Clinical Trials /

Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers



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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Active, not recruiting


Phase 1/Phase 2

Trial Eligibility



  • 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

Clinical Trial IDs

  • ORG STUDY ID: MCC-19091
  • NCT ID: NCT03332498


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


PembrolizumabKeytruda®Pembrolizumab and Ibrutinib
IbrutinibImbruvica®Pembrolizumab and Ibrutinib


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.

Trial Arms

Pembrolizumab and IbrutinibExperimentalPembrolizumab 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.
  • Pembrolizumab
  • Ibrutinib

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

          -  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.,

          -  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.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I - Recommended Phase II Dose (RP2D)
Time Frame:42 days post first dose
Safety Issue:
Description: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. A maximum of 2 cohorts is expected, making a total of approximately 12 evaluable participants during the dose escalation phase.


Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

Trial Keywords

  • colon
  • rectum
  • advanced
  • refractory

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