A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal and Genitourinary Tumors
Phase: PHASE1
Conditions: Metastatic Renal Cell Carcinoma, Advanced Urothelial Carcinoma, Advanced Gastric Adenocarcinoma, Metastatic Colorectal Adenocarcinoma
Sponsor: Pharmacyclics LLC.



Ibrutinib (PCI-32765)                                                                             PCYC-1128-CA Amendment 2.0 
  
 
 
 
 
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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 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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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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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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