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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.

Study Description
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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.

Condition or disease Intervention/treatment Phase
Metastatic Renal Cell Carcinoma Advanced Urothelial Carcinoma Advanced Gastric Adenocarcinoma Metastatic Colorectal Adenocarcinoma Drug: Ibrutinib Drug: Everolimus Drug: Docetaxel Drug: Paclitaxel Drug: Cetuximab Drug: Pembrolizumab Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 348 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of Ibrutinib Combination Therapy in Selected Advanced Gastrointestinal And Genitourinary Tumors
Actual Study Start Date : November 2015
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Ibrutinib

Arms and Interventions
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Arm Intervention/treatment
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.

 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.

 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.

 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.

 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.
 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.
 Drug: Ibrutinib
Drug: Pembrolizumab


Outcome Measures
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Primary Outcome Measures :
  1. 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

  2. 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

  3. 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.

  4. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02599324


Contacts
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Contact: Bhagyashree Yadav 669-224-1104 PCYC-1128@pcyc.com

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Sponsors and Collaborators
Pharmacyclics LLC.
Investigators
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Study Director: George Cole, M.D. Pharmacyclics LLC.
More Information
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Responsible Party: Pharmacyclics LLC.
ClinicalTrials.gov Identifier: NCT02599324     History of Changes
Other Study ID Numbers: PCYC-1128-CA
First Posted: November 6, 2015    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Carcinoma
Adenocarcinoma
Carcinoma, Renal Cell
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Paclitaxel
Docetaxel
 Albumin-Bound Paclitaxel
Pembrolizumab
Everolimus
Sirolimus
Cetuximab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs