commercial confidential information which is the property 
of Basilea Pharmaceutica International Ltd, or is under its control. This information is provided only for the 
purposes identified within the document, and may not be disclosed by the recipient to any third party 
without prior written authorization from Basilea Pharmaceutica International Ltd. If it is determined that 
disclosure to a third party is required by applicable law or regulations, the party to whom the information is 
disclosed must be informed that the information is confidential and that it may not be further disclosed 
without prior written authorization from Basilea Pharmaceutica International Ltd.
Note: This is an electronically controlled document.
NCT02895360




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TABLE OF CONTENTS
LIST OF TABLES ..............................................................................................................4 
1 
INTRODUCTION ........................................................................................................7 
2 
STUDY OBJECTIVES, ENDPOINTS AND DESIGN...............................................7 
2.1 
Study Objectives ..................................................................................................7 
2.1.1 Primary objective .............................................................................................7 
2.1.2 Secondary objectives........................................................................................7 
2.1.3 Exploratory objectives .....................................................................................7 
2.2 
Study Endpoints ...................................................................................................8 
2.2.1 Primary endpoint..............................................................................................8 
2.2.2 Secondary endpoints ........................................................................................8 
2.2.3 Exploratory endpoints ......................................................................................8 
2.2.4 Study Design ....................................................................................................8 
2.2.5 Study design.....................................................................................................8 
2.2.5.1 Dose escalation Portion (Phase 1).................................................................9 
2.2.5.2 Expansion portion (Phase 2a)........................................................................9 
2.2.5.3 Assessments ................................................................................................10 
2.2.6 Planned sample size .......................................................................................19 
2.2.7 Interim analyses .............................................................................................19 
3 
ANALYSIS POPULATIONS ....................................................................................19 
3.1 
Full analysis population .....................................................................................19 
3.2 
Efficacy evaluable population............................................................................19 
3.3 
Safety population................................................................................................20 
3.4 
Maximum tolerated dose-determining population.............................................20 
3.5 
Pharmacokinetic analysis population.................................................................20 
4 
STATISTICAL CONSIDERATIONS AND ANALYSIS.........................................21 
4.1 
Derived variables................................................................................................21 
4.2 
Handling of missing data and/or invalid data and outliers.................................21 
5 
STATISTICAL PLAN AND METHODS..................................................................22 
5.1 
Background characteristics ................................................................................22 
5.1.1 Patient disposition..........................................................................................22 
5.1.2 Protocol deviations.........................................................................................23 
5.1.3 Demographic and baseline characteristics .....................................................23 
5.1.4 Medical history...............................................................................................23 
5.2 
Efficacy analysis ................................................................................................23 


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5.2.1 Dose-limiting toxicity ....................................................................................23 
5.2.2 Objective response rate ..................................................................................23 
5.2.3 Disease control rate........................................................................................24 
5.2.4 Progression-free survival ...............................................................................24 
5.2.5 Exploratory and additional efficacy analysis .................................................25 
5.2.5.1 Tumor measurements..................................................................................25 
5.2.5.2 Biomarker analysis......................................................................................25 
5.2.6 Pharmacokinetic analysis...............................................................................25 
5.3 
Safety analysis....................................................................................................25 
5.3.1 Treatment exposure........................................................................................25 
5.3.2 Adverse events ...............................................................................................26 
5.3.3 Laboratory evaluation ....................................................................................28 
5.3.4 Vital signs.......................................................................................................29 
5.3.5 ECG results ....................................................................................................30 
5.3.5.1 Outlier analysis............................................................................................30 
5.3.6 Physical examination .....................................................................................30 
5.3.7 Prior and concomitant medications................................................................31 
5.3.8 Chest X-ray/CT..............................................................................................31 
5.3.9 ECOG performance status..............................................................................31 
5.3.10 Transthoracic echocardiography..................................................................31 
6 
CHANGES FROM THE PLANNED ANALYSIS IN STUDY PROTOCOL ..........31 
7 
REFERENCES ...........................................................................................................32 
LIST OF TABLES
Table 1 
Phase 1 - Schedule of assessments ................................................................. 11 
Table 2 
Phase 2a - Schedule of assessments ............................................................... 15 


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LIST OF ABBREVIATIONS
AE
Adverse event
ALT
Alanine amino transferase
ANC
Absolute neutrophil count
AST
Aspartate amino transferase
AUC0-
Area under the concentration-time curve from time zero 
to infinity; calculated as AUC0-last + CODVWȜ]
AUC0-last
Area under the concentration-time curve from time zero 
to the last quantifiable concentration
AUC0-t
Area under the concentration-time curve from time zero 
to time (t)
AUC0-Ĳ
Area under the concentration-time curve from time zero 
WRWLPHĲZKHUHWDXLVWhe length of the dosing interval
BP
Blood pressure
BSA
Body surface area
CDI
Cell death inducer
CI
Confidence interval
CLs
Systemic clearance
Cmax
Maximum observed plasma concentration
CK
Creatine phosphokinase
CR
Complete Response
CRF
Case report form
CT
Computed tomography
CTC(s)
Circulating tumor cell(s)
CTCAE v4.03
Common Terminology Criteria for Adverse Events 
version 4.03
CYP
Cytochrome P450
DBP
Diastolic blood pressure
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EEP
Efficacy evaluable population
FAP
Full analysis population
GCP
Good Clinical Practice
hCG
Human chorionic gonadotropin


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HR
Heart rate
ICH
International Council for Harmonisation
INR
International normalized ratio
ITT
Intention-to-treat
IV
Intravenous
LDH
Lactate dehydrogenase
LLN
Lower limit of normal
LVEF
Left ventricular ejection fraction
MAD
Maximum administered dose
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetic(s)
PR
Partial response
PT
Preferred Term
QTcF
QT interval corrected for heart rate (Fridericia correction)
RECIST
Response Evaluation Criteria in Solid Tumors
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Stable disease
SD
Standard deviation
SOC
System Organ Class
t½
Terminal elimination half-life
tmax 
Time to maximum plasma concentration
TFL
Table, Figure and Listing
ULN
Upper limit of normal
WBC
White blood cell


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1
INTRODUCTION
This statistical analysis plan (SAP) specifies the detailed procedures for performing the 
statistical analyses and producing tables, listings and figures in the study described in 
Basilea Pharmaceutica International Ltd. (Basilea) Protocol CDI-CS-003. The version of 
the protocol at the time of preparation of this SAP is Version 6.0 dated 24 May 2018.
At the time of writing this document, the Phase 1 part of the study is completed while the 
Phase 2a part is ongoing.
Pharmacokinetic analysis for this study are addressed in a separate PK-SAP.
Concentration data will be listed.
2
STUDY OBJECTIVES, ENDPOINTS AND DESIGN
2.1
Study Objectives
2.1.1
Primary objective
The primary objectives of this study are to determine the MTD and to characterize dose 
limiting toxicities (DLTs) of BAL101553, administered as an IV infusion over 48 hours 
on study Days 1, 8 and 15 of a 28-day treatment cycle, to adults with advanced or 
recurrent solid tumors who have failed standard therapy, or for whom no effective 
standard therapy is available.
2.1.2
Secondary objectives
The secondary objectives are:
x
To evaluate the safety and tolerability of BAL101553 administered as a 48-hour 
continuous IV infusion.
x
To assess the antitumor activity of BAL101553 administered as a 48-hour continuous 
IV infusion.
x
To assess the PK of BAL101553 and BAL27862 after 48-hour IV infusion; and after 
daily oral administration on study Days 15–21 of Cycle 2 (Phase 1 only).
2.1.3
Exploratory objectives
The exploratory objectives are:
x
To assess the use of biomarkers to characterize the PD effects of BAL101553, 
administered as a 48-hour continuous IV infusion.
x
To explore the potential utility of biomarkers in blood and/or tumor tissue as 
predictive biomarkers.


