Conditions: Metastatic Renal Cell Carcinoma Advanced Urothelial Carcinoma Advanced Gastric Adenocarcinoma Metastatic Colorectal Adenocarcinoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 263
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, and efficacy of single agent ibrutinib or the combination treatments of ibrutinib with everolimus, paclitaxel, docetaxel, pembrolizumab or cetuximab in selected advance gastrointestinal and genitourinary tumors.

Detailed description:

Arms:
arm 1: Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of everolimus to determine the recommended phase 2 dose (RP2D) of ibrutinib. (The RP2D was determined for each cohort separately.)

Phase 2: Participants receive ibrutinib at the RP2D determined in phase 1b in combination with everolimus. arm 2: Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of paclitaxel to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)

Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with paclitaxel. arm 3: Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of docetaxel to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)

Phase 2: Participants receive docetaxel at the RP2D determined in Phase 1b in combination with docetaxel. arm 4: Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of cetuximab to determine RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)

Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with cetuximab. arm 5: Phase 1b: Participants receive ibrutinib at various dose levels to determine the RP2D of ibrutinib.(The RP2D was determined for each cohort separately.)

Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b. arm 6: Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of pembrolizumab to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.)

Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with pembrolizumab.

Interventions: intervention 1: ibrutinib intervention 2: everolimus intervention 3: paclitaxel intervention 4: docetaxel intervention 5: cetuximab intervention 6: pembrolizumab
Intervention descriptions: intervention 1: Ibrutinib administered orally once daily with 8 ounces (approximately 240 mL) of water. intervention 2: Everolimus 10 mg tablets should be taken orally once daily at the same time every day, either consistently with food or consistently without food. Four (4) x 2.5 mg tablets or two (2) x 5.0 mg tablets may be substituted if 10 mg tablet strength is not available. intervention 3: Paclitaxel should be administered as a 60-minute (±10 minutes) infusion. Paclitaxel should be given at a dose level of 80 mg/m\^2, once weekly, in continual 3 weekly cycles. intervention 4: Docetaxel administered as a 60 minute infusion (±10 minutes) at a dose level of 60 - 75 mg/m\^2 (according to local institutional standard of care), given continually in 21-day cycles. intervention 5: Cetuximab 400 mg/m\^2 administered as a 120-minute IV infusion. The recommended subsequent weekly dose (all other infusions) is 250 mg/m\^2 infused over 60 minutes. intervention 6: Pembrolizumab 200 mg intravenous (IV) every 3 weeks.

Protocol document:
Prot_000.pdf: 


































































































































































































































































































































Ibrutinib (PCI-32765)                                                                             PCYC-1128-CA Amendment 2.0 
  
 
 
 
 
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Page 162 
a. Vital signs will be assessed after the subject has been resting in the sitting position for at least 3 minutes. 
b. All assessments are to be performed prior to dosing unless otherwise specified. 
c. Continuous from the signing of ICF or 14 days prior to the first dose of study drug (whichever is greater) through 30 days after the last dose of study drug. 
d. AEs are reported from the time the subject signs the ICF until 30 days following last dose of study drug. All new malignant tumors are to be reported as AEs 
through Long Term Follow-up for OS. 
e. Cycle 1 Day 1 ONLY: Assessment of AEs for 2 hours post everolimus administration. At the discretion of the investigator, subject may leave clinic 2 hours 
post everolimus administration. 
f. 
At Screening, 12-lead ECGs will be recorded. Abnormalities noted at Screening should be included in the medical history. 
g. Hepatitis serologies evaluated by central laboratory. If hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody is positive, then PCR must 
be performed and must be negative prior to enrollment.  
h. Serum or urine pregnancy test will be required at Screening (within 3 days of Day 1) for women of childbearing potential. The test must be repeated prior to 
first dose if not performed within 3 days of C1D1. The test will be performed locally. 
i. 
Measurements of lesions using RECIST 1.1 criteria is required where CT/MRI was obtained. 
j. 
Predose and postdose PK and PDn samples will be collected per the schedule in Appendix 2. 
k. Predose PDn sample will be collected on C1D1. 
l. 
Blood and urine samples for biomarkers will be collected prior to dosing on Day1 for the first 3 cycles and then Day 1of every 3rd cycle thereafter until 
RECIST 1.1 documented disease progression, CR or EOT. 
m. Archival tumor biopsy tissue will be collected when available or optional fresh tumor will be collected on consenting subjects at Screening and upon 
documented disease progression. Fresh tumor biopsy at Screening must be performed 7 days prior to enrollment.  
n. Subjects who are withdrawn for reasons other than RECIST 1.1 determined progression will continue to have normally scheduled clinical and radiological 
disease assessments (CT/MRI) until disease progression is documented, death, withdrawal of consent for further follow up, or lost to follow up, whichever 
occurs first 
o. Everolimus 10 mg PO qd should be administered 6 hours (± 15 minutes) after ibrutinib. 
 
 
 
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Ibrutinib (PCI-32765)                                                                             PCYC-1128-CA Amendment 2.0 
  
 
 
 
 
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Appendix 2. C2D1: Pharmacokinetics and Pharmacodynamics Sampling Schedule – Renal Cell Carcinoma (RCC) Cohort 1c 
Cycle 
Study Day 
Predose 
Time after ibrutinib Dosinga 
1 h ± 15 min 
2 h ± 15 min 
4 h ± 15 min 
6 h ± 15 min 
2 
1 
Xb 
X 
X 
X 
X 
a. Record actual time of sample collection. 
b. PK and PDn samples collected 24 hours (± 2 hours) after previous ibrutinib dose and prior to ibrutinib dosing on Cycle 2 Day 1, which is also 
prior to everolimus administration since ibrutinib is dosed 6 hours before everolimus dosing. 
c. PK samples will be collected in all cohort 1 subjects for ibrutinib PK determination only.  
 
 
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Ibrutinib (PCI-32765)                                                                             PCYC-1128-CA Amendment 2.0 
  
 
 
 
 
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Page 165 
a. 
Vital signs will be assessed after the subject has been resting in the sitting position for at least 3 minutes. 
b. 
All assessments are to be performed prior to dosing unless otherwise specified. 
c. 
Continuous from the signing of ICF or 14 days prior to the first dose of study drug (whichever is greater) through 30 days after the last dose of study drug. 
d. 
AEs are reported from the time the subject signs the ICF until 30 days following last dose of study drug. All new malignant tumors are to be reported as AEs 
through Long Term Follow-up for OS. 
e. 
Cycle 1 Day 1 ONLY: Assessment of AEs for 2 hours post paclitaxel infusion. At the discretion of the investigator, subject may leave clinic 2 hours post 
paclitaxel infusion. 
f. 
At Screening, 12-lead ECGs will be recorded. Abnormalities noted at Screening should be included in the medical history. 
g. 
Hepatitis serologies evaluated by central laboratory. If hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody is positive, then PCR 
must be performed and must be negative prior to enrollment.  
h. 
Serum or urine pregnancy test will be required at Screening (within 3 days of Day 1) for women of childbearing potential. The test must be repeated prior to 
first dose if not performed within 3 days of C1D1. The test will be performed locally. 
i. 
Measurements of lesions using RECIST 1.1 criteria is required where CT/MRI was obtained. 
j. 
Predose and postdose PK and PDn samples will be collected per the schedule in Appendix 4 
k. 
Predose PDn sample will be collected on C1D1. 
l. 
Blood and urine samples for biomarkers will be collected prior to dosing on Day1 for the first 3 cycles and then Day 1of every 3rd cycle thereafter until 
RECIST 1.1 documented disease progression or CR and at EOT. 
m. Archival tumor biopsy tissue will be collected when available or optional fresh tumor will be collected on consenting subjects at Screening and upon 
documented disease progression. Fresh tumor biopsy at Screening must be performed 7 days prior to enrollment.  
n. 
Subjects who are withdrawn for reasons other than RECIST 1.1 determined progression will continue to have normally scheduled clinical and radiological 
disease assessments (CT/MRI) until disease progression is documented, death, withdrawal of consent for further follow up, or lost to follow up, whichever 
occurs first. 
o. 
Paclitaxel 80 mg/m2 IV qweek infusion should start 30 minutes hours (± 5 minutes) after ibrutinib. 
 
 
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a. Vital signs will be assessed after the subject has been resting in the sitting position for at least 3 minutes. 
b. All assessments are to be performed prior to dosing unless otherwise specified. 
c. Continuous from the signing of ICF or 14 days prior to the first dose of study drug (whichever is greater) through 30 days after the last dose of 
study drug. 
d. AEs are reported from the time the subject signs the ICF until 30 days following last dose of study drug. All new malignant tumors are to be 
reported as AEs through Long Term Follow-up for OS. 
e. Cycle 1 Day 1 ONLY: Assessment of AEs for 2 hours post docetaxel infusion. At the discretion of the investigator, subject may leave clinic 2 
hours post completion of docetaxel infusion. 
f. 
At Screening, 12-lead ECGs will be recorded. Abnormalities noted at Screening should be included in the medical history. 
g. Hepatitis serologies evaluated by central laboratory. If hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody is 
positive, then PCR must be performed and must be negative prior to enrollment.  
h. Serum or urine pregnancy test will be required at Screening (within 3 days of Day 1) for women of childbearing potential. The test must be 
repeated prior to first dose if not performed within 3 days of C1D1. The test will be performed locally. 
i. 
Measurements of lesions using RECIST 1.1 criteria is required where CT/MRI was obtained. 
j. 
Predose and postdose PK and PDn samples will be collected per the schedule in Appendix 6. 
k. Predose PDn sample will be collected on C1D1. 
l. 
Blood and urine samples for biomarkers will be collected prior to dosing on Day1 for the first 3 cycles and then Day 1 of every 3rd cycle 
thereafter until RECIST 1.1 documented disease progression or CR and at EOT. 
m. Archival tumor biopsy tissue will be collected when available or optional fresh tumor will be collected on consenting subjects at Screening 
and upon documented disease progression. Fresh tumor biopsy at Screening must be performed 7 days prior to enrollment.  
n. Subjects who are withdrawn for reasons other than RECIST 1.1 determined progression will continue to have normally scheduled clinical and 
radiological disease assessments (CT/MRI) until disease progression is documented, death, withdrawal of consent for further follow up, or lost 
to follow up, whichever occurs first 
o. Docetaxel (75 mg/m2 IV q 3weeks) infusion should start 30 minutes hours (± 5 minutes) after ibrutinib. 
 
 
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a. Vital signs will be assessed after the subject has been resting in the sitting position for at least 3 minutes. 
b. All assessments are to be performed prior to dosing unless otherwise specified. 
c. Continuous from the signing of ICF or 14 days prior to the first dose of study drug (whichever is greater) through 30 days after the last dose of 
study drug. 
d. AEs are reported from the time the subject signs the ICF until 30 days following last dose of study drug. All new malignant tumors are to be 
reported as AEs through Long Term Follow-up for OS. 
e. Cycle 1 Day 1 ONLY: Assessment of AEs for 2 hours post cetuximab infusion. At the discretion of the investigator, subject may leave clinic 2 
hours post cetuximab infusion. 
f. 
At Screening, 12-lead ECGs will be recorded. Abnormalities noted at Screening should be included in the medical history. 
g. Hepatitis serologies evaluated by central laboratory. If hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody is 
positive, then PCR must be performed and must be negative prior to enrollment.  
h. Serum or urine pregnancy test will be required at Screening (within 3 days of Day 1) for women of childbearing potential. The test must be 
repeated prior to first dose if not performed within 3 days of C1D1. The test will be performed locally. 
i. 
Measurements of lesions using RECIST 1.1 criteria is required where CT/MRI was obtained. 
j. 
Predose and postdose PK and PDn samples will be collected per the schedule in Appendix 8.  
k. Predose PDn sample will be collected on C1D1. 
l. 
Blood and urine samples for biomarkers will be collected prior to dosing on Day1 for the first 3 cycles and then Day 1 of every 3rd cycle, 
thereafter until RECIST 1.1 documented disease progression or CR and at EOT. 
m. Archival tumor biopsy tissue will be collected when available or optional fresh tumor will be collected on consenting subjects at Screening 
and upon documented disease progression. Fresh tumor biopsy at Screening must be performed 7 days prior to enrollment.  
n. Subjects who are withdrawn for reasons other than RECIST 1.1 determined progression will continue to have normally scheduled clinical and 
radiological disease assessments (CT/MRI) until disease progression is documented, death, withdrawal of consent for further follow up, or lost 
to follow up, whichever occurs first. 
o. Cetuximab (C1D1- 400 mg/m2 over120-minutes; after that-250 mg/m2 over 60 minutes) infusion should start 30 minutes hours (± 5 minutes) 
after ibrutinib. 
p. CEA will be collected at Screening, prior to dosing on Day1 for the first 3 cycles and then Day 1of every 3rd cycle thereafter until RECIST 
1.1 documented disease progression or CR and at EOT. 
 
 
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Appendix 8. C2D1: Pharmacokinetics and Pharmacodynamics Sampling Schedule – Colorectal Adenocarcinoma (CRC) - 
Cohort 4c 
 
Cycle 
Study Day 
Predose 
Time after ibrutinib Dosinga 
1h ± 15 min 
2 h ± 15 min 
4 h ± 15 min 
6 h ± 15 min 
2 
1 
Xb 
X 
X 
X 
X 
a. Record actual time of sample collection. 
b. PK and PDn samples collected 24 hours (± 2 hours) after previous ibrutinib dose and prior to ibrutinib dosing on Cycle 2 Day 1. 
PK samples will be collected in all cohort 4 subjects for ibrutinib PK determination only. 
 
 
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Appendix 9.  Schedule of Assessments – Urothelial Carcinoma – Ibrutinib Single Agent – Cohort 5 
Urothelial Carcinoma 
Screening 
Phase 
Treatment Phaseb 
FU Phase 
Cycle 1 
Cycle 2 
Cycle 3 through 
Treatment d/c 
Efficacy 
Evaluations 
EOT 
Long-term FU 
D-3 OR 
Earlier D1 
D8 D15 D1 
D8 D15 
D1 
Every 6 
weeks 
30 days after 
treatment d/c 
Every  
4 weeks 
Visit Window 
-28 days 
 
N/A ±2d ±2d ±2d ±2d  ±2d 
±2d 
±7d 
±7d 
±7d 
Informed consent 
X 
 
 
 
 
  
  
  
  
  
  
  
Confirmation of eligibility criteria 
X 
 
 
 
 
  
  
  
  
  
  
  
Medical history 
X 
 
 
 
 
  
  
  
  
  
  
  
Physical examination (including disease-related symptom 
assessment) 
X 
 
X 
 
X 
X 
  
X 
X 
  
X 
  
Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Vital Signsa 
X 
 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
ECOG Performance Status 
X 
 
X 
 
X 
X 
  
X 
X 
  
X 
  
KPS score 
X 
 
 
 
 
  
  
  
  
  
  
  
Concomitant medicationsc 
X 
 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
AEsd 
X 
 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
12-lead ECGf 
X 
 
 
 
 
  
  
  
  
  
  
  
Laboratory 
  
 
 
 
 
  
  
  
  
  
  
  
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Serum Chemistry 
X 
 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Coagulation panel 
X 
 
 
 
 
  
  
  
  
  
  
  
Hepatitis serologiesg 
X 
 
 
 
 
  
  
  
  
  
  
  
Creatinine clearance (Cockcroft-Gault) 
X 
 
 
 
 
  
  
  
  
  
  
  
CRPo 
 
 
Xo 
 
 
Xo 
 
 
Xo 
 
 
 
Urinalysis  
X 
 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Pregnancy Testh 
X 
 
Xh 
 
 
  
  
  
  
  
  
  
Disease Assessment 
  
 
 
 
 
  
  
  
  
  
  
  
CT / MRI scani 
Xi 
 
 
 
 
  
  
  
  
Xi 
Xi 
  
Pharmacokinetics/Biomarkers 
  
 
 
 
 
  
  
  
  
  
  
  
Pharmacokinetics (PK)j 
  
 
 
 
 
Xj 
  
  
  
  
  
  
Molecular markers – bloodk  
  
 
X 
 
 
X 
  
  
Xk  
  
X 
  
Molecular markers- urinek  
  
 
X 
 
 
X 
  
  
Xk 
  
X 
  
Buccal Swab 
  
 
X 
 
 
  
  
  
  
  
  
  
Tumor biopsyl, m, n 
Xl 
Xm 
 
 
 
  
  
  
Xn 
  
  
  
Study Drug Administration 
  
 
 
 
 
  
  
  
  
  
  
  
In-clinic administration of ibrutinib 
  
 
X 
X 
X 
X 
X 
X 
  
  
  
  
Dispense ibrutinib 
  
 
X 
 
 
X  
  
 
X 
  
 
 
Study drug compliance review 
  
 
X 
X 
X 
X 
X 
X 
X  
  
X 
  
Survival and subsequent anticancer therapy 
  
 
 
 
 
  
  
  
  
  
X 
X 
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Page 174 
 
a. 
Vital signs will be assessed after the subject has been resting in the sitting position for at least 3 minutes. 
b. 
All assessments are to be performed prior to dosing unless otherwise specified. 
c. 
Continuous from the signing of ICF or 14 days prior to the first dose of study drug (whichever is greater) through 30 days after the last dose 
of study drug. 
d. 
AEs are reported from the time the subject signs the ICF until 30 days following last dose of study drug. All new malignant tumors are to be 
reported as AEs through Long Term Follow-up for OS. 
f. 
At Screening, 12-lead ECGs will be recorded. Abnormalities noted at Screening should be included in the medical history. 
g. 
Hepatitis serologies evaluated by central laboratory. If hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody is 
positive, then PCR must be performed and must be negative prior to enrollment.  
h. 
Serum or urine pregnancy test will be required at Screening (within 3 days of Day 1) for women of childbearing potential. The test must be 
repeated prior to first dose if not performed within 3 days of C1D1. The test will be performed locally. 
i. 
Measurements of lesions using RECIST 1.1 criteria is required where CT/MRI was obtained. 
j. 
Predose and postdose ibrutinib PK samples will be collected per the schedule in Appendix 10 
k. 
Blood and urine samples for biomarkers will be collected prior to dosing on Day1 for the first 3 cycles and then Day 1 of every 3rd cycle 
thereafter until RECIST 1.1 documented disease progression or CR and at EOT. 
l. 
Archival tumor biopsy tissue will be collected when available or optional fresh tumor will be collected on consenting subjects at Screening 
and upon documented disease progression. Fresh tumor biopsy at Screening must be performed 7 days prior to enrollment. 
m. Applies to subjects enrolled in the paired-biopsy subgroup only. Pre-treatment fresh  tumor biopsy for 5-10 subjects. Cycle 1 dosing should 
be after ~3 days post biopsy. 
n. 
Applies to subjects enrolled in the paired-biopsy subgroup only. On- treatment fresh tumor biopsy should be collected during Cycle 3 
anytime from Cycle 3 Day 1 and prior to Cycle 4 Day 1. 
o. 
C-Reactive Protein will be collected on Day 1 of all cycles. 
 
 
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Appendix 10. C2D1: Pharmacokinetics Sampling Schedule and Scheme – Urothelial Carcinoma (Cohort 5) 
Study Cycle & Day 
Time Points 
brutinib (Cohort 5) 
Cycle 2 Day 1 
Predose a 
X 
Drug Administration 
Drug Administration 
1.0 hr post dose (±15 min) 
X 
2.0 hr post dose (±15 min) 
X 
4.0 hr post dose (±15 min) 
X 
6.0 hr post dose (±15 min) 
X 
 
a. 
Predose samples should be collected prior to the administration of any drug. 
 
 
 
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SAP_001.pdf: 
 
PCYC-1128-CA 
Statistical Analysis Plan 
Page 1 of 23 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 2 
 
 
A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced 
Gastrointestinal and Genitourinary Tumors 
 
PCYC-1128-CA 
 
 
June 30, 2021 
Version 1.0 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document is considered privileged and confidential by Pharmacyclics LLC., and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board approval and informed consent, 
or as required by Federal and State Laws.  Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed. 
 
 
 
 
 
 
NCT02599324


 
PCYC-1128-CA 
Statistical Analysis Plan 
Page 2 of 23 
 
 
 
Proprietary and Confidential 
 
STATISTICAL ANALYSIS PLAN (SAP) APPROVAL 
Protocol Number:   
PCYC-1128-CA 
Protocol Title: 
A Phase 1b/2 Study of Ibrutinib Combination Therapy in 
Selected Advanced Gastrointestinal And Genitourinary 
Tumors 
SAP Version: 
1.0 
 
Author: 
Date: 
30 JUN 2021 
 
By signing below, all parties accept that the analysis methods and data presentations are 
acceptable and that this document is final. 
  
 
 
 
 
 Date (ddMMMyyyy) 
 Statistics 
   
 
 
 
 
  Date (ddMMMyyyy) 
 Oncology Development 
 
 
 
             
   
 
 
 
 
   Date (ddMMMyyyy) 
 Regulatory Affairs 
   
 
 
 
 
   Date (ddMMMyyyy) 
Medical Writing 
   
 
 
 
 
   Date (ddMMMyyyy) 
 Biostatistics  
   
 
 
 
 
  Date (ddMMMyyyy) 
07/01/21
07/01/21
07/01/21
07/06/21
07/06/21
08-Jul-2021
 
 


 
PCYC-1128-CA 
Statistical Analysis Plan 
Page 3 of 23 
 
 
 
Proprietary and Confidential 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .......................................................................................................4 
1. 
INTRODUCTION ..................................................................................................................5 
1.1. 
Study Design ..................................................................................................................5 
1.2. 
Endpoints .......................................................................................................................8 
1.2.1. Primary Endpoint ..............................................................................................8 
1.2.2. Secondary Endpoints ........................................................................................9 
1.2.3. Safety Assessments ...........................................................................................9 
1.2.4. Exploratory Endpoints (Phase 2) ......................................................................9 
1.3. 
Statistical Hypotheses ....................................................................................................9 
1.4. 
Sample Size Determination..........................................................................................10 
1.5. 
Planned Analysis ..........................................................................................................11 
1.5.1. Phase 1b analysis ............................................................................................11 
1.5.2. Interim Analysis (IA) ......................................................................................11 
1.5.3. Final Analysis .................................................................................................12 
1.5.4. Blinding and Randomization Methods ...........................................................12 
2. 
GENERAL ANALYSIS CONSIDERATION ....................................................................13 
2.1. 
Analysis Sets ................................................................................................................13 
2.2. 
Definition of Subgroups ...............................................................................................14 
3. 
SUBJECT INFORMATION................................................................................................15 
3.1. 
Subject Disposition ......................................................................................................15 
3.2. 
Demographics, Baseline Characteristics, and Baseline Disease Characteristics .........16 
3.3. 
Prior and Concomitant Medications ............................................................................16 
3.4. 
Extent of Exposure to Study Treatment .......................................................................16 
3.5. 
Prior Anti-cancer Treatments and Subsequent Anti-cancer Treatment .......................16 
3.6. 
Visit Impact of Logistical Restriction Due to COVID-19 ...........................................17 
4. 
ANALYSIS FOR EFFICACY ENDPOINTS .....................................................................17 
5. 
SAFETY ASSESSMENTS ...................................................................................................21 
5.1. 
Data Summaries for COVID-19 ..................................................................................22 
6. 
CHANGES IN PROTOCOL-PLANNED ANALYSIS .....................................................22 
7. 
REFERENCES .....................................................................................................................22 
 
 
 
Table 1: Number of Subjects and Number of Responders for Simon’s 2-stage Minimax 
Design .......................................................................................................................11 
Table 2: Baseline Subgroup Definition..........................................................................................15 
Table 3: Summary of Efficacy Analyses .......................................................................................18 
Table 4: Summary of Safety Assessments .....................................................................................22 
 
 
 
 


 
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Statistical Analysis Plan 
Page 4 of 23 
 
 
 
Proprietary and Confidential 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
CEA 
carcinoembryonic antigen 
CR 
complete response 
CSR 
clinical study report 
CRC 
colorectal adenocarcinoma 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLRC 
dose level review committee 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
GC 
gastric carcinoma 
IA 
interim analysis 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PR 
partial response  
RCC 
renal cell carcinoma 
RP2D 
recommended Phase 2 dose 
RECIST 
response evaluation criteria in solid tumors  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event 
UC 
urothelial carcinoma 
 


 
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1. INTRODUCTION 
This statistical analysis plan (SAP) is based on protocol Amendment 2.1 and is to define key 
elements including variable definitions, and statistical methods for analysis of data in evaluation 
of efficacy and safety of the study PCYC-1128-CA.  Analyses of biomarkers and 
pharmacokinetics are not in scope of this document. Throughout this SAP, “study treatment” and 
“study drug” are used interchangeably, both refer to any of the study drugs including ibrutinib or 
the companion drug for the combination therapy and ibrutinib for the single-agent therapy.. 
Analysis methods specified in this document take precedence over those described in the 
protocol should there be any difference. Any changes from the protocol will be documented in 
Section 6, Changes in Protocol Planned Analysis.  
There are two clinical study reports (CSRs) for this study. CSR #1 is for RCC Cohort 1, GC 
Cohort 3, and CRC Cohort 4 and was finalized on 10 Nov 2020. CSR #2 is for all UC cohorts 
(Cohorts 2, 5, and 6), and will also contain updated analyses for Cohorts 1, 3, and 4. Database 
extraction will take place after last patient has exited study and necessary cleaning activities have 
been completed, currently anticipated in the third quarter of 2021 to prepare for CSR #2. This 
SAP (referred to as SAP2) is to cover the analysis plan for Cohorts 2, 5 and 6 in CSR #2. A 
previous SAP (referred to as SAP1) was written to cover the analysis plan for CSR #1. The 
updated analyses for Cohorts 1, 3 and 4 that will be included in CSR #2 will be performed in the 
same manner as described in SAP1. 
1.1. 
Study Design 
This is an open-label, Phase 1b/2 multi-center study to assess the safety and efficacy of ibrutinib 
monotherapy (Cohort 5) in subjects with previously-treated urothelial carcinoma (UC) and 
ibrutinib combination therapy (Cohorts 1-4, 6) in subjects with previously treated renal clear cell 
carcinoma (RCC), urothelial transitional cell carcinoma (UC), gastric or gastroesophageal 
junctional adenocarcinoma (GC), and NRAS/KRAS wild-type colorectal adenocarcinoma (CRC) 
as listed below. Each cohort in this study will assess a different malignancy and/or anticancer 
agent in combination with ibrutinib or single-agent ibrutinib and follow an independent and 
parallel design: 
• Metastatic RCC (Cohort 1) minimum of 1 and maximum of 4 prior regimens, one or more of 
which must have included a VEGF-TKI. Treatment with ibrutinib + everolimus. 
• Advanced (locally recurrent inoperable and/or metastatic) UC (Cohorts 2, 5, 6) 
Cohort 2: Minimum of 1 and maximum of 2 prior regimens, one of which must have included 
a platinum-based regimen. Treatment with ibrutinib + paclitaxel. 
 


 
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Cohort 5: Minimum of 1 and maximum of 2 prior regimens, one of which must have included 
a checkpoint inhibitor.  Treatment with single agent ibrutinib. 
Cohort 6: EITHER: not eligible for cisplatin chemo with a PDL-1score (CPS) of ≥ 10 
without prior treatment, OR progressed on platinum chemo or within 12 months of neo- or 
adjuvant therapy with a platinum chemotherapy. A minimum of 1 and maximum of 2 prior 
therapies.  Treatment with ibrutinib + pembrolizumab. 
• Advanced (locally recurrent inoperable and/or metastatic) GC (Cohort 3) minimum of 1 and 
maximum of 3 prior regimens one of which must have included a fluoropyrimidine regimen.  
Treatment with ibrutinib + docetaxel. 
• Metastatic CRC (Cohort 4) minimum of 2 and maximum of 4 prior regimens, which must have 
included both an irinotecan and an oxaliplatin based regimen unless unable to tolerate irinotecan 
chemotherapy. Treatment with ibrutinib + cetuximab. 
This Phase 1b/2 study is divided into 2 parts. An initial Phase 1b portion will evaluate the safety 
and tolerability of single-agent ibrutinib and ibrutinib in combination with each anticancer agent 
to assess any dose limiting toxicity in order to determine the recommended Phase 2 dose (RP2D) 
for each cohort. 
The Phase 2 portion will assess primary endpoints of progression-free survival (PFS) (with an 
incorporated interim analysis) for RCC and UC Cohort 2, and overall response rate (ORR) using 
a Simon’s minimax 2-stage design for GC, CRC, and UC Cohorts 5 and 6.  
Phase 1b 
The Phase 1b portion of this study is performed independently in six separate cohorts defined by 
the clinical indication; RCC, UC, GC, and CRC. 
For cohorts 1-4, safety and dose-limiting toxicity (DLT) assessment will be evaluated in 3-9 
subjects at each dose level in a 3+3+3 design. At each dose level, DLT assessment will be 
performed in the first 3 subjects. If 1 of 3 subjects experiences a DLT during the first treatment 
cycle, the same dose level will be expanded to 6 subjects, and if 2 of the 6 experience a DLT, the 
same dose level will be expanded to 9 subjects. At the 560 mg/day dose level (DL 1), if 0 out of 
3, 1 out of 6 or 2 out of 9 subjects (≤ 22%) experience a DLT during the first treatment cycle, 
dose escalation to 840 mg/day (DL 2) will occur. At DL 1 (560 mg/day), if ≥ 33% of subjects 
experience a DLT (e.g., > 2 out of 6 or > 2 out of 9 subjects), the dose will be de-escalated to 
420 mg/day (dose level minus one; DL -1). At the 840 mg/day dose level (DL 2) cohort, subjects 
will be enrolled in a similar fashion. 
For UC cohort 5, the single-agent dose of 840 mg will be confirmed and documented in the first 
6 patients; safety data will be described. 
 


 
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For UC Cohort 6, a 6+3 dose de-escalation design will be implemented. For the Phase 1b portion 
of Cohort 6, if 2 subjects within the initial cohort of 6 subjects experience a DLT, an additional 3 
subjects will be enrolled at the same dose level. If 3 or more of 6 subjects experience a DLT, 
dose de-escalation will occur and additional 6 evaluable subjects will be enrolled. If the 
incidence of DLTs during the DLT observation period is <33.3% (i.e., ≤1 of 6 or ≤2 of 9), this 
dose level will be considered safe to proceed to Phase 2 and will be defined as the RP2D. 
The RP2D will be determined when 6–9 subjects at the dose level complete the DLT observation 
period based on the totality of the data including dose reductions (of both ibrutinib and/or the 
combination therapy), treatment-limiting toxicities (outside of DLTs), the available 
pharmacokinetic data and the toxicity profile obtained during Phase 1b. In order to determine the 
RP2D dose level, a minimum of 6 DLT-evaluable subjects will be required at the RP2D dose 
level who are defined to have completed at least 21 days of treatment with ibrutinib in 
combination with the relevant anticancer agent, after the initiation of therapy at the start of Cycle 
1. 
For UC Cohorts 5 and 6, a DLT-evaluable subject will have ≥ 90% compliance with ibrutinib 
during Cycle 1 (the first 21 days). At each dose level, the decision of de-escalation will be made 
with at least 6 DLT-evaluable subjects. However, if at any time in a given dose level, 3 subjects 
experience a DLT, additional enrollment within the dose level will be stopped.  
For combination therapy of ibrutinib and other anticancer agent specified below, the starting 
dose of ibrutinib will be 560 mg daily in the following 5 cohorts:  RCC Cohort 1: ibrutinib + 
everolimus, UC Cohort 2: ibrutinib + paclitaxel, GC Cohort 3: ibrutinib + docetaxel, CRC 
Cohort 4: ibrutinib + cetuximab, UC Cohort 6: ibrutinib + pembrolizumab. 
For single-agent ibrutinib, the starting dose will be 840 mg:  UC Cohort 5: single-agent ibrutinib. 
A dose level review committee (DLRC) will evaluate the safety data at the completion of the 
initial Phase 1b portion in each cohort to determine the RP2D, prior to continuing with 
enrollment into the Phase 2 portion (enrollment may not be held for UC Cohort 5 as safety data 
is available for more than 40 subjects for ibrutinib 840 mg in combination with paclitaxel data). 
The DLRC will review the safety data in the first 6 evaluable subjects enrolled in Cohort 5 to 
confirm 840 as the single-agent dose. Members of this committee will include the Medical 
Monitor or designee, a drug safety representative, a biostatistician, and at least 2 participating 
investigators/designees. 
Any Phase 1b subjects who discontinue one or more study drugs, or require dose reduction 
within 21 days after the initiation of therapy at the start of Cycle 1 will be replaced, unless the 
discontinuation is in association with a DLT. Subjects who miss one or more scheduled doses 
(more than 2 doses for UC cohorts 5 and 6) of either study drug within 21 days after the 
initiation of therapy at the start of Cycle 1 will continue. However, such a subject will not be 
evaluable for DLT assessment and will be replaced for DLT assessment purposes. 
 


 
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After the RP2D has been defined for each cohort, enrollment in Phase 2 will commence in that 
cohort. 
Phase 2 
For each cohort in the study, a separate analysis will be performed to evaluate its response and 
safety profile.  
Subjects treated at RP2D in Phase 1b will be included in the Phase 2 analyses. 
In all cohorts, subjects who are dosed at the RP2D level and withdraw prior to the completion of 
at least 2 cycles of study treatment, for reasons other than unacceptable toxicity or disease 
progression, may be replaced after consultation with the Sponsor. 
For GC (Cohort 3), CRC (Cohort 4), and UC Cohorts 5 and 6, if a subject in Simon’s Stage-1 
discontinues prior to the first tumor response assessment for reasons other than disease 
progression, the subject may be replaced. Enrollment may continue into Stage-2, whilst the 
response evaluation and analysis from the Stage-1 are completed. If the number of responders 
observed among the evaluable subjects in Stage-1 is less than the number of responders required 
to proceed per the Simon’s 2-stage design, the relevant cohort may be terminated for futility. 
1.2. 
Endpoints 
The rest of this SAP2 document describes endpoints and analysis relevant to CSR #2. Updated 
analyses from CSR #1 (Cohorts 1, 3, and 4) will be performed in the same manner described in 
SAP1, based on updated data extraction. 
1.2.1. 
Primary Endpoint 
Phase 1b 
 
 To determine the RP2D of ibrutinib in combination with paclitaxel (Cohort 2) and 
pembrolizumab (Cohort 6) in UC, confirm the RP2D of single-agent ibrutinib in UC 
Cohort 5 and assess DLTs during the 21-day DLT assessment period. 
 
