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A Study to Evaluate Ibrutinib Combination Therapy in Patients With Selected Gastrointestinal and Genitourinary Tumors

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ClinicalTrials.gov Identifier: NCT02599324
Recruitment Status : Recruiting
First Posted : November 6, 2015
Last Update Posted : June 11, 2019
Sponsor:
Information provided by (Responsible Party):
Pharmacyclics LLC.

Tracking Information
First Submitted Date  ICMJE November 4, 2015
First Posted Date  ICMJE November 6, 2015
Last Update Posted Date June 11, 2019
Actual Study Start Date  ICMJE November 2015
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 7, 2019)
  • Phase 1b: To determine the recommended Phase 2 dose (RP2D) of ibrutinib in combination with everolimus in RCC, paclitaxel in UC cohort 2, docetaxel in GC, cetuximab in CRC, and pembrolizumab in UC cohort 6 [ Time Frame: Approximately 6 months after evaluation ]
    Evaluated by the number of dose-limiting toxicities (DLT) graded using the NCI CTCAE v 4.03
  • Phase 1b: To confirm the RP2D of single-agent ibrutinib in UC cohort 5 [ Time Frame: Approximately 6 months after evaluation ]
    Evaluated by the number of dose-limiting toxicities (DLT) graded using the NCI CTCAE v 4.03
  • Phase 2: To assess progression-free survival (PFS) of ibrutinib in combination with everolimus in RCC, and ibrutinib in combination with paclitaxel for UC cohort 2. [ Time Frame: Approximately 12 months ]
    Defined by the time from the date of first dose of study drug until confirmed disease progression based on investigator assessment, per RECIST 1.1, or death from any cause, whichever comes first.
  • Phase 2: To assess the ORR of ibrutinib combination therapy in GC, CRC, UC cohort 6, and ibrutinib as a single agent in UC cohort 5 [ Time Frame: Approximately 12 months ]
    Defined by the proportion of subjects with a best response of complete response (CR) or partial response (PR) by investigator assessment, per RECIST 1.1.
Original Primary Outcome Measures  ICMJE
 (submitted: November 4, 2015)
  • Phase 1b: Determination of the recommended Phase 2 dose (RP2D) of ibrutinib in combination with everolimus in RCC, paclitaxel in urothelial carcinoma, docetaxel in gastric adenocarcinoma and cetuximab in CRC. [ Time Frame: Approximately 12 months after last patient enrolled ]
    Evaluated by the number of dose-limiting toxicities (DLT) graded using the NCI CTCAE v 4.03
  • Phase 2: Progression-free survival (PFS) of ibrutinib combination therapy in RCC and urothelial carcinoma [ Time Frame: Approximately 36 months after last patient enrolled. ]
    Defined by the time from the date of first dose of study drug until confirmed disease progression based on investigator assessment, per RECIST 1.1, or death from any cause, whichever comes first
  • Phase 2: ORR of ibrutinib combination therapy in gastric adenocarcinoma and CRC [ Time Frame: Approximately 36 months after last patient enrolled. ]
    Estimated using the All Treated Population as the proportion of subjects with a best response of complete response (CR) or partial response (PR) by investigator assessment
Change History Complete list of historical versions of study NCT02599324 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 7, 2019)
  • Phase 2: To assess the PFS of ibrutinib combination therapy in GC, CRC, and UC cohort 6, and ibrutinib as a single agent in UC cohort 5. [ Time Frame: Approximately 12 months ]
    Defined by the time from the date of first dose of study drug until confirmed disease progression based on investigator assessment, per RECIST 1.1, or death from any cause, whichever comes first.
  • Phase 2: To assess the ORR of ibrutinib combination therapy in RCC and UC cohort 2. [ Time Frame: Approximately 12 months ]
    Defined by the proportion of subjects with a best response of complete response (CR) or partial response (PR) by investigator assessment, per RECIST 1.1.
  • Phase 2: To assess the DOR in each cohort [ Time Frame: Approximately 12 months ]
    Defined for responders as duration of time from initial response (CR or PR by investigator assessment) to first documentation of disease progression or death from any cause, whichever occurs first.
  • Phase 2: To assess the DCR in each cohort [ Time Frame: Approximately 12 months ]
    Defined by the proportion of subjects with a best response of complete response (CR), partial response (PR), stable disease (greater than or equal to 6 weeks) by investigator assessment, per RECIST 1.1.
  • Phase 2: To assess the median OS of ibrutinib combination or single-agent therapy in each cohort [ Time Frame: Approximately 24 months ]
    Defined as the time from first dose of study drug to death due to any cause.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2015)
  • Phase 2: PFS of ibrutinib combination therapy in gastric adenocarcinoma and CRC [ Time Frame: Approximately 36 months after last patient enrolled. ]
    Defined by the time from the date of first dose of study drug until confirmed disease progression based on investigator assessment, per RECIST 1.1, or death from any cause, whichever comes first
  • Phase 2: ORR of ibrutinib combination therapy in RCC and urothelial carcinoma [ Time Frame: Approximately 36 months after last patient enrolled. ]
    Estimated using the All Treated Population as the proportion of subjects with a best response of complete response (CR) or partial response (PR) by investigator assessment
  • Phase 2: DCR of ibrutinib combination therapy in each cohort [ Time Frame: Approximately 36 months after last patient enrolled. ]
    Estimated using the All Treated Population as the proportion of subjects with a best response of CR, PR or stable disease (SD) of length greater than or equal to six weeks.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate Ibrutinib Combination Therapy in Patients With Selected Gastrointestinal and Genitourinary Tumors
Official Title  ICMJE A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal And Genitourinary Tumors
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 advanced gastrointestinal and genitourinary tumors.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Renal Cell Carcinoma
  • Advanced Urothelial Carcinoma
  • Advanced Gastric Adenocarcinoma
  • Metastatic Colorectal Adenocarcinoma
Intervention  ICMJE
  • Drug: Ibrutinib
  • Drug: Everolimus
  • Drug: Docetaxel
  • Drug: Paclitaxel
  • Drug: Cetuximab
  • Drug: Pembrolizumab
Study Arms  ICMJE
  • Experimental: Renal Cell Carcinoma - Enrollment Closed

