Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers

• ClinicalTrials.gov Identifier: NCT03332498
• Recruitment Status: Completed
• First Posted: November 6, 2017
• Results First Posted: January 22, 2021
• Last Update Posted: June 3, 2022
• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborators: Janssen Scientific Affairs, LLC; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): H. Lee Moffitt Cancer Center and Research Institute

Tracking Information

• First Submitted Date: November 2, 2017
• First Posted Date: November 6, 2017
• Results First Submitted Date: December 4, 2020
• Results First Posted Date: January 22, 2021
• Last Update Posted Date: June 3, 2022
• Actual Study Start Date: January 24, 2018
• Actual Primary Completion Date: December 5, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 4, 2020)

• Phase I - Recommended Phase II Dose (RP2D) [ Time Frame: 42 days post first dose ]
  Standard 3+3 Design: The first cohort will enroll a minimum of 3 participants, according to a standard 3+3 design. If 0 out of the first 3 participants in the first cohort experience a dose-limiting toxicity (DLT), then dose escalation will continue as planned. If 1 out of the first 3 participants experience a DLT, then the cohort will be expanded to a total of 6 participants, and if no more than 1 out of 6 participants experiences a DLT in a given dose cohort, dose escalation will continue as planned. If ≥ 2 DLTs are observed in the first dose cohort, the principle investigator will discuss with Janssen on how to proceed. The DLT evaluation period will be defined as the time from the first dose of pembrolizumab and ibrutinib to 42 days after the first dose or if a participant experiences a DLT within this time period.
• Phase II - Disease Control Rate at 4 Months [ Time Frame: 4 months ]
  Percentage of participants who achieved disease control at 4 months. Disease control rate = Complete Response (CR) + Partial Response (PR) + Stable Disease (SD). Tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and RECIST based immune-related response criteria (irRC).

Original Primary Outcome Measures (submitted: November 2, 2017)

• Phase I - Recommended Phase II Dose (RP2D) [ Time Frame: 42 days post first dose ]
  Standard 3+3 Design: The first cohort will enroll a minimum of 3 subjects, according to a standard 3+3 design. If 0 out of the first 3 participants in the first cohort experience a dose-limiting toxicity (DLT), then dose escalation will continue as planned. If 1 out of the first 3 participants experience a DLT, then the cohort will be expanded to a total of 6 participants, and if no more than 1 out of 6 subjects experiences a DLT in a given dose cohort, dose escalation will continue as planned. If ≥ 2 DLTs are observed in the first dose cohort, the principle investigator will discuss with Janssen on how to proceed. The DLT evaluation period will be defined as the time from the first dose of pembrolizumab and ibrutinib to 42 days after the first dose or if a participant experiences a DLT within this time period. A maximum of 2 cohorts is expected, making a total of approximately 12 evaluable subjects during the dose escalation phase.
• Phase II - Disease Control Rate at 4 Months [ Time Frame: 4 months ]
  Complete Response (CR) + Partial Response (PR) + Stable Disease (SD). Tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and RECIST based immune-related response criteria (irRC).

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers
• Official Title: A Phase I/II Study of Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers
• Brief Summary: The purpose of this study is to determine the safety and tolerability, describe the dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) (or the highest protocol-defined dose level in the absence of establishing an MTD) of ibrutinib in combination with pembrolizumab in participants with advanced, refractory colorectal cancers.
• Detailed Description: On this study, one treatment cycle equals 21 days. On the first day of each study treatment cycle, 200 milligrams of pembrolizumab will be given through an IV (intravenously) for about thirty minutes. In addition, participants will begin taking the ibrutinib capsules every day starting on cycle 1, day 1. Participants will have a follow-up visit every 3 weeks, on about the first day of each cycle with laboratories drawn to make sure that the study drugs are not causing any side effects. In addition, participants will have a computed tomography (CT) scan every 6 to 7 weeks to determine whether your cancer is getting better or worse.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Colon Cancer
• Colorectal Cancer
• Colorectal Carcinoma
• Colon Disease

Intervention

• Drug: Pembrolizumab
  200 milligrams of pembrolizumab will be given through an IV (intravenously) for about thirty minutes. Pembrolizumab is an anti-PD1 that functions by inhibiting checkpoint inhibition and reversing T cell suppression.
  Other Name: Keytruda®
• Drug: Ibrutinib
  Ibrutinib oral capsules every day starting on cycle 1, day 1. Ibrutinib is primarily a BTK inhibitor which has been approved for the treatment of several hematologic malignancies.
  Other Name: Imbruvica®

Study Arms

Experimental: Pembrolizumab and Ibrutinib

Pembrolizumab intravenously (IV): 200 mg every 3 weeks (Q3W).

Ibrutinib by mouth (PO): Phase I Dose Escalation at doses of 420 mg daily (cohort 0) and 560 mg daily (cohort 1);. Phase II treatment at Recommended Phase II dose.

Interventions:

• Drug: Pembrolizumab
• Drug: Ibrutinib

• Publications *: Kim DW, Tan E, Zhou JM, Schell MJ, Martinez M, Yu J, Carballido E, Mehta R, Strosberg J, Imanirad I, Kim RD. A phase 1/2 trial of ibrutinib in combination with pembrolizumab in patients with mismatch repair proficient metastatic colorectal cancer. Br J Cancer. 2021 May;124(11):1803-1808. doi: 10.1038/s41416-021-01368-z. Epub 2021 Apr 7.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 12, 2019): 40
• Original Estimated Enrollment (submitted: November 2, 2017): 42
• Actual Study Completion Date: September 9, 2021
• Actual Primary Completion Date: December 5, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed diagnosis of colorectal adenocarcinoma.
• Measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Stage IV or recurrent disease is required.
• Participants must have received and progressed through or become intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab. If RAS wild type, participants should have received and progressed or become intolerant to the above as well as cetuximab or panitumumab containing therapies. Prior therapy with Regorafenib and/or TAS 102 is allowed.
• Eastern Cooperative Oncology Group (ECOG) Performance Score 0 or 1.
• Estimated life expectancy > 3 months.

• Adequate bone marrow, liver and renal function as assessed by the following:

  • Hemoglobin > 8.0 g/dl
  • Absolute neutrophil count (ANC) > 1,000/mm^3 independent of growth factor support
  • Platelet count > 100,000/mm^3
  • Total bilirubin < 1.5 times upper limit of normal (ULN) unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
  • AST, ALT and Alkaline Phosphatase ≤2.5 times the ULN ( ≤5 x ULN for potential participants with liver involvement)
  • Creatinine clearance ≥ 30 ml/min
• Must not have had chemotherapy, major surgery, monoclonal antibody therapy or experimental therapy within the 21 days prior to the start of ibrutinib administration
• Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women and surgically sterilized women are not required to undergo a pregnancy test.
• Men and women of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent form (ICF) until at least 4 months for both females and males after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate.
• Must agree to not donate sperm (males) or eggs (females) during and up to 120 days after the last dose of study treatment.
• Must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure. Must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other study requirements.

Exclusion Criteria:

• Active central nervous system (CNS) metastases. If CNS metastases are treated and patients are at neurologic baseline for at least 2 weeks prior to enrollment, they will be eligible but will need a Brain MRI prior to enrollment. Must be off corticosteroids or on a dose of less than 10mg per day.
• Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• A condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
• Prior therapy with ibrutinib or other BTK inhibitors.
• Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
• Known history of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
• Serologic status reflecting active hepatitis B or C infection. Patients who are hepatitis B core antibody positive and who are antigen negative, will need to have a negative PCR result prior to enrollment. Those who are hepatitis B antigen positive or PCR positive, will be excluded.
• Child Pugh B or C cirrhosis.
• History of severe hypersensitivity reactions to other monoclonal antibodies.
• Substance abuse, medical, psychological or social conditions that may interfere with participation in the study or evaluation of the study results.
• History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function.
• Unresolved toxicity higher than CTCAE grade 1 attributed to any prior therapy or procedure, excluding alopecia.
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months prior to first dose with study drug.
• Unable to swallow capsules or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption such as; malabsorption syndrome, resection of the small bowel, or poorly controlled inflammatory bowel disease affecting the small intestine.
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon).
• Requires treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• Any illness or medical conditions that are unstable or could jeopardize the safety of the participant and his/her compliance in the study.
• Major surgery or a wound that has not fully healed within 4 weeks of enrollment.
• Vaccinated with live, attenuated vaccines within 4 weeks of enrollment.
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis within 6 months.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03332498
• Other Study ID Numbers: MCC-19091
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Original Study Sponsor: Same as current

Collaborators

• Janssen Scientific Affairs, LLC
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Richard Kim, M.D.; H. Lee Moffitt Cancer Center and Research Institute

• PRS Account: H. Lee Moffitt Cancer Center and Research Institute
• Verification Date: June 2022