Phase 2 
 Progression-free survival (PFS) in accordance with RECIST 1.1 criteria in UC Cohort 2 
 Overall response rate (ORR) in accordance with RECIST 1.1 criteria of ibrutinib as 
single agent in UC Cohort 5 and ibrutinib combination therapy in UC Cohort 6  
 


 
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1.2.2. 
Secondary Endpoints 
Phase 1b 
 
 Secondary endpoints are to assess ORR and disease control rate (DCR) in each cohort. 
ORR is defined as the proportion of patients who have a best response of partial response 
(PR) or complete response (CR) to therapy. DCR is the proportion of patients who have a 
best response of PR, CR, or stable disease (SD). 
Phase 2  
 Disease control rate (DCR) in all cohorts 
 PFS in UC Cohorts 5 and 6 
 ORR in UC Cohort 2 
 Overall survival (OS) in all cohorts 
 Duration of response (DOR) in all cohorts 
1.2.3. 
Safety Assessments 
Phase 1b 
 
 To assess the safety and tolerability of ibrutinib in each cohort 
Phase 2 
 
 Safety and tolerability of ibrutinib combination therapy in each cohort 
1.2.4. 
Exploratory Endpoints (Phase 2) 
 
 
 
1.3. 
Statistical Hypotheses 
For each cohort, the design will provide approximately 80% power to perform one-sided 
hypothesis testing at an α level of 0.05. 
Cohort 
Hypothesis Testing 
UC Cohort 2 
H0: m ≤ 2.3 months versus H1: m ≥ 4.1 months, where m is the median PFS. 
UC Cohort 5 
H0: π ≤ 5% versus H1: π ≥ 20%, where π is the overall response rate. 
UC Cohort 6 
H0: π ≤ 20% versus H1: π ≥ 35%, where π is the overall response rate. 
 H0 is the null hypothesis. H1 is the alternative hypothesis. 
 


 
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1.4. 
Sample Size Determination 
The number of subjects required to be treated with ibrutinib at the RP2D level for the efficacy 
evaluation is determined for each disease cohort using the following methods.  
UC Cohort 2 
The primary endpoint for UC cohort 2 is median PFS. A sample size of approximately 55 
efficacy evaluable subjects will provide 80% power at a 1-sided 0.05 significance level when 
testing the null hypothesis median PFS ≤ 2.3 months versus the alternative hypothesis median 
PFS ≥ 4.1 months. The median PFS for paclitaxel is assumed to be 2.3 months under the null 
hypothesis. The study is designed to detect a 78% increase in median PFS to 4.1 months for 
ibrutinib in combination with paclitaxel. With the assumption of an exponential distribution for 
PFS, the sample size n = 55 to achieve at a minimum of 80% power is determined by a 
simulation method with an enrollment rate of 5 subjects per month and with the data cut time for 
analysis to be at 6 months following the last subject enrollment. 
UC Cohort 5 
The primary endpoint is ORR for this cohort. A total of up to 27 subjects treated with single-
agent ibrutinib are to be enrolled based on Simon’s 2-stage design. In Stage-1, 13 subjects will 
be enrolled and if at least one responder is observed, an additional 14 subjects will be enrolled in 
Stage-2. At the end of the study, if there are 4 or more responders, the null hypothesis will be 
rejected, and the study treatment would be considered acceptable for further clinical 
development.  
This Simon’s 2-stage minimax design would provide 80% power to test the historical response 
rate of 5% (null hypothesis) against the target response rate of 20% (alternative hypothesis) at a 
1-sided significance level of 0.05. 
UC Cohort 6 
The primary endpoint is ORR for this cohort. A total of up to 53 subjects are to be enrolled based 
on Simon’s 2-stage design. In Stage-1, 31 subjects will be enrolled and if at least 7 responders 
are observed, an additional 22 subjects will be enrolled in Stage-2. At the end of the study, if 
there are a minimum of 16 or more responders, the null hypothesis may be rejected and the study 
treatment may be considered acceptable for further clinical development. 
This Simon’s 2-stage minimax design would provide 80% power to test the pembrolizumab 
response rate of 20% (null hypothesis) against the target response rate of 35% (alternative 
hypothesis) at a 1-sided significance level of 0.05. 
 


 
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Table 1 provides a summary for number of subjects needed in Stage 1 and Stage 2 of Simon’s 2-
stage design for UC Cohorts 5 and 6 in order to declare success.  
Table 1: Number of Subjects and Number of Responders for Simon’s 2-stage 
Minimax Design 
Cohort (Total 
Number of 
Subjects) 
Number of 
Subjects for 
Stage 1  
Number of Responders in 
Stage 1 Needed to 
proceed to Stage 2  
Number of Subjects 
for Stage 2 
Number of 
Responders Need to 
Reject the Null 
Hypothesis for the 
Study 
UC Cohort 5 
(N=27) 
13 
≥ 1  
14 
≥ 4 
UC Cohort 6 
(N=53) 
31 
≥ 7 
22 
≥ 16 
1.5. 
Planned Analysis  
1.5.1. 
Phase 1b analysis 
Analysis for Phase 1b will be conducted separately for each disease cohort and dose level when 
appropriate. 
1.5.2. 
Interim Analysis (IA)  
An interim analysis will be conducted for each cohort independently for the Efficacy Evaluable 
Population. UC Cohorts 5 and 6 were based on Simon’s 2-stage design and the interim analysis 
stopping rule was determined by the design. For UC Cohort 2, interim analysis timing is when 
approximately 25 efficacy evaluable subjects dosed at the RP2D level have completed 4 months 
of follow-up. Details are provided below. Enrollment may continue while the interim analysis is 
being performed for each cohort. The analysis will be conducted on subjects who received RP2D 
from Phase 1b and Phase 2.  
Go/No Go decisions at the time of the interim analyses will include all available clinical and 
safety data for that cohort and are not based solely on the efficacy data for the endpoint involved 
in the interim analysis. No multiplicity adjustment will be made for Cohort 2 final efficacy 
analysis. 
UC Cohort 2 
PFS is the primary efficacy endpoint for this cohort. A single interim analysis for futility will 
take place after approximately 25 efficacy evaluable subjects dosed at the RP2D level have 
completed 4 months of follow-up. The proportion of subjects that are PFS event-free at 4 months 
 


 
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will be assessed along with other safety and efficacy data in making the determination if the 
study should continue. Point estimator and 2-sided 90% Brookmeyer-Crowley confidence 
interval with log-log-transformed Greenwood variance estimate of the median PFS (mPFS) will 
be calculated to assess efficacy.  
UC Cohorts 5 and 6 
For those two cohorts, ORR is the primary endpoint and Simon’s 2-stage minimax design is 
implemented to evaluate ORR following the Stage-1 boundaries in Table 1.  
At the interim analysis of the Stage-1, the proportion of responding subjects (best response of CR 
or PR) will be calculated, along with other safety and efficacy data when making the 
determination if the study should continue into the Stage-2. Confirmation of response is not 
required for the interim analysis. 
1.5.3. 
Final Analysis 
The final analysis will be conducted after all efficacy evaluable subjects have completed a 
minimum period of follow-up for the primary endpoint or other key endpoint(s), or after all 
patients have exited the study.  
There are two CSRs for this study. CSR #2 is for all UC cohorts (Cohorts 2, 5 and 6) and is 
covered in SAP2.  
1.5.4. 
Blinding and Randomization Methods 
Not Applicable. This is an open-label non-randomized study.   
 


 
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2. GENERAL ANALYSIS CONSIDERATION 
Phase 1b 
Data summary and data analysis will be conducted for each disease cohort separately. Data will 
not be pooled across disease cohorts or tested between disease cohorts.  
Limited tables and listings will be generated, constituting a subset of the Phase 2 outputs, and 
include: baseline demographic, baseline characteristics, disease characteristics, treatment and 
study disposition, study drug exposure, DLTs, ORR, DCR, overview of treatment emergent 
adverse events (TEAEs), TEAEs by Systems Organ Class/Preferred Term/maximum severity, 
grade 3 or higher TEAEs, serious TEAEs, TEAEs leading to death, TEAEs leading to ibrutinib 
discontinuation. No subgroup will be summarized for this phase. Data will be summarized 
separately for each cohort by dose. 
Phase 2 
Data summary and data analysis will be conducted for each disease cohort separately. Data will 
not be pooled across disease cohorts or tested between disease cohorts.  
Baseline, demographics, disposition, and safety data will be summarized by dose level (RP2D). 
Efficacy analysis will only be conducted for subjects treated at R2PD. Subjects who were treated 
with ibrutinib at the R2PD level in Phase 1b or Phase 2 will be combined in the summary. 
Subgroup analyses may be undertaken to evaluate potential efficacy and/or safety trends and to 
assess internal consistency of any apparent treatment benefit. The subgroups for these cohorts 
will be determined by the level of clinical interest/relevance. Statistical hypothesis testing will 
not be performed for the subgroup analyses.  
General Definitions:  
For disease cohorts with a combination treatment, date of first dose of study treatment is defined 
as the date the subject received the first dose of ibrutinib or the companion drug (whichever 
occurs first) and date of last dose of study treatment is defined as the date the subject receive the 
last dose of ibrutinib or the companion drug (whichever occurs later). 
Baseline value is defined as the last non-missing valid value collected prior to the first 
administration of study treatment. For subjects who have been enrolled but not treated, 
enrollment date will be used as the reference date for baseline if needed. 
2.1. 
Analysis Sets 
DLT Evaluable Population: Defined as subjects from Phase 1b who completed at least 21 days 
of treatment with ibrutinib in combination with the relevant anticancer agent after the initiation 
 


 
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of study treatment at the start of Cycle 1, or those who discontinued from study treatment due to 
a DLT event prior to completion of DLT observation period. The DLT Evaluable Population will 
be used for DLT assessments. Per protocol, subjects in Cohort 2 who miss one or more 
scheduled doses of either study drug within 21 days after the initiation of therapy at the start of 
Cycle 1 will continue. However, such a subject will not be evaluable for DLT assessment and 
will be replaced for DLT assessment purposes. For Cohorts 5 and 6, subjects may miss up to 2 
doses of ibrutinib within 21 days after the initiation of therapy and still be evaluable for DLT 
assessment.  
All Enrolled Population: Defined as all eligible subjects enrolled in the study. 
All Treated Population: Defined as all subjects who received at least 1 dose of study treatment 
(ibrutinib or the companion drug for the combination therapy and ibrutinib for the single-agent 
therapy). This population is the same as the Safety Population defined in the protocol. For the 
purpose of analysis and CSR, All Treated Population will be used as the data set to summarize 
all the data unless otherwise indicated. Sensitivity analysis of efficacy endpoints will be 
performed based on this population.  
Efficacy Evaluable Population: This population will be used to perform the primary analysis 
for the efficacy endpoint(s) and is defined as eligible (meet all of the inclusion and none of the 
exclusion criteria) subjects who received at least one dose of ibrutinib (at RP2D) in combination 
with at least one dose of the relevant companion drug or ibrutinib (at RP2D) for the single-agent 
therapy and fulfil the following criteria: 
UC Cohort 2 (PFS as the primary endpoint) 
1) Had at least one adequate post-baseline overall disease assessment per RECIST 1.1 
guidelines or died prior to the first adequate post-baseline overall disease assessment. 
UC Cohorts 5 and 6 (ORR as the primary endpoint) 
1) Had measurable disease (i.e. at least one target lesion as defined in the protocol) per 
RECIST 1.1 guidelines at baseline. 
2) Had at least one adequate post-baseline overall disease assessment per RECIST 1.1 
guidelines. 
2.2. 
Definition of Subgroups 
Subgroup analyses will be performed for the selected variables in an exploratory fashion. Further 
clinically relevant and biomarker subgroups will be assessed if appropriate. The subgroup 
variables and the cutoff values are subject to change if warranted to better represent the data. 
 


 
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Otherwise subgroup analysis will not be carried out if the distribution for the subgroup variable 
does not warrant the analysis. 
 
Table 2: Baseline Subgroup Definition 
Subgroup 
Definition of Subgroup 
Analysis Type 
ECOG Performance status  
0 v 1  
E 
Renal function (creatinine 
clearance) 
< 60, ≥ 60 mL/min 
E 
Hepatic function (NCI ODWG 
definition) 
normal, mild, moderate, severe (or normal 
vs. non-normal as appropriate) 
E 
Neutrophil;lymphocyte ratio 
>3 v  ≤3 
E 
Hemoglobin <10mg/dL 
<10 v ≥10 
E 
Bellmunt prognostic risk factors 
0, 1, 2, 3 
E 
Liver metastasis 
Present, absent 
E 
Number of prior lines of therapy 
0 (Cohort 6 only), 1,2,3,4 
E 
Analysis type: E = Efficacy – Primary endpoint only (PFS or ORR). 
 
3. SUBJECT INFORMATION 
Subject information will be summarized descriptively by ibrutinib dose level (RP2D versus other 
dose level) for each disease cohort individually. Subjects who were treated with ibrutinib at the 
R2PD level in Phase 1b or Phase 2 will be combined in the summary. 
3.1. 
Subject Disposition 
The disposition tables will include the following summaries: 
 
Analysis populations (all enrolled subjects) 
 
Enrollment by country and investigator/site (all enrolled subjects) 
 
Study treatment disposition, study treatment duration and discontinuation of study treatment 
(All Treated Population) 
 
Study status and study exit for all enrolled subjects. 
Time on study is defined in the same way as overall survival with reversed censoring, i.e., 
subjects who died will be censored at death date. The Kaplan-Meier method will be used to 
estimate the median time on study. 
 


 
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3.2. 
Demographics, Baseline Characteristics, and Baseline Disease Characteristics 
Subject demographics and baseline characteristics will be summarized with descriptive statistics 
for the All Treated Population by cohort.  
3.3. 
Prior and Concomitant Medications 
Medications will be coded to a generic name and an Anatomical Therapeutic Chemical (ATC) 
class according to World Health Organization drug dictionary.  
Prior medications are defined as medications that started prior to the first dose of study 
treatment. Concomitant medications are defined as medications that were taken on treatment (i.e. 
from the date of first dose of study treatment through the date of last dose of study treatment).   
Concomitant medications will be summarized by ATC class and preferred term (PT) based on 
All Treated Population for each disease cohort. Each subject will be counted once only for 
overall, each PT, and each ATC class.  The following concomitant medications will be 
summarized separately:  
 
CYP3A inhibitors and inducers – This list requires a medical review, with finalization at the 
time of analysis 
 
Anticoagulants and antiplatelet agents will need medical review, with finalization at the time 
of analysis 
3.4. 
Extent of Exposure to Study Treatment 
For each disease cohort, exposure to study treatment will be summarized for each study drug for 
the All Treated Population. Descriptive statistics will be provided, by study drug, for the 
followings: treatment duration (month), total number of doses received, total number of cycles 
received (for chemotherapy), total cumulative dose administered, dose intensity and relative dose 
intensity (%), and number (%) of subjects with dose reduction due to adverse events (AEs), dose 
delay due to AEs and dose reduction or delay due to AEs.  
3.5. 
Prior Anti-cancer Treatments and Subsequent Anti-cancer Treatment 
Anti-cancer treatment includes drug therapies, radiation, and surgeries and procedures performed 
with therapeutic intent. The ATC level of anti-cancer drug therapies will be specified in the 
mock-up table footnote. Prior anti-cancer treatments are treatments received prior to study 
treatment. Subsequent anti-cancer treatment are treatments received after date of last dose of 
study treatment. Prior and subsequent anti-cancer treatment will be summarized separately using 
All Treated population for each disease cohort. 
 


 
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3.6. 
Visit Impact of Logistical Restriction Due to COVID-19 
Visit and assessment impacts of logistical restrictions due to the COVID-19 pandemic will be 
summarized by the type of impact (missed visit, in person/partial assessment done, and virtual 
visit/phone call) recorded on the Visit Impact CRP page for each treatment arm. 
Information for treatment discontinuation and study exit during the COVID-19 pandemic will be 
listed. 
4. ANALYSIS FOR EFFICACY ENDPOINTS 
For Phase 1b, data will be summarized by dose level for each cohort separately. As described in 
Sections 1.5 and 2, limited tables and listings will be included. Descriptive summaries will be 
provided, and confidence intervals described in Table 4 for ORR, DCR can be applied as data 
warrant. No subgroup will be summarized for this phase.  
For Phase 2, efficacy and safety data will be summarized for each disease cohort separately.  All 
subjects treated at the RP2D dose level of ibrutinib in Phase 2 or Phase 1b will be analyzed 
together). Hereafter this will be referred to as “Phase 1b/2 RP2D” in the tables. 
Primary analysis of each efficacy endpoint will be performed using the Efficacy Evaluable 
Population at the time of final analysis, unless otherwise indicated. Sensitivity analyses will be 
performed for some efficacy endpoints using the All Treated Population. Safety data will be 
summarized using the All Treated Population. 
Efficacy analyses will be based on the overall disease assessments determined by the investigator 
per RECIST 1.1 guidelines. Efficacy endpoint definitions and analysis methods for Phase 2 are 
described in Table 4.  
 
 


 
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Table 3: Summary of Efficacy Analyses 
 
Endpoint 
Definition 
Analysis Methods 
Primary Endpoint (UC Cohort 2) 
PFS  
Time from the date of first dose of  
study treatment to the date of first 
documentation of progressive disease 
(PD) or date of death from any cause, 
whichever occurs first, regardless of 
the use of subsequent anti-cancer 
treatment.  
Subjects who were not known to have 
disease progression or death at the 
data extraction will be censored at 
date of last adequate post-baseline 
disease assessment showing no 
evidence of disease progression. For 
the evaluation of disease progression, 
an adequate post-baseline assessment 
is defined as an assessment where 
there is enough evidence to indicate 
the subject had progressed or not 
based on RECIST 1.1 guidelines. 
In the situation where subjects did not 
have baseline disease assessment or 
who did not have adequate post-
baseline disease assessment, they will 
be censored at the date of first dose of 
study treatment.  
 
 
Primary Analysis: 
For each disease cohort, the following 
analysis methods will be used to perform 
the analysis based on Efficacy Evaluable 
population. 
Kaplan-Meier curve will be provided. The 
2-sided 90% Brookmeyer-Crowley 
confidence interval (CI) based on the log-
log-transformed Greenwood variance 
estimate will be calculated for median PFS 
(mPFS) to test the hypotheses. The null 
hypothesis will be rejected if the confidence 
interval of the observed mPFS is above the 
mPFS in the null hypothesis. 
Kaplan-Meier point estimate and its 2-sided 
90% confidence interval will also calculated 
for PFS rate at selected landmark points. 
Sensitivity Analyses: 
 
All Treated Population. Same analysis 
methods . 
 
Subjects who received subsequent anti-
cancer treatment will be censored at the 
last adequate post-baseline disease 
assessment showing no evidence of PD 
prior to initiation of  subsequent anti-
cancer treatment:  Efficacy Evaluable 
Population. Same analysis methods. 
 
Primary Endpoint (UC Cohorts 5 and 6) 
ORR 
Proportion of subjects achieving 
complete response (CR) or partial 
response (PR) with confirmation 
based on the best overall response 
(BOR) per RECIST 1.1 guidelines 
recorded since date of first dose of 
study treatment until first 
documentation of progressive disease 
Primary Analysis: 
For each disease cohort, ORR will be 
estimated using the Efficacy Evaluable 
Population according to the crude 
proportion of subjects meeting the criteria.  
 


 
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Endpoint 
Definition 
Analysis Methods 
or initiation of subsequent anti-cancer 
treatment, whichever occurs first. 
Confirmation of CR or PR requires 
two consecutive assessments that are 
at least 28 days apart. 
Two-sided 90% confidence interval (CI) for 
ORR will be calculated using the exact 
binomial distribution (Clopper-Pearson) to 
test the null hypothesis. The null hypothesis 
will be rejected if the confidence interval of 
the observed ORR is above the ORR in the 
null hypothesis. 
Sensitivity Analyses: 
 
All Treated population. Same analysis 
method. 
 
ORR without confirmation: Efficacy 
Evaluable Population. Same analysis 
method. 
 
ORR without confirmation: All Treated 
Population. Same analysis method. 
Subgroup Analysis:  
Forest plots of ORR and its two-sided 90% 
CIs will be provided for each subgroup to 
show the trend. 
Secondary Endpoints 
ORR (UC Cohort 2)  
Same as above 
Same as the above primary analysis. No 
sensitivity analysis will be performed.  
PFS (UC Cohorts 5 and 6) 
Same as above 
Same as the above primary analysis. No 
sensitivity analysis will be performed.  
DOR  
Defined for confirmed responders (PR 
or better) as time from the date of 
initial response (PR or better) to the 
date of first documentation of PD or 
death, whichever occurs first, 
regardless of use of subsequent anti-
cancer treatment. Confirmed 
responders without documentation of 
PD or death or with unknown status at 
the data extraction will be censored at 
the last adequate post-baseline disease 
assessment showing no evidence of 
PD. 
If there are enough confirmed responders in 
the Efficacy Evaluable population, Kaplan-
Meier curves will be provided and 2-sided 
90% Brookmeyer-Crowley confidence 
interval (CI) based on the log-log-
transformed Greenwood variance estimate 
will be calculated for median DOR (mDOR) 
and Kaplan-Meier point estimates at 
selected landmark time points. Otherwise, 
only descriptive statistics will be provided. 
 
DCR 
Proportion of subjects achieving CR , 
PR, or SD of length ≥ 6 weeks (SD 
only) based on the best overall 
Primary Analysis: 
For each disease cohort, DCR will be 
estimated using the Efficacy Evaluable 
 


 
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Endpoint 
Definition 
Analysis Methods 
response (BOR) per RECIST 1.1 
guidelines recorded since date of first 
dose of study treatment until first 
documentation of progressive disease 
or initiation of subsequent anti-cancer 
treatment, whichever occurs first. 
Confirmation of CR or PR is not 
required 
Population according to the crude 
proportion of subjects meeting the criteria. 
Two-sided 90% confidence interval (CI) for 
DCR will be calculated using the exact 
binomial distribution (Clopper-Pearson).  
Sensitivity Analyses: 
 
DCR based on confirmed CR or PR: 
Efficacy Evaluable Population. Same 
analysis method. 
 
DCR based on confirmed CR or PR: 
All Treated Population. Same analysis 
method. 
 
 
OS 
Time from the date of first dose of 
study treatment to the date of death 
from any cause. Subjects who were 
not known to have died at the data 
extraction will be censored at date last 
known alive. 
Primary analysis:  
For each disease cohort, the following 
analysis methods will be used to perform 
the analysis based on Efficacy Evaluable 
population. 
Kaplan-Meier curve will be provided. The 
2-sided 90% Brookmeyer-Crowley 
confidence interval (CI) based on the log-
log-transformed Greenwood variance 
estimate will be calculated for median OS 
(mOS). 
Kaplan-Meier point estimate and its 90% 
confidence interval will be calculated for 
OS rate at selected landmark points. 
Sensitivity Analysis: 
All Treated Population. Same analysis 
methods. 
 
 
 


 
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5. SAFETY ASSESSMENTS 
Safety data will be summarized using All Treated Population by ibrutinib dose level (RP2D 
versus other dose level) for each disease cohort separately. Adverse events (AEs) will be coded 
in accordance with the Medical Dictionary for Regulatory Activities (MedDRA). Severity of 
AEs will be graded by the investigator according to the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.  
In general, the treatment-emergent (TE) period is defined as the period from the date of the first 
dose of study treatment up to 30 days after the date of the last dose of study treatment or the day 
before initiation of subsequent anti-cancer treatment, whichever comes first.  
Treatment-emergent adverse events are those events that: 
 Are not present prior to the TE period and occur during the TE period, 
 The onset dates are missing and resolution dates are during the TE period, 
 Are considered related (at least possibly related) to the study treatment by the investigator 
regardless of the start dates of the events, or 
 Are present prior to the TE period but worsen in severity during the TE period or are 
subsequently considered related to study drug by the investigator. 
Dose limiting toxicities (DLTs) as determined by the investigator and identified by the check box 
on the Adverse Event page will be summarized for each cohort and dose level TEAE will be 
presented by relationship to individual study drugs (Cohorts 2 and 6) and also separately for 
those considered related to both study drugs. 
Events of special interest as listed below will be summarized: 
 Protocol-defined events of clinical interest including hemorrhagic events and major 
hemorrhage. 
 Other safety observations including tumor lysis syndrome (TLS), neutropenic AEs, 
infections, atrial fibrillation, cardiac arrhythmias (including ventricular tachyarrhythmia), 
cardiac failure, other malignancies (including non-melanoma skin cancer, melanoma skin 
cancer, non-skin cancer), hepatic disorders, interstitial lung disease (ILD), hypertension, 
ischemic stroke, diarrhea, and sepsis. 
All laboratory values will be converted to and reported as international standard (SI) units. In 
general, only data from the central laboratory will be summarized and analyzed. Laboratory 
parameters will be graded using the NCI CTCAE, Version 4.03. Unless otherwise specified, only 
 


 
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baseline and post-baseline values collected during the treatment-emergent period will be 
included in the safety analysis. 
Table 4: Summary of Safety Assessments 
Assessment 
Type 
Definition   
Analysis Methods 
Adverse 
Events 
Treatment emergent DLTs, TEAEs, SAEs, Grade 3 or higher 
TEAEs, related TEAEs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose reduction, TEAEs leading 
to dose delay, TEAEs leading to dose modification, TEAEs leading 
to death, protocol- defined events of special interest and other safety 
observations  
Descriptive summary 
statistics and/or listings 
Laboratory 
Parameters 
Worst post-baseline toxicity grade for CTCAE gradable hematology 
and chemistry.  Abnormalities in creatinine clearance, uric acid, and 
liver function.  
Descriptive summary 
statistics and/or listings 
Vital Signs 
and other 
Observations 
Related to 
Safety 
Systolic blood pressure (SBP), diastolic blood pressure (DBP), 
abnormal physical examination findings  
Descriptive summary 
statistics and/or listings 
AE: adverse event; CTCAE: Common Terminology Criteria for Adverse Events; SAE: serious adverse event; 
TEAE: treatment-emergent adverse event. 
5.1. 
Data Summaries for COVID-19 
TEAEs and deaths related to a COVID-19 infection will be summarized and included in the 
corresponding tables. COVID-19 laboratory tests will be summarized. 
6. CHANGES IN PROTOCOL-PLANNED ANALYSIS 
No changes have been made in protocol-planned analyses. 
7. REFERENCES 
Bellmunt J, Choueiri TK, Fougeray R, et al. Prognostic factors in patients with advanced transitional cell 
carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. JCO. 
2010;28:1850-1855. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47. 
Koyama T, Chen H. Proper inference from Simon’s two-stage designs. Stat Med. 2008; 27:3145-54.  
 


 
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Niegisch G,  Fimmers R, Siener R, et al. Prognostic factors in second-line treatment of urothelial cancers 
with gemcitabine and paclitaxel (German Association of Urological Oncology Trial AB20/99). Eur 
Urology. 2011;60:1087-96. 
 
 








 
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Statistical Analysis Plan 1 
 
 
A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced 
Gastrointestinal and Genitourinary Tumors 
 
PCYC-1128-CA 
 
 
November 12, 2019 
Version 1.0 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document is considered privileged and confidential by Pharmacyclics LLC., and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board approval and informed consent, 
or as required by Federal and State Laws.  Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed. 
 
 
 
 
 
 
 
 
 
 




 
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LIST OF ABBREVIATIONS .......................................................................................................4 
1. 
INTRODUCTION ..................................................................................................................5 
1.1. 
Study Design ..................................................................................................................5 
1.2. 
Endpoints .......................................................................................................................9 
1.2.1. Primary Endpoint ..............................................................................................9 
1.2.2. Secondary Endpoints ........................................................................................9 
1.2.3. Safety Assessments ...........................................................................................9 
1.2.4. Exploratory Endpoints (Phase 2) ....................................................................10 
1.3. 
Statistical Hypotheses ..................................................................................................10 
1.4. 
Sample Size Determination..........................................................................................10 
1.5. 
Planned Analysis ..........................................................................................................11 
1.5.1. Phase 1b analysis ............................................................................................11 
1.5.2. Interim Analysis (IA) ......................................................................................11 
1.5.3. Final Analysis .................................................................................................12 
1.5.4. Blinding and Randomization Methods ...........................................................13 
2. 
GENERAL ANALYSIS CONSIDERATION ....................................................................14 
2.1. 
Analysis Sets ................................................................................................................14 
2.2. 
Definition of Subgroups ...............................................................................................15 
3. 
SUBJECT INFORMATION................................................................................................16 
3.1. 
Subject Disposition ......................................................................................................16 
3.2. 
Demographics, Baseline Characteristics, and Baseline Disease Characteristics .........17 
3.3. 
Prior and Concomitant Medications ............................................................................17 
3.4. 
Extent of Exposure to Study Treatment .......................................................................17 
3.5. 
Prior Anti-cancer Treatments and Subsequent Anti-cancer Treatment .......................18 
4. 
ANALYSIS FOR ENDPOINTS ..........................................................................................18 
5. 
SAFETY ASSESSMENTS ...................................................................................................21 
6. 
CHANGES IN PROTOCOL PLANNED ANALYSIS ......................................................23 
7. 
REFERENCES .....................................................................................................................23 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
CEA 
carcinoembryonic antigen 
CR 
complete response 
CRC 
colorectal adenocarcinoma 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLRC 
dose level review committee 
DLT 
dose limiting toxicity 
ECOG 
Eastern Cooperative Oncology Group 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PR 
partial response  
RCC 
renal cell carcinoma 
RP2D 
recommended Phase 2 dose 
RECIST 
response evaluation criteria in solid tumors  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse event 
 
 
 
 
 


 
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1. INTRODUCTION 
This statistical analysis plan (SAP) is based on the protocol Amendment 2.1 and is to define key 
elements including variable definitions, and statistical methods for analysis of data in evaluation 
of efficacy and safety of the study PCYC-1128-CA.  Analyses of biomarker and 
pharmacokinetics are not in scope of this document. 
, both refer to any of the study drugs including ibrutinib, 
and/or backbone/standard of care drugs. 
Analysis methods specified in this document take precedence over those described in protocol 
should there be any difference. Any changes from the protocol will be documented in Section 6, 
Changes in Protocol Planned Analysis.  
There will be two CSRs for this study. CSR #1 is for RCC Cohort 1, GC Cohort 3, and CRC 
Cohort 4 and CSR #2 is for all UC cohorts (Cohorts 2, 5, and 6). Database extraction will take 
place in the first quarter of 2020 to prepare for CSR #1. This SAP (referred to as SAP1) is to 
cover the analysis plan for CSR #1. A second SAP (referred to as SAP2) will be written to cover 
the analysis plan for CSR #2 in the future. 
1.1. 
Study Design 
This is an open-label, Phase 1b/2 multi-center study to assess the safety and efficacy of ibrutinib 
monotherapy (Cohort 5) in subjects with previously-treated urothelial carcinoma (UC) and 
ibrutinib combination therapy (Cohorts 1-4, 6) in subjects with previously treated renal cell 
carcinoma (RCC), UC, gastric carcinoma (GC), and colorectal carcinoma (CRC) as listed below. 
Each cohort in this study will assess a different malignancy and/or anticancer agent in 
combination with ibrutinib or single-agent ibrutinib and follow an independent and parallel 
design: 
Metastatic RCC (Cohort 1) 
Advanced (locally recurrent and/or metastatic) UC (Cohorts 2, 5, 6) 
Advanced (locally recurrent and/or metastatic) GC (Cohort 3) 
Metastatic CRC (Cohort 4) 
This Phase 1b/2 study is divided into 2 parts. An initial Phase 1b portion will evaluate the safety 
and tolerability of single-agent ibrutinib and ibrutinib in combination with each anticancer agent 
to assess any dose limiting toxicity in order to determine the recommended Phase 2 dose (RP2D) 
for each cohort. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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The Phase 2 portion will assess primary endpoints of PFS, progression-free survival, (with an 
incorporated interim analysis) for RCC and UC cohort 2, and overall response rate (ORR) using 
-stage design for GC, CRC, and UC Cohorts 5 and 6.  
Phase 1b 
The Phase 1b portion of this study is performed independently in six separate cohorts defined by 
the clinical indication; RCC, UC, GC, and CRC. 
For cohorts 1-4, safety and dose-limiting toxicity (DLT) assessment will be evaluated in 3-9 
subjects at each dose level in a 3+3+3 design. At each dose level, DLT assessment will be 
performed in the first 3 subjects. If 1 of 3 subjects experiences a DLT during the first treatment 
cycle, the same dose level will be expanded to 6 subjects, and if 2 of the 6 experience a DLT, the 
same dose level will be expanded to 9 subjects. At the 560 mg/day dose level (DL 1), if 0 out of 
 
dose escalation to 840 mg/day (DL 2) wi
experience a DLT (eg, >2 out of 6 or >2 out of 9 subjects), the dose will be de-escalated to 420 
mg/day (dose level minus one; DL -1). At the 840 mg/day dose level (DL 2) cohort, subjects will 
be enrolled in a similar fashion. 
For UC cohort 5, the single-agent dose of 840 mg will be confirmed and documented in the first 
6 patients; safety data will be described. 
For UC cohort 6, a 6+3 dose de-escalation design will be implemented. For the Phase 1b portion 
of cohort 6, if 2 subjects within the initial cohort of 6 subjects experience a DLT, an additional 3 
subjects will be enrolled at the same dose level. If 3 or more of 6 subjects experience a DLT, 
dose de-escalation will occur and additional 6 evaluable subjects will be enrolled. If incidence of 
DLTs during the DLT observation period is 
be considered safe to proceed to Phase 2 and will be defined as the RP2D. 
The RP2D will be determined when 6 9 subjects at the dose level complete the DLT observation 
period based on the totality of the data including dose reductions (of both ibrutinib and the 
combination therapy), treatment-limiting toxicities (outside of DLTs), the available 
pharmacokinetic data and the toxicity profile obtained during Phase 1b. In order to determine the 
RP2D dose level, a minimum of 6 DLT-evaluable subjects will be required at the RP2D dose 
level who are defined to have completed at least 21 days of treatment with ibrutinib in 
combination with the relevant anticancer agent, after the initiation of therapy at the start of Cycle 
1. 
For UC cohorts 5 and 6, a DLT-
 
during Cycle 1 (the first 21 days). At each dose level, the decision of de-escalation will be made 
for at least 6 DLT-evaluable subjects. However, if at any time in a given dose level, 3 subjects 
experience a DLT, additional enrollment within the dose level will be stopped.  
 
 
 
 
 
 
 
  
  
 
  
  
 
  
 
 
  
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


 
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For combination therapy of ibrutinib and other anticancer agent specified below, the starting 
dose of ibrutinib will be 560 mg daily in the following 5 cohorts: 
 RCC cohort 1: ibrutinib + everolimus 
 UC cohort 2: ibrutinib + paclitaxel 
 GC cohort 3: ibrutinib + docetaxel 
 CRC cohort 4: ibrutinib + cetuximab 
 UC cohort 6: ibrutinib + pembrolizumab 
For single-agent ibrutinib, the starting dose will be 840 mg. 
UC cohort 5: single-agent ibrutinib 
A dose level review committee (DLRC) will evaluate the safety data at the completion of the 
initial Phase 1b portion in each cohort to determine the RP2D, prior to continuing with 
enrollment into the Phase 2 portion (enrollment may not be held for UC cohort 5 as safety data is 
available for more than 40 subjects for ibrutinib 840 mg in combination with paclitaxel data). 
The DLRC will review the safety data in the first 6 evaluable subjects enrolled in cohort 5 to 
confirm 840 as the single-agent dose. Members of this committee will include the Medical 
Monitor or designee, a Drug Safety representative, a Biostatistician, and at least 2 participating 
investigators/designees. 
The DLT observation period will encompass 21 days after the initiation of combination therapy 
(or single agent ibrutinib for Cohort 5) at the start of Cycle 1. A DLT is defined as any Grade 3 
or higher non-hematologic or Grade 4 hematologic adverse event (AE) occurring during the DLT 
observation period and considered to be at least possibly related to the study treatment (ibrutinib 
or combination). Details of DLTs are  documented in the protocol Section 3. 
If a subject experience a DLT during the DLT observation period, the subject will discontinue 
treatment. Dose reductions will not be permitted during the DLT observation period. However, 
any other subject(s) tolerating the dose level through the DLT observation period will continue to 
receive the same dose of study drugs even if a dose escalation or de-escalation occurs for 
subsequent study subjects. 
Any Phase 1b subjects who discontinue one or more study drugs, or require dose reduction 
within 21 days after the initiation of therapy at the start of Cycle 1 will be replaced, unless the 
discontinuation is in association with a DLT. Subjects who miss one or more scheduled doses 
(more than 2 doses for UC cohorts 5 and 6) of either study drug within 21 days after the 
initiation of therapy at the start of Cycle 1 will continue. However, such a subject will not be 
evaluable for DLT assessment and will be replaced for DLT assessment purposes. 
 
 
 
 
 


 
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After Cycle 1, all subjects will be treated until unacceptable toxicity or disease progression, 
whichever occurs first. Tumor assessment by CT/MRI will occur every 6 weeks and will be 
evaluated according to RECIST 1.1 guidelines. After the RP2D has been defined for each cohort, 
enrollment in Phase 2 will commence in that cohort. 
Dosing regimen in Phase 1b for each cohort is described in Table 1 below: 
Table 1: Dosing Regimen in Phase 1b 
 
Cohort 
DL-1 
DL 1 
DL2 
RCC (Cohort 1) 
Ibrutinib: 420 mg PO qd  
Everolimus: 10 mg PO qd 
Ibrutinib: 560 mg PO qd  
Everolimus: 10 mg PO qd 
Ibrutinib: 840 mg PO qd  
Everolimus: 10 mg PO qd 
UC (Cohort 2 ) 
Ibrutinib: 420 mg PO qd 
Paclitaxel: 80 mg/m2 IV 
qweek 
Ibrutinib: 560 mg PO qd 
Paclitaxel: 80 mg/m2 IV qweek 
Ibrutinib: 840 mg PO qd 
Paclitaxel: 80 mg/m2 IV qweek 
GC (Cohort 3 ) 
Ibrutinib: 420 mg PO qd  
Docetaxel: 60-75 mg/m2 IV 
q3weeks 
Ibrutinib: 560 mg PO qd  
Docetaxel: 60-75 mg/m2 IV 
q3weeks 
Ibrutinib: 840 mg PO qd  
Docetaxel: 60-75 mg/m2 IV 
q3weeks 
CRC (Cohort 4) 
Ibrutinib: 420 mg PO qd  
Cetuximab: 400 mg/m2 IV,     
then 250 mg/m2 IV qweek 
Ibrutinib: 560 mg PO qd  
Cetuximab: 400 mg/m2 IV, then 
250 mg/m2 IV qweek 
Ibrutinib: 840 mg PO qd  
Cetuximab: 400 mg/m2 IV, then 
250 mg/m2 IV qweek 
UC (Cohort 5) 
Ibrutinib 560 mg PO qd 
Ibrutinib 840 mg PO qd 
NA 
UC (Cohort 6) 
Ibrutinib: 420 mg PO qd  
Pembrolizumab: 200 mg IV 
q3weeks 
Ibrutinib: 560 mg PO qd  
Pembrolizumab: 200 mg IV 
q3weeks 
NA 
PO = orally, qd = daily, qweek = weekly, q3weeks = every 3 weeks 
Study treatment will be given in 21-day cycles for all cohorts. 
       
Phase 2 
For each cohort in the study, a separate analysis will be performed to evaluate the response and 
safety profile. Tumor assessment by CT/MRI will occur every 6 weeks and will be evaluated 
according to RECIST 1.1 guidelines. Subjects will be treated until unacceptable toxicity or 
disease progression, whichever occurs first. Subjects treated at RP2D in Phase 1b will be 
included in Phase 2 analyses. 
In all cohorts, subjects who are dosed at the RP2D level and withdraw prior to the completion of 
at least 2 cycles of study treatment, for reasons other than unacceptable toxicity or disease 
progression, may be replaced after consultation with the Sponsor. 
For GC (Cohort 3), CRC (Cohort 4), and UC Cohorts 5 and 6, if a subject in Stage-1 
discontinues prior to the first tumor response assessment for reasons other than disease 
progression, the subject may be replaced. Enrollment may continue into stage-2, while the 
response evaluation and analysis from the Stage-1 are completed. If the number of responders 
observed among the evaluable subjects in Stage-1 is less than the number of responders required 
-stage design, the relevant cohort may be terminated for futility. 
 
 
 
 
 
 
 
 
 
  


 
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1.2. 
Endpoints 
The rest of this SAP1 document only describes endpoints and analysis relevant to CSR #1. 
1.2.1. 
Primary Endpoint 
Phase 1b 
 
To determine the RP2D of ibrutinib in combination with everolimus in RCC, docetaxel in 
GC and cetuximab in CRC and assess DLTs during the 21-day DLT assessment period. 
 
Phase 2 
Progression-free survival (PFS) in accordance with RECIST 1.1 criteria in RCC in 
Cohort 1 
Overall response rate (ORR) in GC in Cohort 3 and CRC in Cohort 4 
1.2.2. 
Secondary Endpoints 
Phase 1b 
 
Secondary objectives are to assess ORR and disease control rate (DCR). 
Phase 2  
Disease control rate (DCR) in all cohorts 
PFS in GC Cohort 3 and CRC Cohort 4 
ORR in RCC Cohort 1 
Overall survival (OS) in all cohorts 
Duration of response (DOR) in all cohorts 
1.2.3. 
Safety Assessments 
Phase 1b 
 
To assess the safety and tolerability of ibrutinib in each cohort 
Phase 2 
 
Safety and tolerability of ibrutinib combination therapy in each cohort 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 
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analysis stopping rule was determined by the design. For Cohort 1 (RCC), interim analysis 
timing is when approximately 25 efficacy evaluable subjects dosed at the RP2D level have 
completed 6 months of follow-up. Details are provided below. Enrollment may continue while 
the interim analysis is being performed for each cohort. The analysis will be conducted on 
subjects who received RP2D from Phase 1b and Phase 2.  
Go/No Go decisions at the time of the interim analyses will include all available clinical and 
safety data for that cohort and are not based solely on the efficacy data for the endpoint involved 
in the interim analysis. No multiplicity adjustment will be made for Cohort 1 final efficacy 
analysis. 
RCC Cohort 1  
PFS is the primary efficacy endpoint for this cohort. A single interim analysis for futility will 
take place after approximately 25 efficacy evaluable subjects dosed at the RP2D level have 
completed 6 months of follow-up. The proportion of subjects that are PFS event-free at 6 months 
will be assessed along with other safety and efficacy data in making the determination if the 
study should continue. Point estimator and 2-sided 90% Brookmeyer-Crowley confidence 
interval with log-log-transformed Greenwood variance estimate of the median PFS (mPFS) will 
be calculated to assess efficacy.  
GC Cohort 3 and CRC Cohort 4 
For those two cohorts, ORR is the primary endpoint and 
-stage minimax design is 
implemented to evaluate ORR following the Stage-1 boundaries in Table 2.  
At the interim analysis of the Stage-1, the proportion of responding subjects (best response of CR 
or PR) will be calculated, along with other safety and efficacy data when making the 
determination if the study should continue into the stage-2. Confirmation of response is not 
required for the interim analysis. 
1.5.3. 
Final Analysis 
The final analysis will be conducted after all efficacy evaluable subjects have completed a 
minimum period of follow-up for the primary endpoint or other key endpoint(s).  
There will be two CSRs for this study. CSR #1 is for RCC Cohort 1, GC Cohort 3, and CRC 
Cohort 4 and is covered in SAP1. When all subjects in these three cohorts have exited the study, 
an addendum will be written to summarize disposition and selected safety data. 
RCC Cohort 1 
Primary endpoint for RCC Cohort 1 is PFS. Final analysis will be performed 6 months after last 
enrolled subject (LPI) completes the treatment and assessment.  
 
 
 
 
 
  


 
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GC Cohort 3 and CRC Cohort 4  
Primary endpoint for those two cohorts is ORR. Confirmation of response is required for the 
final analysis per RECIST 1.1 since this is an open label single arm study. That is, CR or PR may 
be claimed only if the criteria for each are met at a subsequent visit (generally 4 weeks or later). 
See Table 3 in RECIST 1.1 [2] for the scenarios of the best overall response when confirmation 
is required. 
1.5.4. 
Blinding and Randomization Methods 
Not Applicable. This is an open-label non-randomized study.   
 