    Phase 1b: Patients will receive ibrutinib at various dose levels in combination with everolimus to determine the Recommended Phase 2 Dose (RP2D) of ibrutinib.

    Phase 2: Patients will receive ibrutinib at the RP2D determined in Phase 1b in combination with everolimus.

    Interventions:
    • Drug: Ibrutinib
    • Drug: Everolimus
  • Experimental: Urothelial Carcinoma - Enrollment Closed

    Phase 1b: Patients will receive ibrutinib at various dose levels in combination with paclitaxel to determine the RP2D of ibrutinib.

    Phase 2: Subjects will receive paclitaxel at the RP2D determined in Phase 1b in combination with paclitaxel.

    Interventions:
    • Drug: Ibrutinib
    • Drug: Paclitaxel
  • Experimental: Gastric Adenocarcinoma - Enrollment Closed

    Phase 1b: Patients will receive ibrutinib at various dose levels in combination with docetaxel to determine the RP2D of ibrutinib.

    Phase 2: Subjects will receive docetaxel at the RP2D determined in Phase 1b in combination with docetaxel.

    Interventions:
    • Drug: Ibrutinib
    • Drug: Docetaxel
  • Experimental: Colorectal Adenocarcinoma - Enrollment Closed

    Phase 1b: Patients will receive ibrutinib at various dose levels in combination with cetuximab to determine RP2D of ibrutinib.

    Phase 2: Subjects will receive ibrutinib at the RP2D determined in Phase 1b in combination with cetuximab.