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2.2
Study Endpoints
2.2.1
Primary endpoint
The primary study endpoint is the frequency and characteristics of DLT, or other 
toxicities which are relevant for determination of the MTD of BAL101553. 
2.2.2
Secondary endpoints
Secondary endpoints are:
x
Overall safety endpoints:

Type and frequency of AE, SAEs, laboratory, echocardiogram and ECG 
abnormalities; abnormalities in vital signs, physical examination results, chest 
X-ray/CT; frequency and causes of study withdrawals and dose modifications.
x
Efficacy endpoints:

Best objective response according to RECIST v1.1 (patients with solid tumors, 
excluding GBM) or RANO criteria (GBM patients), based on the change from 
baseline in tumor measurements as measured in patients with measurable disease.

Progression-free survival.
x
Pharmacokinetic assessments (BAL101553 and BAL27862):
Phase 1

Cmax, Tmax, AUC0-Ĳ, AUC0-last, AUC0-, t½, systemic clearance and volume of 
distribution.

Bioavailability of oral BAL101553 (relative bioavailability of BAL27862).
Phase 2a

Tabulated listing of BAL101553 and BAL27862 plasma concentrations. 
2.2.3
Exploratory endpoints
The exploratory endpoints are:
x
PK samples may be used to investigate and identify metabolites; known metabolites 
for which standards are available may also be quantified in these samples. These 
investigations will not be reported in the Clinical Study Report, but will be the subject 
of (a) separate report(s). 
x
Change from baseline in biomarkers (including but not limited to number of CTCs).
2.2.4
Study Design
2.2.5
Study design
This Phase 1/2a study is divided into two parts, with different designs: 
x
The first part is a Phase 1 multiple-ascending-dose-escalation portion using a 3+3 
titration design to determine the MTD, to be carried out in up to 42 evaluable patients
(completed with 20 patients dosed, of which 16 patients were evaluable).
x
The second part is a Phase 2a expansion portion to further characterize safety and 
tolerability of BAL101553 at the MTD (70 mg/m2) and to obtain efficacy data. The 
Phase 2a part of the trial will include two target populations, each with up to 20 
evaluable patients: the first will comprise platinum-resistant/refractory ovarian, 


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fallopian tube or primary peritoneal cancer (collectively referred to herein as 'ovarian 
cancer') patients; and the second will comprise GBM patients in first relapse.
2.2.5.1
Dose escalation Portion (Phase 1)
Patients were enrolled in sequential (escalating) dose levels comprising three to six 
patients, using a body surface area (BSA)-adjusted dosing approach. BAL101553 was
administered over 48 hours beginning on days 1, 8 and 15 of an every 28 day treatment 
cycle with the exception Cycle 2 where, instead of the Day 15 infusion, each patient was
administered a daily oral dose of BAL101553 from Days 15 to 21. For each dose cohort, 
new patients were recruited and evaluated for safety, pharmacokinetics, and efficacy.
Cohort size was variable, dependent primarily on whether patients experienced DLTs 
during Cycle 1. Each dose level utilized a 3+3 dose-escalation design and was based 
upon the occurrence of BAL101553-related dose limiting toxicities (DLTs) during Cycle
1 of treatment. The dose in the first cohort was 30 mg/m2 (per 48 hour infusion). Dose 
increments of approximately 50% were planned from 30 mg/m2 onwards, until DLT was 
observed. Once a DLT was observed in any patient, the dose increment for all subsequent 
dose levels would be approximately 33%.
If a DLT was observed in one patient at the starting dose level (30 mg/m2), this dose level 
would be expanded [up] to six patients. If two or more of these [up to] six patients 
experience a DLT, the dose for the subsequent dose level would be decreased to 15 
mg/m2 and all subsequent dose levels would be increased by approximately 33%.
Dose escalation and cohort enrollment will be decided by the Dose-cohort Escalation 
Committee who will meet at appropriate intervals to review the safety information. 
2.2.5.2
Expansion portion (Phase 2a)
Once the MTD has been defined, up to 40 additional evaluable patients will be enrolled 
and treated at the MTD dose, comprising of up to 20 evaluable patients in two target 
populations. The first population will include platinum-resistant/refractory ovarian, 
fallopian tube or primary peritoneal cancer (collectively referred to herein as 'ovarian 
cancer') patients; while the second will consist of GBM patients in first relapse.
For each target population, a separate cumulative safety evaluation will be performed 
after six patients have completed their first 28-day cycle or have discontinued treatment 
and after completion of the first cycle, or discontinuation, by each subsequent group of 
six patients.
BAL101553 treatment will be continued in patients enrolled in the dose-expansion 
portion until disease progression, occurrence of unacceptable toxicity, or until the patient 
withdraws from the study. Efficacy assessments to assess objective response to treatment 
must be scheduled at the end of at least each even-numbered treatment cycle (e.g., end of 
Cycle 2, 4, 6, etc.) and subsequent treatment cycles may not be initiated if disease 
progression is observed. Section 5.4.3 of the protocol provides criteria for assessing 
response, stable disease, and disease progression.


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2.2.5.3
Assessments
Table 1 presents a summary of the schedule of assessments performed from Screening 
through the End of Study visit in the phase 1 part of the study. Table 2 presents a 
summary of the Schedule of Assessments in the Phase 2 part. (Cross-references in the 
footnotes are to protocol sections).


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Table 1
Phase 1 - Schedule of assessments
Screening
Cycle 1
Cycle 2
Cycle 3 and subsequent cycles
End of 
Study
Day (D) of cycle1
íWRí
D1
D8
D15
D22
D28
D1
D8
D15
D21/22†
D28
D1
D8
D15
D22
*
D28
Informed consent2
X
Inclusion/exclusion criteria
X
Diagnosis and extent of cancer/prior anticancer therapy
X
Demographics/medical history/baseline medical conditions and 
medications
X
Physical examination/ECOG performance status3
X
X
X
X
X
Vital signs4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood pressure5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG6
X
X
X
X
X
X
X
X
X
X
Echocardiography7
X
X
Chest X-ray8
X
Hematology9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation11
X
X
X
X
X
Urinalysis11
X
X
X
X
X
Cardiac troponin12
X
X
X
X
X
X
X
X
Pregnancy test13
X
X
X
X
X
Radiological assessment of tumor8,14 (RECIST v1.1 criteria)
X
X
X(ENC)
X
Implantable venous access system (PORT system)15
X
BAL101553 administration16
X
X
X
X
X
X
X
X
X
X
Drug dispensing and accountability
X
X
X
X
X
X
X
X
X
X
Adverse events/ Serious adverse events 17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/treatments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for pharmacokinetics18
X
X
X
X
X
X
X
X
Dried-blood-spot analysis (Centogene cards)19
X
Blood for CTC analysis20
X
X
X
X
Tumor biopsy21
X
X
X
X
Archival tumor specimen collection (when available)
X
ENC = even-numbered cycles (Note that from Cycle 6 onwards, the interval between CT/MRI scans may be extended from 8 weeks to 12 weeks).
†Note: Assessments normally scheduled for D22 visits should be performed on D21 of Cycle 2.; *Note: D22 visits are optional from Cycle 3 onwards


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1.
Deviations from the visit schedule by ± 2 days are permitted for reasons other than toxicity, e.g., for administrative reasons or to accommodate travel logistics. D28 assessments 
of a given cycle may be performed on D29 of that cycle, i.e., pre-dose on D1 of the subsequent cycle. 
2.
Informed consent must be obtained within the 28 days prior to D1 of Cycle 1. Screening assessments must be performed and completed within the 15 days prior to D1/Cycle 1, 
with the exception of radiology assessments, which if conducted within the 28 days prior to D1 of Cycle 1, do not need to be repeated during Screening.
3.
For D1 of all cycles, the physical exam and ECOG status must be performed within the 3 days prior to dosing; if the Screening exam was pHUIRUPHGGD\VSULRUWR'WKHVH
do not need to be repeated on D1/Cycle 1 (see Sections 5.4.2.3 and 5.4.2.1).
4.
Complete vital signs (see Section 5.4.2.4) will be obtained at Screening, at any D22 in-clinic visit, at the End-of-Study visit, and:
Cycle 1: 
On D1, pre-dose and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 24 h 30 h, 48 h, 52 h, 54 h and 72 h after the start of study-drug infusion. 
On D8 and D15, pre-dose, and 0.5 h and 1 h after the start of study-drug infusion, and at the end of the 48-hour study-drug infusion. 
Cycle 2: 
On D1, pre-dose, and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 24 h, 30 h, 48 h and 72 h after the start of study-drug infusion. 
On D8, pre-dose, and 0.5 h and 1 h after the start of study-drug infusion, and at the end of the 48-hour study-drug infusion.
On D15, pre-dose, and 1 h, 2 h, 4 h and 6 h after the first intake of oral BAL101553.
On D21, pre-dose, and 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 30 h and 48 h after the last intake of oral BAL101553. 
Cycle 3 onwards: Pre-dose, 1 h after the start of study-drug infusion and at the end of the 48-hour study-drug infusion, on all dosing days. 
The body weight measurement must be obtained within the 3 days prior to dosing on D1 of all cycles.
5.
Triple BP measurements should be taken at Screening, pre-dose on all dosing days, at any D22 in-clinic visit, and at the End-of-Study visit. Single BP measurements will be 
obtained:
Cycle 1: 
On D1, every 30 min after the start of the study-drug infusion, until 4 h after the start of the study-drug infusion; and then at 6 h, 8 h, 24 h, 30 h, 48 h, 52 h, 54 h, 
and 72 h
after the start of study-drug infusion.
On D8 and D15, 0.5 h and 1 h after the start of study-drug infusion; and at the end of the 48-hour study-drug infusion.
Cycle 2:
On D1, every 30 min after the start of the study-drug infusion, until 4 h after the start of the study-drug infusion; and then at 6 h, 8 h, 24 h, 30 h, 48 h and 72 h after 
the start of study-drug infusion.
On D8, 0.5 h and 1 h after the start of study-drug infusion; and at the end of the 48-hour study-drug infusion.
On D15, 1 h, 2 h, 4 h and 6 h after the first intake of oral BAL101553.
On D21, 0.5 h, 1 h, 2 h, 4 h, 8h, 24 h, 30 h and 48 h after the last intake of oral BAL101553. 
Cycle 3 onwards: 1 h after the start of study-drug infusion and at the end of the 48-hour study-drug infusion, on all dosing days. 
SBP must be < 140 mmHg and DBP < 90 mmHg prior to dosing on D1 of Cycle 1 and Cycle 2. Pre-dose on D8 or D15 of Cycles 1 and 2, and on all dosing days from Cycle 3 
onwards, a patient’s SBP must be < 160 mmHg and DBP < 100 mmHg. If a patient’s SBP is > 180 mmHg or DBP is > 110 mmHg on any dosing day, then their SBP must be 
< 140 mmHg and their DBP < 90 mmHg, prior to any subsequent dosing.
If post-dose SB3PP+JRU'%3PP+JRFFXUWULSOH%3PHDVXUHPHQWVZLOOEHWDNHQHYHU\–15 min until return to SBP/DBP < 160/90 mmHg. Patients should 
only be discharged home once BP levels have stabilized to SBP levels < 160 mmHg and DBP levels < 100 mmHg (see Section 5.4.2.5).


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6.
Three sequential (i.e., triplicate) 12-lead ECG are to be obtained, each separated by ~1 min and all taken within a 5-min time window, at Screening to determine study eligibility 
of patients, at the End-of-Study visit and as follows (see Section 5.4.2.6):
Cycle 1: 
On D1, pre-dose, and 1 h, 2 h, 4 h, 8 h, 24 h, 48 h and 72 h after start of study-drug infusion. 
On D8 and D15, pre-dose, 1 h after the start of study-drug infusion, and at the end of the 48-hour study-drug infusion.
Cycle 2:
On D1, pre-dose; and 1 h, 2 h, 4 h, 8 h, 24 h and 48 h after start of study-drug infusion.
On D8, pre-dose, 1 h after the start of study-drug infusion, and at the end of the 48-hour study-drug infusion.
On D15, pre-dose and 6 h after the first intake of oral BAL101553.
On D21, pre-dose, and 1 h, 2 h, 4 h, 8h, 24 h and 48 h after the last intake of oral BAL101553.
Cycle 3 onwards:
Pre-dose on D1 only.
In patients undergoing intra-patient dose escalation or dose reduction; on D1, D8 and D15 of the first two cycles at each new dose level: prior to and 1 h after the start of study-
drug infusion, and at the end of the 48-hour study-drug infusion. 
Triplicate 12-lead ECG should also be obtained when patients experience SBP > 200 mmHg or DBP > 110 mmHg, or whenever clinical cardiovascular signs or symptoms 
occur.
Any abnormal on-study ECG must be transmitted to a central ECG laboratory for evaluation (including QTc assessment).
7.
A transthoracic echocardiography (M-Mode, 2D or 3D) must be performed at Screening and at the End-of-Study visit (see Section 5.4.2.7).
8.
Chest X-ray to establish a baseline for safety assessments, to be repeated as clinically indicated. For tumor assessments where a chest CT scan is performed, a chest X-ray is not 
required. Radiology assessments conducted within the 28 days prior to D1 of Cycle 1 do not need to be repeated during Screening.
9.
Hematology (see Section 5.4.2.8.1) must be performed at each study visit and reviewed:
x Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1.
x Within 1 day prior to administration of BAL101553 on any other dosing day.
10. Biochemistry (see Section 5.4.2.8.2) must be performed according to the same schedule as Hematology.
11. Coagulation and urinalysis (see Sections 5.4.2.8.4 and 5.4.2.8.5) must be performed and reviewed:
x Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1.  
x Within 1 day prior to administration of BAL101553 on D1 of all subsequent cycles.
12. Cardiac troponin (see Section 5.4.2.8.3) must be performed and reviewed:
x Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1.
x At the end of the 48-hour study-drug infusion on D1 of Cycle 1.
x Within 1 day prior to administration of BAL101553 on: Cycle 1 D8 and D15; and Cycle 2 D1, D8 and D15. 
The same test (cardiac troponin-I or troponin-T) must be used consistently for a given patient at Screening and throughout the study.   
13. Women of child-bearing potential must have a negative serum pregnancy test (hCG) at Screening; and a negative serum or urine pregnancy test (hCG) prior to BAL101553 
dosing on D1 of every cycle and at the End-of-6WXG\YLVLW6FUHHQLQJODEVSHUIRUPHG 3 days prior to first dosing, and labs performed within 1 day prior to all other in-clinic 
dosing days, do not need to be repeated (see Section 5.4.2.8.6).


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14. Tumor assessment by radiological exam (CT/MRI scans) will be performed at Screening (or within the 28 days prior to D1) and within the 7 days prior to completion of every 
even-numbered cycle, before administration of the next cycle of BAL101553. From Cycle 6 onwards, the interval between CT/MRI scans may be extended from 8 weeks to 
12 weeks. The End-of-Study assessment does not need to be repeated if an assessment was done within the 28 days prior (see Section 5.4.3.1).
15. Patients who do not have an implantable venous access system (PORT) will undergo (ambulatory) surgery and will receive subsequent training by a qualified nursing team on 
the use and proper handling of the venous access system (see Section 5.4.1.4.6). Implantation of the PORT will be recorded in medical history (see Section 5.4.1.4).
16. On D1 of Cycle 1 and D21 of Cycle 2, patients will be hospitalized up to 3 days after the start of study-drug infusion or first oral-drug administration for serial PK sampling and 
safety monitoring.  The pump should be inspected for functionality 1 h after the start of infusion, after the 30-h PK sample, and 2 h prior to the end of infusion. On all other IV 
dosing days, patients must stay in the study unit for at least 1 h after the start of the BAL101553 infusion, and must return to the unit at least 2 h before the end of the 48-hour 
infusion. Seven consecutive days of BAL101553 oral dosing (Cycle 2 D15–21) will replace the Cycle 2 D15 IV administration of the drug.
17. Non-serious changes in, or worsening of, a patient’s condition that occur between informed consent and first study-drug administration will be collected as pre-dose medical 
history (see Section 5.4.1.1). If any such occurence is considered to be serious, it will additionally be reported following the procedures of an serious adverse event (SAE), to 
allow for an assessment of serious procedure-related events. All AEs occurring from the time of first study-drug administration to 28 days following the last dose of study drug 
will be collected following the procedures outlined in Section 7.3.2.1. AEs occurring between D1 and D28 of Cycle 1 will be assessed against the DLT definitions outlined in 
Table 2. DLTs will additionally be recorded on the End-of-Cycle 1 assessment page of the CRF.
18. Blood PK samples will be collected from all patients at the End-of-Study visit, when a patient reports a DLT (if possible) and as follows (see Section 5.4.4): 
Cycle 1: 
On D1, pre-dose, and 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 30 h, 48 h, 52 h, 54 h and 72 h after the start of study-drug infusion.
On D8 and D15, pre-dose, and 1 h and 48 h after the start of study-drug infusion.
Cycle 2:
On D1, pre-dose, and 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 30 h, 48 h and 72h after the start of study-drug infusion.
On D8, pre-dose, and 1 h and 48 h after the start of study-drug infusion.
On D15, pre-dose.
On D21, pre-dose, and 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 30 h and 48 h after oral administration of BAL101553.
The sampling schedule may be amended based on observed PK in humans. In patients undergoing intra-patient dose escalation or dose reduction, blood PK samples will be 
collected during one cycle at each new dose level for a given patient, according to the schedule for Cycle 1 above. 
19. One blood sample (approximately 4 mL) will be obtained in an EDTA-tube pre-dose on D1 of Cycle 1 and distributed onto Centogene filtercards for dried-blood-spot analysis 
of single nucleotide polymorphisms and/or genes involved in drug transport or drug metabolism or potential biomarkers (see Section 5.4.5.1.2).  
20. Samples for CTCs will be taken at at least two study sites, with the goal to obtain samples from at least 50% of patients at each dose level. Samples will be obtained pre-dose on: 
D1 and D15 of Cycle 1; and D22 of Cycles 1 and 2. Samples for CTCs will also be obtained using the same schedule in patients undergoing intra-patient dose escalation or dose 
reduction, at each new dose level (see Section ). 
21. Where possible, a tumor biopsy will be obtained during Screening if it is agreed to by the patient, is easily accessible, and is deemed safe for the patient. Also, if possible, a post-
treatment biopsy can be obtained on D22 of Cycle 1 and/or Cycle 2. Additional post-treatment biopsies may be obtained on D22 of one subsequent cycle after Cycle 2, or at 
progressive disease (see Section 5.4.5.2).


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Table 2 
Phase 2a - Schedule of assessments
Screening
Cycle 1
Cycle 2
Cycle 3 and subsequent cycles
End of 
Study **
Day (D) of cycle1
íWRí
D1
D8
D15
D22
D28
D1
D8
D15
D22
D28
D1
D8
D15
D22*
D28
Informed consent2
X
Inclusion/exclusion criteria
X
Diagnosis and extent of cancer/prior anticancer therapy3
X
Demographics/medical history/baseline medical conditions and 
medications
X
Physical examination/ECOG performance status4
X
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood pressure6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG7
X
X
X
X
X
X
X
X
X
Echocardiography8
X
X
Chest X-ray9
X
Hematology10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation12
X
X
X
X
X
Urinalysis12
X
X
X
X
X
Cardiac troponin13
X
X
X
X
X
X
X
X
Pregnancy test14
X
X
X
X
X
Radiological assessment of tumor9,15 (RECIST v1.1/RANO criteria)
X
X
X(ENC)
X
CA-125 monitoring (ovarian cancer patients only)
X
X
X(ENC)
X
Implantable venous access system (PORT system)16
X
BAL101553 administration17
X
X
X
X
X
X
X
X
X
Drug dispensing and accountability
X
X
X
X
X
X
X
X
X
Adverse events/ Serious adverse events 18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/treatments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for pharmacokinetics19
X
X
X
X
X
Dried-blood-spot analysis (Centogene cards)20
X
Blood for CTC analysis (ovarian cancer patients only)21
X
X
X
X
Tumor biopsy (ovarian cancer patients only)22
X
X
X
X
Archival tumor specimen collection (when available)
X
ENC = even-numbered cycles.
*Note: D22 visits are optional from Cycle 3 onwards. **Note: For patients in the Phase 2a portion of the study who did not have disease progression at the end of the 28-day safety follow-up period, the 
patient and/or their treating physicians will also be contacted at 4 months and 6 months after the date of their first study-drug administration for the purpose of assessing progression-free survival.


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1.
Deviations from the visit schedule by ± 2 days are permitted for reasons other than toxicity, e.g., for administrative reasons or to accommodate travel logistics. D28 assessments 
of a given cycle may be performed on D29 of that cycle, i.e., pre-dose on D1 of the subsequent cycle. 
2.
Informed consent must be obtained within the 28 days prior to D1 of Cycle 1. Screening assessments must be performed and completed within the 15 days prior to D1/Cycle 1, 
with the exception of radiology assessments, which if conducted within 21 days (GBM patients) or 28 days (ovarian cancer patients) prior to D1 of Cycle 1, do not need to be 
repeated during Screening.
3.
This includes results available regarding BRCA1/BRCA2 mutation status in patients with ovarian cancer and IDH mutation status in GBM patients.
4.
For D1 of all cycles, the physical exam and ECOG status must be performed within the 3 days prior to dosing; if the Screening H[DPZDVSHUIRUPHGGD\VSULRUWR'WKHVH
do not need to be repeated on D1/Cycle 1 (see Sections 5.4.2.3 and 5.4.2.1).
5.
Complete vital signs (see Section 5.4.2.4) will be obtained at Screening, at any D22 in-clinic visit, at the End-of-Study visit, and:
Cycle 1: 
On D1, pre-dose; 0.5 h, 1 h, 2 h, 4 h and 24–30 h after the start of study-drug infusion; at the end of infusion; and 6 h and 24–48* h after the end of infusion.
*Patients treated prior to the first Safety Evaluation only.
All other dosing days: pre-dose, 1 h after the start of study-drug infusion, and at the end of infusion.
The body weight measurement must be obtained within the 3 days prior to dosing on D1 of all cycles.
6.
Triple BP measurements should be taken at Screening, pre-dose on all dosing days, at any D22 in-clinic visit, and at the End-of-Study visit. Single BP measurements will be 
obtained:
Cycle 1: 
On D1, 0.5 h, 1 h, 2 h, 4 h and 24–30 h after the start of study-drug infusion; at the end of infusion; and 6 h and 24–48* h after the end of infusion.
*Patients treated prior to the first Safety Evaluation only.
All other dosing days: 1 h after the start of study-drug infusion, and at the end of infusion.
SBP must be < 140 mmHg and DBP < 90 mmHg prior to dosing on D1 of Cycle 1 and Cycle 2. Pre-dose on D8 or D15 of Cycles 1 and 2, and on all dosing days from Cycle 3 
onwards, a patient’s SBP must be < 160 mmHg and DBP < 100 mmHg. If a patient’s SBP is > 180 mmHg or DBP is > 110 mmHg on any dosing day, then their SBP must be 
< 140 mmHg and their DBP < 90 mmHg, prior to any subsequent dosing.
If post-GRVH6%3PP+JRU'%3PP+JRFFXUWULSOH%3PHDVXUHPHQWVwill be taken every 10–15 min until return to SBP/DBP < 160/90 mmHg. Patients should 
only be discharged home once BP levels have stabilized to SBP levels < 160 mmHg and DBP levels < 100 mmHg (see Section 5.4.2.5).
7.
Three sequential (i.e., triplicate) 12-lead ECG are to be obtained, each separated by ~1 min and all taken within a 10-min time window, at Screening to determine study 
eligibility of patients, at the End-of-Study visit and as follows (see Section 5.4.2.6):
Cycle 1: 
On D1, pre-dose; 1 h, 2 h, 4 h and 24–30 h after the start of study-drug infusion; at the end of infusion; and 6 h and 24–48* h after the end of infusion.
*Patients treated prior to the first Safety Evaluation only.
All other dosing days in Cycles 1 and 2:
pre-dose, 1 h after start of study-drug infusion, and at the end of infusion.
Cycle 3 onwards:
Pre-dose on D1 only.
Triplicate 12-lead ECG should also be obtained when patients experience SBP > 200 mmHg or DBP > 110 mmHg, or whenever clinical cardiovascular signs or symptoms 
occur.
Any abnormal on-study ECG must be transmitted to a central ECG laboratory for evaluation (including QTc assessment).


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8.
A transthoracic echocardiography (M-Mode, 2D or 3D) must be performed at Screening and at the End-of-Study visit (see Section 5.4.2.7).
9.
Chest X-ray to establish a baseline for safety assessments, to be repeated as clinically indicated. For tumor assessments where a chest CT scan is performed, a chest X-ray is not 
required. Radiology assessments conducted within 21 days (GBM patients)  or 28 days (ovarian cancer patients) prior to D1 of Cycle 1 do not need to be repeated during 
Screening.
10. Hematology (see Section 5.4.2.8.1) must be performed at each study visit and reviewed:
x Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1.
x Within 1 day prior to administration of BAL101553 on any other dosing day.
11. Biochemistry (see Section 5.4.2.8.2) must be performed according to the same schedule as Hematology.
12. Coagulation and urinalysis (see Sections 5.4.2.8.4 and 5.4.2.8.5) must be performed and reviewed:
x At Screening and at the End-of-Study visit
x Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1.  
x Within 1 day prior to administration of BAL101553 on D1 of all subsequent cycles.
13. Cardiac troponin (see Section 5.4.2.8.3) must be performed and reviewed:
x At Screening and at the End-of-Study visit
x Within the 3 days prior to first administration of BAL101553 on D1 of Cycle 1. 
x At the end of the 48-hour study-drug infusion on D1 of Cycle 1.
x Within 1 day prior to administration of BAL101553 on: Cycle 1 D8 and D15; and Cycle 2 D1, D8 and D15. 
The same test (cardiac troponin-I or troponin-T) must be used consistently for a given patient at Screening and throughout the study.   
14. Women of child-bearing potential must have a negative serum pregnancy test (hCG) at Screening; and a negative serum or urine pregnancy test (hCG) prior to BAL101553 
dosing on D1 of every cycle and at the End-of-6WXG\YLVLW6FUHHQLQJODEVSHUIRUPHG 3 days prior to first dosing, and labs performed within 1 day prior to all other in-clinic 
dosing days, do not need to be repeated (see Section 5.4.2.8.6).
15. Tumor assessment by radiological exam (CT/MRI scans) and CA-125 monitoring (only in ovarian cancer patients) will be performed at Screening, or within the 28 days prior to 
D1 (within the 21 days prior to D1 for GBM patients); and within the 7 days prior to completion of every even-numbered cycle, before administration of the next cycle of 
BAL101553. The End-of-Study assessment does not need to be repeated if an assessment was done within the 28 days prior (see Section 5.4.3.1).
16. Patients who do not have an implantable venous access system (PORT) will undergo (ambulatory) surgery and will receive subsequent training by a qualified nursing team on 
the use and proper handling of the venous access system (see Section 5.4.1.4.6). Implantation of the PORT will be recorded in medical history (see Section 5.4.1.4).
17. On D1 of Cycle 1, patients may be hospitalized up to 3 days after the start of study-drug infusion for serial PK sampling and safety monitoring (see Section 6.5). The pump 
should be inspected for functionality 1 h after the start of infusion, after the 24–30-h PK sample, and 2 h prior to the end of infusion. On all other IV dosing days, patients must 
stay in the study center for at least 1 h after the start of the BAL101553 infusion, and must return to the unit at least 2 h before the end of the 48-hour infusion. 


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18. Non-serious changes in, or worsening of, a patient’s condition that occur between informed consent and first study-drug administration will be collected as pre-dose medical 
history (see Section 5.4.1.1). If any such occurence is considered to be serious, it will additionally be reported following the procedures of an serious adverse event (SAE), to 
allow for an assessment of serious procedure-related events. All AEs occurring from the time of first study-drug administration to 28 days following the last dose of study drug 
will be collected following the procedures outlined in Section 7.3.2.1.
19. Blood PK samples will be collected from all patients at the End-of-Study visit and as follows (see Section 5.4.4): 
Cycle 1: 
On D1, pre-dose; 1 h, 4 h and 24–30 h after the start of study-drug infusion; at the end of infusion; and 6 h and 24–48* h after the end of infusion.
On D8, pre-dose and at the end of infusion.
*Patients treated prior to the first Safety Evaluation only.
Cycle 2:
on D1 and D8, pre-dose and at the end of infusion.
In patients undergoing intra-patient dose reduction: at each new dose level, D1 and D8 of the first cycle: pre-dose and at the end of infusion.
The sampling schedule may be amended based on observed PK in humans. 
20. One blood sample (approximately 4 mL) will be obtained in an EDTA-tube pre-dose on D1 of Cycle 1 and distributed onto Centogene filtercards for dried-blood-spot analysis 
of single nucleotide polymorphisms and/or genes involved in drug transport or drug metabolism or potential biomarkers (see Section 5.4.5.1.2).  
21. Samples for CTCs will be taken at at least two study centers, with the goal to obtain samples from at least 50% of ovarian cancer patients. Samples will be obtained pre-dose on: 
D1 and D15 of Cycle 1; and D22 of Cycles 1 and 2 (see Section 5.4.5.1). Samples for CTC analysis will not be obtained from GBM patients.
22. Where possible, a tumor biopsy will be obtained from ovarian cancer patients during Screening if it is agreed to by the patient, is easily accessible, and is deemed safe for the 
patient. Also, if possible, a post-treatment biopsy can be obtained on D22 of Cycle 1 and/or Cycle 2. Additional post-treatment biopsies may be obtained on D22 of one 
subsequent cycle after Cycle 2, or at progressive disease (see Section 5.4.5.2). Tumor biopsies will not be obtained from GBM patients.


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2.2.6
Planned sample size
Of the 20 patients dosed in the dose-escalation portion, 16 were MTD-evaluable.
Up to 20 evaluable ovarian cancer patients and up to 20 evaluable GBM patients will be
included in the expansion portion. 
Assuming an ~25% drop-out rate, up to 70 patients may be enrolled.
The 3+3 design does not require sample size specification; the escalation is continued
until the MAD (i.e., a dose with an unacceptable number of DLT) is observed. The 
expansion portion is exploratory; therefore, no statistical sample size justification has 
been applied.
2.2.7
Interim analyses
No interim analyses are planned.
3
ANALYSIS POPULATIONS
3.1
Full analysis population
The full analysis population (FAP) includes all patients who received at least one partial 
or complete dose of study drug. The FAP will be used for analyzing efficacy.
For efficacy analyses, patients will be primarily analyzed according to their originally-
assigned dose level. In the case that intra-patient dose escalation or reduction occurs in a
substantial number of patients, additional analyses may be produced.
3.2
Efficacy evaluable population
Separate Efficacy evaluable populations (EEPs) will  be  defined for  the  Phase  2a  
ovarian  cancer  and  GBM  target populations.
The EEPs include all Phase 2a patients:
x
With progressive disease who completed at least Cycle 1 dosing (i.e., received study 
drug on Days 1, 8 and 15) and who underwent at least one on-study clinical tumor 
assessment, or radiological assessment by RECIST v1.1 guidelines (ovarian cancer 
patients) or RANO criteria (GBM patients).
x
With stable disease, partial response, or complete response, based on a radiological
assessment by RECIST v1.1 guidelines (ovarian cancer patients) or RANO criteria 
(GBM patients) at the end of Cycle 2, who received at least four doses of study drug 
in the first two cycles.
The EEPs will be the primary populations for analyzing efficacy in Phase 2a. Efficacy
will also be analyzed in the FAP population.
Separate analyses will be performed for the ovarian cancer and GBM target populations.


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3.3
Safety population
All patients who receive at least one full or partial dose of BAL101553 and had at least 
one post-baseline safety assessment must be included in the safety analysis population. In 
this context, documented information that a patient had no AEs constitutes a safety 
assessment. The safety analysis population must be used for all safety related analyses 
(AEs, vital signs, laboratory data, etc.).
For safety analyses, patients will be primarily analyzed according to their originally-
assigned dose level. In the case that intra-patient dose escalation or reduction occurs in a
substantial number of patients, additional analyses may be produced.
3.4
Maximum tolerated dose-determining population
The MTD-determining population includes all Phase 1 patients from the safety set who 
meet the following minimum criteria during the first 28-day treatment cycle (Cycle 1):
x
Received at least one partial or complete dose of BAL101553 and has experienced a
DLT;
x
Received all three doses of BAL101553 without experiencing a DLT (including the 
ability to initiate treatment Cycle 2), 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 full
analysis/safety population but will be excluded from the calculation of DLT incidence
and will be replaced by recruitment of additional patients.
Patients who received less than 80% of the assigned dose at any visit during Cycle 1, e.g. 
due to a protocol recommended dose reduction following an AE or due to an 
administration error, will only be considered as valid for the MDT-determining 
population if these patients experience a subsequent DLT during Cycle 1. Patients who
have received a lower-than-assigned dose and have tolerated BAL101553 without a DLT 
will be excluded from the MTD-determining population, as the toxicity assessment is not 
considered to be representative for the originally-assigned dose level.
Patients who received more than 125% of the assigned dose at any visit during Cycle 1, 
e.g., due to an administration error, will only be considered as valid for the MTD-
determining population if these patients experience no subsequent DLT during Cycle 1.
3.5
Pharmacokinetic analysis population
The PK analysis set includes all patients who received at least one partial or complete
dose of study drug and had at least one post-baseline PK assessment.


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4
STATISTICAL CONSIDERATIONS AND ANALYSIS
4.1
Derived variables
The following derived variables will be applied throughout the study:
x
Baseline is defined as the last available assessment prior to first dose intake 
(including unscheduled assessments), e.g., Cycle 1 Day 1 pre-dose.
x
Last/Final for safety is the first available value after treatment or, if not available, 
then the value immediately before last treatment (but not before first treatment).
x
Adverse event duration (in days, hours or fractions of hours) will be calculated as: 

(<event end date.time> minus <event onset date.time>) in days or hours.
If only the date is collected:

((<event end date> minus <event onset date>) + 1) in days
x
The following algorithm will be used for the study day determination:

Day 1 = Day of first study drug administration (i.e., at Cycle 1 Day 1). The day 
before Day 1 is Day í1.

Prior to Day 1 the algorithm is (<visit/examination date> minus <date of first 
study drug administration >)

Day 1 and subsequent days = (<visit/examination date> minus <date of first study 
drug administration >) + 1.
x
Age will not be recalculated rather, that collected by the investigator will be used for 
all analyses.
x
Duration of exposure (in days) will be calculated as: Date of last study drug 
administration í Date of first study drug administration + 1.
x
The response according to RECIST v1.1 guidelines (ovarian cancer patients) or 
RANO criteria (GBM patients) will be as reported in the CRF.
4.2
Handling of missing data and/or invalid data and outliers
Patients whose clinical response is unknown or not reported will be treated as non-
responders for summarizing the overall response rate.
Incomplete/partial dates will be replaced by derived variables and imputed using the 
following rules:
x
If the day of the month is missing, it is imputed to be the 15th if not in the month of 
treatment. In the event that this leads to inconsistencies with other available data for 
the patient or if in the month of treatment, the imputation values will be handled case-
by-case.
x
If both the day and month are missing, they are imputed to be 30 June if not in the 
year of treatment. In the event that this leads to inconsistencies with other available 
data for the patient or if in the year of treatment, the imputation values will be 
handled case-by-case.
x
Missing years will be left as missing.


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x
Missing time will be replace by ‘00:00’ for start times and ‘23:59’ for end times if 
time is required.
x
Missing minutes will be replace by ‘00’ for start times and ‘59’ for end times if time 
is required.
5
STATISTICAL PLAN AND METHODS
The statistical analysis will be performed using the software package SAS version 9.3 or 
higher (SAS Institute Inc., Cary, NC 27513, USA). All individual patient data, and results 
of statistical analyses, will be presented in individual patient data listings and statistical 
summary tables. 
Where necessary, tables, figures and listings (TFLs) will be presented by phase in which 
case Phase 1 TFLs will be presented by dose level and overall while Phase 2a will be 
presented by cancer type and overall.
In general, continuous variables will be summarized using the following standard 
descriptive summary statistics: mean, standard deviation, median, minimum, maximum 
and number of observations. Categorical data will be described using frequency and 
percentage. Shift tables will be provided, where appropriate. One additional decimal 
point will be used for mean, median, Q1, Q3, and two additional decimal points will be 
used for SD. Percentages will be rounded to one decimal place or more if most results are 
close to 0 or 100.
Any changes in the planned statistical methods will be documented in the clinical study 
report.
The following international dictionaries will be used for medical coding:
x
Medical History events:
MedDRA (version 19.0 or later)
x
Medications: WHO Drug Dictionary (WHODrug Enhanced version March 2017 or 
later)
x
Adverse events: MedDRA (version 19.0 or later)
x
Prior cancer related surgery (MedDRA Version 19.0 or later)
x
Prior and concomitant procedures (MedDRA Version 19.0 or later)
x
Prior cancer treatments  (WHODrug Enhanced version March 2017)
5.1
Background characteristics
5.1.1
Patient disposition
Enrollment and disposition data will be presented for each patient in data listings, and 
summarized by frequency tables.
Inclusion and exclusion criteria violations and patient enrollment eligibility will be 
presented by dose cohort and patient in data listings.


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5.1.2
Protocol deviations
Important protocol deviations such as the following will be tabulated by center and 
category and listed:
x
Entered into the study even though they did not satisfy entry criteria
x
Development of withdrawal criteria (as per protocol) during the study, but patient not 
withdrawn
x
Wrong study treatment received, or an incorrect dose 
x
Use of prohibited concomitant medications (as per protocol)
x
Other data deviations as observed upon review of the data
Reported protocol deviations will be reviewed prior to database lock.
5.1.3
Demographic and baseline characteristics
Background and demographic characteristics of the full analysis population (FAP) 
including age at screening, gender, height, weight, race, patient status at selection, child-
bearing potential status for female patients, birth control details, tumor type, body surface 
area (BSA) at baseline, ECOG performance status and medical conditions (including 
diagnosis and extent of cancer at screening), will be summarized by dose cohort using 
descriptive statistics or frequency tables, as appropriate. Percentages will be based on the 
number of patients with available observations in the FAP.
Demographic information will be presented in data listings sorted by dose cohort and 
patient.
5.1.4
Medical history
Previous or current diseases as well as previous cancer treatments (including surgery and 
radiotherapy) will be presented in data listings sorted by dose cohort and patient.
Medical history data will be summarized by dose cohort, system organ class and 
preferred term using the FAP.
5.2
Efficacy analysis
5.2.1
Dose-limiting toxicity
The dose limiting toxicities in Phase 1 will be listed by patient, and will be summarized
for each dose cohort from Phase 1 using the MTD-determining population.
5.2.2
Objective response rate
The objective response rate (ORR) will be calculated using the EEPs and FAP as the 
proportion of patients responding (i.e., with a best objective response of complete 
response [CR] or partial response [PR] based on RECIST v1.1 guidelines for patients 
with solid tumors (excluding GBM), and RANO criteria for patients with GBM).
Progressive disease may be determined based on clinical or radiological (RECIST v1.1 or 
RANO criteria) assessments. Clinical progression is considered PD.


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A patient who has a clinical response unknown or not reported will be treated as a non-
responder.
The proportion and its exact 95% confidence interval (CI) will be presented by dose 
cohort and disease subgroup, if appropriate.
5.2.3
Disease control rate
The disease control rate will be calculated using the EEPs and FAP as the proportion of 
patients with disease controlled (i.e., CR, PR or stable disease [SD]) after two treatment 
cycles, after four treatment cycles, and at the end of treatment. 
A patient who has a clinical response unknown or not reported will be treated as a non-
responder.
The proportion and its exact 95% CI will be presented by dose cohort and disease 
subgroup if appropriate.
5.2.4
Progression-free survival
Progression-free survival (PFS) is defined as the interval between the date that the first 
infusion started, and the earliest date of objective disease progression according to 
RECIST v1.1 criteria (excluding GBM patients), RANO criteria (GBM patients) or
Investigator-confirmed clinical progression; or death due to any cause in the absence of 
progression.
Patients who have not progressed or died at study closure will be censored at the time of 
their last objective tumor assessment. 
If a patient has no post-baseline objective tumor assessment, the PFS will be censored to 
0 days.
Progression-free survival at 6 months defined as the proportion of patients who have not 
progressed 6 months after first study drug administration will be summarized alongside 
the overall Progression-free survival.


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Progression-free survival at 6 months and overall will be summarized for the EEPs and 
FAP by dose group. The following statistics will be displayed:
x
The proportion of patients progression-free associated with its exact 95% CI.
x
The median time to progression or death will be determined by Kaplan-Meier 
method. Its 95% CI will be performed using the Brookmeyer-Crowley method. The 
associated survival curve will be displayed.
x
PFS at 6 month timepoint to be estimated using the Kaplan-Meier method
Progression-free survival will be listed for the EEPs and the FAP by patient and dose 
level, and by disease subgroup if appropriate.
5.2.5
Exploratory and additional efficacy analysis
5.2.5.1
Tumor measurements
The percentage change from baseline to the smallest tumor size (in the sum of diameters 
i.e., the sum of the longest diameter for non-nodal target lesions plus the sum of the short 
axis for nodal lesions based on RECIST criteria or sum of products of perpendicular 
diameters of all measurable enhancing lesions based on RANO criteria) will be 
summarized using standard descriptive statistics. These data will also be listed by patient 
and dose group. The percentage changes in the sum of tumor diameters will be presented 
in waterfall and spider plots.
5.2.5.2
Biomarker analysis
This SAP does not address biomarker analysis for this study. 
5.2.6
Pharmacokinetic analysis
Pharmacokinetic analysis for this study is addressed in a separate SAP (concentrations 
will however be listed).
5.3
Safety analysis
Safety assessments will be conducted throughout the entire study period. Analyses will 
be performed using safety population, unless otherwise specified. 
The safety evaluations will include analyses of adverse events, laboratory assessments 
(hematology, biochemistry, cardiac troponin, coagulation and urinalysis), pregnancy 
testing in women of childbearing potential, ECG, transthoracal echocardiography, chest 
X-ray/CT scan, vital signs, ECOG performance status, physical examination, and 
evaluation of concomitant medications.
5.3.1
Treatment exposure
The duration (in days) of BAL101553 exposure will be listed by patient and summarized 
using descriptive statistics by dose group.
The actual dose of BAL101553 received and study drug dose (including oral dose)
interruptions and reductions will be listed by patient, and summarized using descriptive 
statistics by dose group and treatment cycle.


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Actual dose administered at visit (for infusions) is computed as:
Actual dose = planned dose *(total amount administered [ml] / pump volume [ml])
Treatment compliance per administration will be computed as:
Compliance [%] = actual amount / planned amount = (Total Amount [ml] / nominal 
pump volume [ml])*100%
Overall treatment compliance will be computed as the average of treatment compliance 
per administration over all administrations.
5.3.2
Adverse events
Adverse event (AE) tables and listings will display only treatment-emergent adverse 
events. Any non-treatment-emergent AEs will be displayed in a separate listing.
Treatment-emergent events are defined as all events occurring after BAL101553 
treatment begins, up to 28 days after last study drug administration. Any adverse event 
starting prior to the first treatment on Cycle 1 Day 1 will be considered as medical 
history, while AEs that start more than 28 days after last study drug administration will 
be considered as non-treatment-emergent. The relationship of an AE to study drug is 
recorded as not related, unlikely, possible, or probable.
For analysis purposes, ‘related’ AEs will be those reported as possibly related or probably 
related, or those for which the relationship is unknown.
Adverse events will be presented in data listings including dose cohort, patient, 
dates/times, study day of event, MedDRA System Organ Class, Preferred Term, duration 
of the event, seriousness, CTCAE grade, intensity, drug adjustment, treatment taken, 
relationship to study drug, and outcome.
An overview table (including only treatment-emergent AEs) will also be presented with 
the number (and percentage) of patients with:
x
At least one AE
x
At least one related AE
x
CTCAE grade 3/4 or severe AEs
x
CTCAE grade 3/4 or severe related AEs
x
At least one SAE
x
At least one related SAE
x
AEs leading to dose modifications (i.e., dose reduced or dose interrupted)
x
Related AEs leading to dose modifications (i.e., dose reduced or dose interrupted)
x
AEs leading to study drug discontinuation
x
Related AEs leading to study drug discontinuation
x
AEs leading to death


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x
Related AEs leading to death
The number of events will be also included in this overview table. This table will be 
displayed by dose cohort for the full study period. 


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All treatment-emergent AEs and treatment-emergent AEs related to treatment will be 
summarized by incidence rate tables broken down by:
x
System Organ Class, Preferred Term and lowest level term.
x
System Organ Class, Preferred Term and worst CTCAE grade.
x
System Organ Class, Preferred Term, lowest level term and worst CTCAE 
grade/severity.
x
System Organ Class, Preferred Term and drug relationship (only for treatment-
emergent AEs).
The incidence rate table for treatment-emergent AEs and treatment-emergent AEs related 
to treatment by System Organ Class, Preferred Term, lowest level term and worst 
CTCAE grade/intensity will be repeated by treatment cycle using the actual dose received 
within each cycle.
In addition, all treatment-emergent AEs and treatment-emergent AEs related to study 
drug will be summarized by System Organ Class, Preferred Term, lowest level term and:
x
Worst CTCAE grade and cycle of occurrence of first event
x
Worst CTCAE grade during Cycle 1 and during the study overall
Treatment-emergent AEs leading to dose modifications or study drug discontinuation will 
be also summarized by System Organ Class and Preferred Term.
5.3.3
Laboratory evaluation
The laboratory tests for safety analyses comprise the following:
x
Hematology: Hemoglobin (Hb), hematocrit (Hct), red blood cell (RBC) count, 
platelet count, and total and differential white blood cell (WBC) count (neutrophil 
including bands, lymphocyte, monocyte, eosinophil, and basophil counts).
x
Serum biochemistry: Serum creatinine, blood urea nitrogen (BUN), uric acid, sodium, 
potassium, chloride, calcium, inorganic phosphorus, glucose, albumin, total protein, 
AST, 
ALT, 
total 
bilirubin, 
alkaline 
phosphatase 
(AP), 
lipase, 
lactate 
dehydrogenase(LDH), and creatine phosphokinase (CK).
x
Cardiac troponin: Either troponin T or troponin I.
x
Coagulation: International normalized ratio (INR) for reporting prothrombin time and 
activated partial thromboplastin time (APTT).
x
Urinalysis: Dipstick analysis for specific gravity, glucose, protein, and blood. 
Microscopic analysis for white blood cells, red blood cells and any additional 
findings (such as casts). 
x
Pregnancy test (at screening, D1 of every cycle): Serum or urine test for human 
chorionic gonadotropin (hCG).
Laboratory values will be converted into SI units and the severity grade determined based 
on CTCAE v4.03.


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Descriptive statistics for each laboratory analyte at each assessment time will be 
tabulated. The change from baseline will also be summarized.
An analysis of individual patient changes by dose cohort will be presented using shift 
tables showing the change from CTCAE grade/intensity at baseline to the worst CTCAE 
grade/intensity (including unscheduled assessments) during the study.
The laboratory parameters will be presented in data listings sorted by dose cohort, 
patient, study day, study time, and analyte. Out-of-range values will be flagged with 
h (high) or l (low). Out-of-marked-range values
(defined by Basilea SOP 
LIS-GLO-000412 Preferred Units and Marked Factors) will be flagged with H (marked 
high) or L (marked low). 
The number and percentage of patients with laboratory values outside the marked 
reference range will also be tabulated by visit for each analyte.
A laboratory adverse change is defined as a change from baseline of either normal or
high to low, or normal or low to high, as defined by the reference ranges. 
A laboratory marked adverse change is defined as a change from baseline of either low, 
normal, high or marked high to marked low, or marked low, low, normal or high to 
marked high, as defined by the reference ranges and marked reference ranges. 
The number and percentage of patients who have an adverse change (defined from the 
normal reference range) from baseline will be summarized by laboratory parameter and 
visit. The same analysis will be performed for marked adverse changes.
The number and percentage of patients with (1) any adverse change, (2) an adverse 
change that either occurs at the first post-treatment assessment or at two subsequent 
assessments, or (3) an adverse change that occurs on treatment and is not repeated at the 
subsequent assessment, will be tabulated. The same analysis will be performed for 
marked adverse changes.
5.3.4
Vital signs
Summary statistics by dose cohort and scheduled time point will be presented for each 
vital sign. The change from baseline will also be presented. 
Summary statistics for baseline blood pressure and change from baseline (pre-dose on the 
study day on which infusion starts, to post-dose infusion timepoints 0.5, 1, 1,5, 2,…72 h
according to schedule) will be presented by dose at study days C1D1, C1D8, C1D15,
C2D1 C2D15 and C2D21. The mean maximum change from baseline (the average of the 
maximum change between baseline and all timepoints post baseline) will also be 
presented.
If blood pressure is collected on both arms, the average value of measurements from both 
arms and positions will be taken for the analyses. 
The number of patients with values outside marked reference ranges will also be 
tabulated by dose cohort and scheduled time point.
The vital signs marked reference ranges are:


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x
Diastolic blood pressure: < 60 mmHg or > 100 mmHg.
x
Systolic blood pressure: < 80 mmHg or > 180 mmHg.
x
Pulse: < 40 beats/min or > 120 beats/min.
x
Temperature: < 36.0 degrees Celsius or > 38.5 degrees Celsius.
Vital sign assessments will be presented for each patient in a data listing.
5.3.5
ECG results
A summary of clinically-significant findings from the 12-lead ECG (CRF data) will be 
provided for each dose cohort and time point using a shift table. For this analysis, if the 
findings for the three assessments at Cycle 1 Day 1 pre-dose are different, the baseline 
will be defined as the worst assessment prior to administration of the first dose (if Cycle 1 
Day 1 assessments are not done, screening assessments will be used as baseline). For 
each post-dose time point, the worst assessment of the three triplicates will be taken for 
the analysis. 
The 12-lead ECG results (RR interval and QTcF interval reported in the CRF) and 
changes from baseline will be summarized using standard descriptive statistics by dose 
cohort and scheduled time point. The mean of the three ECGs measurements taken at 
each time point will be used for the summary. For this analysis, the baseline value will be 
defined as the mean of the three ECGs measurements taken prior to first dose intake.
The same analysis will be repeated on central ECG data (HR, RR, PR, QRS, QT, QTcB, 
QTcF) 
ECG results will be presented for each patient in a data listing.
5.3.5.1
Outlier analysis
The number and percentage of patients with maximum on-treatment value of QT/QTc 
LQWHUYDOV FDWHJRUL]HG DV  450 msec, > 450 msec and  480 msec, > 480 msec and 
 500 msec, and > 500 msec, as well as maximum on-treatment change from baseline 
value of QT/QTc intervals, categorized as < 5 msec, 5 msec and < 10 msec,  10 msec 
and < 20 msec, 20 msec and < 30 msec, 30 msec and < 60 msec, and 60 msec will 
be tabulated based on scheduled and unscheduled 12-lead ECG measurements (CRF and 
central ECG data).
The following abnormalities will also be tabulated:
x
PR abnormality: PR increase from baseline 25% when PR > 200msec
x
QRS abnormality: QRS increase from baseline 25% when QRS > 100 msec
x
HR abnormality: HR decrease from baseline 25% when HR < 50bpm, or  25% 
increase when HR > 100bpm.
5.3.6
Physical examination
General physical examination assessments will be listed by dose cohort, patient, and 
study day.
The incidence of abnormality in physical examination will be tabulated for each visit.


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5.3.7
Prior and concomitant medications 
Medications and significant non-drug therapies prior to and after first administration of 
the study drug will be listed by patient.
The concomitant medications taken after the first administration of the study drug (i.e.,
medications which either starts before and stops after first study drug administration, or 
medications which start after first study drug administration) will be summarized by ATC 
term and dose group.
5.3.8
Chest X-ray/CT 
Chest X-ray/CT scan abnormality results will be presented for each patient in a data 
listing.
5.3.9
ECOG performance status
All patients will be evaluated for ECOG performance status at Screening, at Day 1 (or 
within 72 hours prior to Day 1) of each treatment cycle prior to BAL101553 
administration, and at the End of Study visit. 
ECOG performance status will be presented in a frequency table by dose cohort and 
scheduled time point. ECOG performance status will also be presented for each patient in 
a data listing.
5.3.10 Transthoracic echocardiography
A transthoracic echocardiography (M-mode, 2D, or 3D) will be performed at Screening,
and at the end of study visit to assess the left ventricular ejection fraction (LVEF) and 
regional wall motion abnormalities.
Transthoracic echocardiography results will be presented for each patient in a data listing.
6
CHANGES 
FROM 
THE 
PLANNED 
ANALYSIS 
IN 
STUDY
PROTOCOL
Not applicable.


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7
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