 
 
 
 


 
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2. GENERAL ANALYSIS CONSIDERATION 
Phase 1b 
Limited tables and listings will be included. They are baseline demographic, baseline 
characteristics, disease characteristics, treatment and study disposition, DLTs, ORR, DCR, 
overview of treatment emergent adverse events (TEAEs), TEAEs by Systems Organ 
Class/Preferred Term/maximum severity, serious TEAEs, TEAEs leading to death, TEAEs 
leading to ibrutinib discontinuation. No subgroup will be summarized for this phase. Data will be 
summarized separately for each cohort by dose. 
Phase 2 
Data summary and data analysis will be conducted for each disease cohort separately. Data will 
not be pooled across disease cohorts or tested between disease cohorts.  
Baseline, demographics, disposition, and safety data will be summarized by dose level (RP2D). 
Efficacy analysis will only be conducted for subjects treated at R2PD. Subjects who were treated 
with ibrutinib at the R2PD level in Phase 1b or Phase 2 will be combined in the summary. 
Subgroup analyses are mainly to evaluate for trends and assess internal consistency of any 
treatment benefit. Analysis will be carried out for the CRC and GC cohorts only. The subgroups 
for these cohorts are of clinical interest/relevance. Statistical hypothesis testing will not be 
performed for the subgroup analyses.  
General Definitions:  
For disease cohorts with a combination treatment, date of first dose of study treatment is defined 
as the date the subject received the first dose of ibrutinib or the companion drug (whichever 
occurs first) and date of last dose of study treatment is defined as the date the subject receive the 
last dose of ibrutinib or the companion drug (whichever occurs later). 
Baseline value is defined as the last non-missing valid value collected prior to the first 
administration of study treatment. For subjects who have been enrolled but not treated, 
enrollment date will be used as the reference date for baseline if needed. 
2.1. 
Analysis Sets 
DLT Evaluable Population: Defined as subjects from Phase 1b who completed at least 21 days 
of treatment with ibrutinib in combination with the relevant anticancer agent after the initiation 
of study treatment at the start of Cycle 1, or those who discontinued from study treatment due to 
a DLT event prior to completion of DLT observation period. The DLT Evaluable Population will 
be used for DLT assessments. Per protocol, subjects who miss one or more scheduled doses of 
either study drug within 21 days after the initiation of therapy at the start of Cycle 1 will 
 
 
 
 
 


 
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continue. However, such a subject will not be evaluable for DLT assessment, and will be 
replaced for DLT assessment purposes. 
All Enrolled Population: Defined as all eligible subjects enrolled in the study. 
All Treated Population: Defined as all subjects who received at least 1 dose of study treatment 
(ibrutinib or the companion drug for the combination therapy). This population is the same as  
the Safety Population defined in the protocol. For the purpose of analysis and CSR, All Treated 
Population will be used as the data set to summarize all the data unless otherwise indicated. 
Sensitivity analysis of efficacy endpoints will be performed based on this population.  
Efficacy Evaluable Population: This population will be used to perform the primary analysis 
for the efficacy endpoint(s) and is defined as eligible subjects who received at least one dose of 
ibrutinib (at RP2D) in combination with at least one dose of the relevant companion drug and 
fulfil the following criteria: 
RCC Cohort 1 (PFS as the primary endpoint) 
1) Had at least one adequate post-baseline overall disease assessment per RECIST 1.1 
guidelines or died prior to the first adequate post-baseline overall disease assessment. 
GC Cohort 3 and CRC Cohort 4 (ORR as the primary endpoint) 
1) Had measurable disease (i.e. at least one target lesion as defined in the protocol) per 
RECIST 1.1 guidelines at baseline. 
2) Had at least one adequate post-baseline overall disease assessment per RECIST 1.1 
guidelines. 
2.2. 
Definition of Subgroups 
Subgroup analyses will be performed for the selected variables in an exploratory fashion. Further 
clinically relevant and biomarker subgroups will be assessed at the time of the final CSR if 
appropriate. The subgroup variables and the cutoff values are subject to change if warranted to 
better represent the data. Otherwise subgroup analysis will not be carried out if the distribution 
for the subgroup variable does not warrant the analysis. 
Subgroup analysis is relevant only for the primary endpoints of GC and CRC cohorts. 
 
Table 3.1: Baseline Subgroup Definition  
 
 
 
 
 




 
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Enrollment by country and investigator/site (all enrolled subjects) 
Study treatment disposition, study treatment duration and discontinuation of study treatment 
(All Treated Population) 
Study status and study exit for all enrolled subjects. 
Time on study is defined in the same way as overall survival with reversed censoring, i.e., 
subjects who died will be censored at death date. The Kaplan-Meier method will be used to 
estimate the median time on study. 
3.2. 
Demographics, Baseline Characteristics, and Baseline Disease Characteristics 
Subject demographics and baseline characteristics will be summarized with descriptive statistics 
for the all treated population by cohort.  
3.3. 
Prior and Concomitant Medications 
Medications will be coded to a generic name and an Anatomical Therapeutic Chemical (ATC) 
class according to World Health Organization drug dictionary.  
Prior medications are defined as medications that started prior to the first dose of study 
treatment. Concomitant medications are defined as medications that were taken on treatment (i.e. 
from the date of first dose of study treatment through the date of last dose of study treatment).   
Concomitant medications will be summarized by ATC class and preferred term (PT) based on 
All Treated Population for each disease cohort. Each subject will be counted once only for 
overall, each PT, and each ATC class.  The following concomitant medications will be 
summarized separately:  
CYP3A inhibitors and inducers  This list requires a medical review, with finalization at the 
time of analysis 
Anticoagulants and antiplatelet agents will need medical review as above. 
3.4. 
Extent of Exposure to Study Treatment 
For each disease cohort, exposure to study treatment will be summarized for each study drug for 
the All Treated Population. Descriptive statistics will be provided, by study drug, for the 
followings: treatment duration (month), total number of doses received, total number of cycles 
received (for chemotherapy), total cumulative dose administered, dose intensity and relative dose 
intensity (%), and number (%) of subjects with dose reduction due to adverse events (AEs), dose 
delay due to AEs and dose reduction or delay due to AEs.  
 
 
 
 
 
 
 
 
 
 


 
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3.5. 
Prior Anti-cancer Treatments and Subsequent Anti-cancer Treatment 
Anti-cancer treatment includes drug therapies, radiation, and surgeries and procedures performed 
with therapeutic intent. The ATC level of anti-cancer drug therapies will be specified in the 
mock-up table footnote. Prior anti-cancer treatments are treatments received prior to study 
treatment. Subsequent anti-cancer treatment are treatments received after date of last dose of 
study treatment. Prior and subsequent anti-cancer treatment will be summarized separately using 
All Treated population for each disease cohort. 
4. ANALYSIS FOR ENDPOINTS 
For Phase 1b, data will be summarized by dose level for each cohort separately. As described in 
Sections 1.5 and 2, limited tables and listings will be included. Descriptive summaries will be 
provided and confidence intervals described in Table 4 for ORR, DCR can be applied as data 
warrant. No subgroup will be summarized for this phase.  
For Phase 2, efficacy and safety data will be summarized by RP2D dose level of ibrutinib (same 
RP2D in both phases will be pooled together) for each disease cohort separately. Hereafter this 
will be referred to 
 
Primary analysis of each efficacy endpoint will be performed using the Efficacy Evaluable 
Population at the time of final analysis, unless otherwise indicated. Sensitivity analyses will be 
performed for some efficacy endpoints using the All Treated Population. Safety data will be 
summarized using the All Treated Population. 
Efficacy analyses will be based on the overall disease assessments determined by the investigator 
per RECIST 1.1 guidelines. Efficacy endpoint definitions and analysis methods for Phase 2 are 
described in Table 4.  
Table 4: Summary of Efficacy Analyses 
 
Endpoint 
Definition 
Analysis Methods 
Primary Endpoint (RCC) 
 
 
 
 
 
 
  
 
 
 
 
 
 
 






 
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Endpoint 
Definition 
Analysis Methods 
whichever occurs first. Confirmation 
of CR or PR is not required. 
 
DCR will be calculated using the exact 
binomial distribution (Clopper-Pearson).  
 
 
OS 
Time from the date of first dose of 
study treatment to the date of death 
from any cause. Subjects who were 
not known to have died at the data 
extraction will be censored at date last 
known alive. 
Primary analysis:  
For each disease cohort, the following 
analysis methods will be used to perform 
the analysis based on Efficacy Evaluable 
population. 
Kaplan-Meier curve will be provided. The 
2-sided 90% Brookmeyer-Crowley 
confidence interval (CI) based on the log-
log-transformed Greenwood variance 
estimate will be calculated for median OS 
(mOS). 
Kaplan-Meier point estimate and its 90% 
confidence interval will be calculated for 
OS rate at selected landmark points. 
Sensitivity analysis: 
All Treated Population. Same analysis 
methods. 
 
 
5. SAFETY ASSESSMENTS 
Safety data will be summarized using All Treated Population by ibrutinib dose level (RP2D 
versus other dose level) for each disease cohort separately. Adverse events (AEs) will be coded 
in accordance with the Medical Dictionary for Regulatory Activities (MedDRA). Severity of 
AEs will be 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.  
In general, the treatment-emergent (TE) period is defined as the period from the date of the first 
dose of study treatment up to 30 days after the date of the last dose of study treatment or the day 
before initiation of subsequent anti-cancer treatment, whichever comes first.  
Treatment-emergent adverse events are those events that: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Are not present prior to the TE period and occur during the TE period, 
The onset dates are missing and resolution dates are during the TE period, 
Are considered related to the study treatment by the investigator regardless of the start 
dates of the events, or 
Are present prior to the TE period but worsen in severity during the TE period or are 
subsequently considered related to study drug by the investigator. 
Treatment emergent dose limiting toxicities (DLTs) as determined by the investigator and 
identified by the check box on the Adverse Event page will be summarized for each cohort.  
All laboratory values will be converted to and reported as international standard (SI) units. In 
general, only data from the central laboratory will be summarized and analyzed. Laboratory 
parameters will be graded using the NCI CTCAE, Version 4.03. Unless otherwise specified, only 
baseline and post-baseline values collected during the treatment-emergent period will be 
included in the safety analysis. 
Table 5: Summary of Safety Assessments 
Assessment 
Type 
Definition   
Analysis Methods 
Adverse 
Events 
Treatment emergent DLTs, TEAEs, SAEs, Grade 3 or higher 
TEAEs, related TEAEs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose reduction, TEAEs leading 
to dose delay, TEAEs leading to dose modification, TEAEs leading 
to death, protocol- defined events of special interest and other safety 
observations  
Descriptive summary 
statistics and/or listings 
Laboratory 
Parameters 
Worst post-baseline toxicity grade for CTCAE gradable hematology 
and chemistry.  Abnormalities in creatinine clearance, uric acid, and 
liver function. CEA levels (for CRC Cohort 4 only)  
Descriptive summary 
statistics and/or listings 
Vital Signs 
and other 
Observations 
Related to 
Safety 
Systolic blood pressure (SBP), diastolic blood pressure (DBP), 
abnormal physical examination findings  
Descriptive summary 
statistics and/or listings 
AE: adverse event; CTCAE: Common Terminology Criteria for Adverse Events; SAE: serious adverse event; 
TEAE: treatment-emergent adverse event. 
 
 
 
 
 
 
 
 
 
 


 
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6. CHANGES IN PROTOCOL PLANNED ANALYSIS 
a)
All Treated Population  
Section 10.1.2.  However, for analysis 
be used as the data set for efficacy and safety analyses.  
b) All Treated Population is used for sensitivity analysis for the primary efficacy endpoints 
and OS analysis. 
c) Other than changes in CEA levels, analysis for other exploratory endpoints are not 
covered in the scope of the SAP. 
d) Subgroup analyses will only be performed for the respective primary endpoints in the GC 
and CRC cohorts for CSR #1. Analysis for CSR #2 will be discussed in SAP2 to be 
finalized later. 
 
 
7. REFERENCES 
Bellmunt J, Choueiri TK, Fougeray R, et al. Prognostic factors in patients with advanced transitional cell 
carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. JCO. 
2010;28:1850-1855. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47. 
-stage designs. Stat Med. 2008; 27:3145-54.  
Niegisch G,  Fimmers R, Siener R, et al. Prognostic factors in second-line treatment of urothelial cancers 
with gemcitabine and paclitaxel (German Association of Urological Oncology Trial AB20/99). Eur 
Urology. 2011;60:1087-96.