    Interventions:
    • Drug: Ibrutinib
    • Drug: Cetuximab
  • Experimental: Urothelial Carcinoma Single Agent Ibrutinib - Recruiting
    Phase 1b: Patients will receive ibrutinib at various dose levels to determine the RP2D of ibrutinib Phase 2: Subjects will receive ibrutinib at the RP2D determined in Phase 1b.
    Intervention: Drug: Ibrutinib
  • Experimental: Urothelial Carcinoma with Pembrolizumab - Recruiting
    Phase 1b: Patients will receive ibrutinib at various dose levels in combination with pembrolizumab to determine the RP2D of ibrutinib Phase 2: Subjects will receive ibrutinib at the RP2D determined in Phase 1b in combination with pembrolizumab.
    Interventions:
    • Drug: Ibrutinib
    • Drug: Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 7, 2019)
348
Original Estimated Enrollment  ICMJE
 (submitted: November 4, 2015)
189
Estimated Study Completion Date  ICMJE May 2021
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • RCC (clear cell), urothelial carcinoma (UC) (transitional cell), gastric or gastro-esophageal junctional (GEJ) adenocarcinoma, or K-RAS or N-RAS wild-type EGFR expressing CRC
  • For RCC: minimum of 1 and maximum of 4 prior regimens, one or more of which must have included a VEGF-TKI
  • For UC cohort 2: minimum of 1 and maximum of 2 prior regimens, one of which must have included a platinum-based regimen
  • For UC cohort 5: Minimum of 1 and maximum of 2 prior regimens, one of which must have included a checkpoint inhibitor.
  • For UC cohort 6:

    • Locally advanced or mUC who are not eligible for cisplatin chemo with a PDL-1 score (CPS) of ≥ 10 without prior treatment.
    • Locally advanced or mUC who have 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.
  • For gastric or GEJ adenocarcinoma: minimum of 1 and maximum of 3 prior regimens one of which must have included a fluoropyrimidine regimen
  • For CRC: 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

Laboratory:

  • Adequate hematologic function:

    • Absolute neutrophil count ≥1500 cells/mm3 (1.5 x 109/L)
    • Platelet count >80,000 cells/mm3 (80 x 109/L) for cohort 1 (RCC)
    • Platelet counts >100,000 cells/mm3 (100 x 109/L) for all UC cohorts
    • Hemoglobin ≥8.0 g/dL. for cohort 1 (RCC),all UC cohorts, and cohort 3 (GC)
    • Hemoglobin ≥9.0 g/dL for cohort 4 (CRC)
  • Adequate hepatic and renal function defined as:

    • Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤5.0 x upper
    • limit of normal (ULN) if liver metastases, or ≤3 x ULN without liver metastases
    • Alkaline phosphatase <3.0 x ULN or ≤5.0 x ULN if liver or bone metastases present
    • Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic
    • origin, such as hemolysis) with the exception of subjects in the GC cohort where
    • docetaxel is administered, these subjects must have bilirubin within normal limits (WNL)
    • Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault)

Exclusion Criteria

  • Prior treatment with:

    • Everolimus or temsirolimus (RCC cohort 1)
    • Any taxane ( UC cohort of ibrutinib + paclitaxel) (cohort 2)
    • Checkpoint inhibitors (UC cohort 6)
    • Any taxane (GC cohort 3)
    • Cetuximab or panitumumab (CRC cohort 4)
  • For all Cohorts:

    • Concomitant use of warfarin or other Vitamin K antagonists
    • History of stroke or intracranial hemorrhage within 6 months prior to enrollment
    • Major surgery within 4 weeks of first dose of study drug
    • Requires treatment with strong CYP3A inhibitors known bleeding disorders or hemophilia
  • UC cohort 6 only:

    • Subjects who have an active, known or suspected autoimmune disease.
    • Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis.
    • Non-steroid immunosuppressive medications within 14 days before the first dose of ibrutinib and pembrolizumab.
    • Subjects in whom prior anti PD-1 / anti-PD-L1 therapy was intolerable and required discontinuation of treatment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Bhagyashree Yadav 669-224-1104 PCYC-1128@pcyc.com
Listed Location Countries  ICMJE United States,   Korea, Republic of,   Spain,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02599324
Other Study ID Numbers  ICMJE PCYC-1128-CA
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Pharmacyclics LLC.
Study Sponsor  ICMJE Pharmacyclics LLC.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: George Cole, M.D. Pharmacyclics LLC.
PRS Account Pharmacyclics LLC.
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP