Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers

Sponsor
H. Lee Moffitt Cancer Center and Research Institute (Other)
Overall Status
Completed
CT.gov ID
NCT03332498
Collaborator
Janssen Scientific Affairs, LLC (Industry), Merck Sharp & Dohme LLC (Industry)
40
1
1
43.5
0.9

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
40 participants
Allocation:
N/A
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I/II Study of Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers
Actual Study Start Date :
Jan 24, 2018
Actual Primary Completion Date :
Dec 5, 2019
Actual Study Completion Date :
Sep 9, 2021

Arms and Interventions

Arm Intervention/Treatment
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.

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 Names:
  • 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 Names:
  • Imbruvica®
  • Outcome Measures

    Primary Outcome Measures

    1. Phase I - Recommended Phase II Dose (RP2D) [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.

    2. Phase II - Disease Control Rate at 4 Months [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).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 H. Lee Moffitt Cancer Center and Research Institute Tampa Florida United States 33612

    Sponsors and Collaborators

    • H. Lee Moffitt Cancer Center and Research Institute
    • Janssen Scientific Affairs, LLC
    • Merck Sharp & Dohme LLC

    Investigators

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

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    H. Lee Moffitt Cancer Center and Research Institute
    ClinicalTrials.gov Identifier:
    NCT03332498
    Other Study ID Numbers:
    • MCC-19091
    First Posted:
    Nov 6, 2017
    Last Update Posted:
    Jun 3, 2022
    Last Verified:
    Jun 1, 2022
    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
    Keywords provided by H. Lee Moffitt Cancer Center and Research Institute
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Phase 1 Cohort 0: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 1 Cohort 1: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 2: Treatment at RP2D
    Arm/Group Description Pembrolizumab intravenously (IV): 200 mg every 3 weeks (Q3W). Ibrutinib by mouth (PO): Phase I Dose Escalation at 420 mg daily. Pembrolizumab intravenously (IV): 200 mg every 3 weeks (Q3W). Ibrutinib by mouth (PO): Phase I Dose Escalation at 560 mg daily Phase 2: Treatment at Recommended Phase 2 Dose (RP2D) - 200 mg Pembrolizumab and 560 mg Ibrutinib 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. 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.
    Period Title: Overall Study
    STARTED 4 4 32
    COMPLETED 4 4 30
    NOT COMPLETED 0 0 2

    Baseline Characteristics

    Arm/Group Title Phase 1 Cohort 0: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 1 Cohort 1: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 2: Treatment at RP2D Total
    Arm/Group Description Pembrolizumab intravenously (IV): 200 mg every 3 weeks (Q3W). Ibrutinib by mouth (PO): Phase I Dose Escalation at 420 mg daily. Pembrolizumab intravenously (IV): 200 mg every 3 weeks (Q3W). Ibrutinib by mouth (PO): Phase I Dose Escalation at 560 mg daily Phase 2: Treatment at Recommended Phase 2 Dose (RP2D) - 200 mg Pembrolizumab and 560 mg Ibrutinib 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. 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. Total of all reporting groups
    Overall Participants 4 4 32 40
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    3
    75%
    4
    100%
    24
    75%
    31
    77.5%
    >=65 years
    1
    25%
    0
    0%
    8
    25%
    9
    22.5%
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    2
    50%
    15
    46.9%
    17
    42.5%
    Male
    4
    100%
    2
    50%
    17
    53.1%
    23
    57.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    1
    3.1%
    1
    2.5%
    Not Hispanic or Latino
    4
    100%
    4
    100%
    29
    90.6%
    37
    92.5%
    Unknown or Not Reported
    0
    0%
    0
    0%
    2
    6.3%
    2
    5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    1
    3.1%
    1
    2.5%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    5
    15.6%
    5
    12.5%
    White
    4
    100%
    4
    100%
    25
    78.1%
    33
    82.5%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    1
    3.1%
    1
    2.5%
    Region of Enrollment (participants) [Number]
    United States
    4
    100%
    4
    100%
    32
    100%
    40
    100%

    Outcome Measures

    1. Primary Outcome
    Title Phase I - Recommended Phase II Dose (RP2D)
    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.
    Time Frame 42 days post first dose

    Outcome Measure Data

    Analysis Population Description
    All participants in Phase 1 portion of study who received at least one dose of study drugs
    Arm/Group Title Pembrolizumab and Ibrutinib
    Arm/Group Description 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) 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. 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.
    Measure Participants 8
    Number [mg]
    560
    2. Primary Outcome
    Title Phase II - Disease Control Rate at 4 Months
    Description 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).
    Time Frame 4 months

    Outcome Measure Data

    Analysis Population Description
    All participants in Phase 2 portion who received at least one dose of study drugs.
    Arm/Group Title Phase 2: Treatment at RP2D
    Arm/Group Description Phase 2: Treatment at Recommended Phase 2 Dose (RP2D) - 200 mg Pembrolizumab and 560 mg Ibrutinib 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. 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.
    Measure Participants 31
    Number [percentage of participants]
    13
    325%

    Adverse Events

    Time Frame 1 year, 5 months
    Adverse Event Reporting Description Includes only participants who received at least one dose of study drugs.
    Arm/Group Title Phase 1 Cohort 0: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 1 Cohort 1: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 2: Treatment at RP2D
    Arm/Group Description Pembrolizumab intravenously (IV): 200 mg every 3 weeks (Q3W). Ibrutinib by mouth (PO): Phase I Dose Escalation at 420 mg daily. Pembrolizumab intravenously (IV): 200 mg every 3 weeks (Q3W). Ibrutinib by mouth (PO): Phase I Dose Escalation at 560 mg daily Phase 2: Treatment at Recommended Phase 2 Dose (RP2D) - 200 mg Pembrolizumab and 560 mg Ibrutinib 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. 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.
    All Cause Mortality
    Phase 1 Cohort 0: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 1 Cohort 1: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 2: Treatment at RP2D
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/4 (75%) 4/4 (100%) 26/32 (81.3%)
    Serious Adverse Events
    Phase 1 Cohort 0: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 1 Cohort 1: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 2: Treatment at RP2D
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/4 (50%) 3/4 (75%) 13/32 (40.6%)
    Blood and lymphatic system disorders
    Anemia 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 3
    Cardiac disorders
    Sinus tachycardia 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Atrial fibrillation 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Chest pain -cardiac 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Gastrointestinal disorders
    Rectal hemorrhage 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Nausea 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Vomiting 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Abdominal Pain 1/4 (25%) 1 2/4 (50%) 2 1/32 (3.1%) 2
    Ascites 1/4 (25%) 1 0/4 (0%) 0 0/32 (0%) 0
    Constipation 1/4 (25%) 1 0/4 (0%) 0 0/32 (0%) 0
    Abdominal distension 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Bowel Obstruction 0/4 (0%) 0 1/4 (25%) 2 0/32 (0%) 0
    Low colostomy output 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    General disorders
    Rib pain 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Edma limbs 1/4 (25%) 1 0/4 (0%) 0 0/32 (0%) 0
    Fever 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Fatigue 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Hepatobiliary disorders
    Cholangitis 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Cholecystitis 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Infections and infestations
    Bronchial infection 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 2
    Infections and Infestations - Other 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Urinary tract infection-Pyelonephritis 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Investigations
    Blood bilirubin increased 0/4 (0%) 0 1/4 (25%) 1 1/32 (3.1%) 1
    Creatinine increased 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Metabolism and nutrition disorders
    Dehydration 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Musculoskeletal and connective tissue disorders
    Back pain 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Flank pain 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Disease progression 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Neoplasms benign, malignant and unspecified-Other 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Nervous system disorders
    Dysarthria 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Encephalopathy 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Renal and urinary disorders
    Acute kidney injury 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Renal calculi 1/4 (25%) 1 0/4 (0%) 0 0/32 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 3
    Pneumonia 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Vascular disorders
    Hypotension 0/4 (0%) 0 0/4 (0%) 0 3/32 (9.4%) 3
    Thromboembolic event 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Other (Not Including Serious) Adverse Events
    Phase 1 Cohort 0: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 1 Cohort 1: Dose Escalation (Pembrolizumab and Ibrutinib) Phase 2: Treatment at RP2D
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/4 (100%) 4/4 (100%) 29/32 (90.6%)
    Blood and lymphatic system disorders
    Anemia 3/4 (75%) 7 3/4 (75%) 22 13/32 (40.6%) 21
    Leukocytosis 0/4 (0%) 0 1/4 (25%) 1 1/32 (3.1%) 1
    Cardiac disorders
    Sinus tachycardia 0/4 (0%) 0 1/4 (25%) 1 1/32 (3.1%) 1
    Atrial fibrillation 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Chest pain -cardiac 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Eye disorders
    Blurred vision 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Dry eye 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Eye disorders - Other 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Eye pain 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 2/4 (50%) 3 1/4 (25%) 1 11/32 (34.4%) 15
    Diarrhea 2/4 (50%) 2 1/4 (25%) 1 10/32 (31.3%) 11
    Nausea 3/4 (75%) 3 0/4 (0%) 0 8/32 (25%) 9
    Vomiting 0/4 (0%) 0 2/4 (50%) 3 7/32 (21.9%) 7
    Gastrointestinal disorders - Other 1/4 (25%) 2 1/4 (25%) 1 6/32 (18.8%) 7
    Constipation 1/4 (25%) 1 2/4 (50%) 3 3/32 (9.4%) 4
    Dyspepsia 1/4 (25%) 2 0/4 (0%) 0 3/32 (9.4%) 3
    Ascites 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Gastroesophageal reflux disease 0/4 (0%) 0 1/4 (25%) 1 2/32 (6.3%) 2
    Abdominal distension 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 3
    Dysphagia 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Oral pain 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 3
    Flatulence 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Lip pain 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Mucositis oral 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Oral hemorrhage 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 4
    Rectal hemorrhage 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 2
    Stomach pain 0/4 (0%) 0 1/4 (25%) 2 0/32 (0%) 0
    General disorders
    Fatigue 1/4 (25%) 1 3/4 (75%) 4 13/32 (40.6%) 15
    Fever 1/4 (25%) 1 1/4 (25%) 1 5/32 (15.6%) 7
    Edema limbs 1/4 (25%) 1 0/4 (0%) 0 5/32 (15.6%) 5
    General disorders and administration site conditions - Other 2/4 (50%) 4 1/4 (25%) 1 1/32 (3.1%) 1
    Chills 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Flu like symptoms 0/4 (0%) 0 1/4 (25%) 3 1/32 (3.1%) 1
    Pain 1/4 (25%) 1 0/4 (0%) 0 1/32 (3.1%) 1
    Irritability 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Non-cardiac chest pain 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Infections and infestations
    Urinary tract infection 0/4 (0%) 0 1/4 (25%) 1 6/32 (18.8%) 7
    Upper respiratory infection 1/4 (25%) 1 0/4 (0%) 0 2/32 (6.3%) 2
    Infections and infestations - Other 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Sinusitis 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Rash pustular 1/4 (25%) 1 0/4 (0%) 0 0/32 (0%) 0
    Injury, poisoning and procedural complications
    Bruising 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 2
    Gastrointestinal anastomotic leak 1/4 (25%) 1 0/4 (0%) 0 0/32 (0%) 0
    Injury, poisoning and procedural complications -Other 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Investigations
    Alkaline phosphatase increased 0/4 (0%) 0 1/4 (25%) 1 11/32 (34.4%) 11
    Alanine aminotransferase increased 0/4 (0%) 0 2/4 (50%) 2 8/32 (25%) 12
    Aspartate aminotransferase increased 0/4 (0%) 0 1/4 (25%) 3 9/32 (28.1%) 9
    Blood bilirubin increased 1/4 (25%) 1 1/4 (25%) 3 8/32 (25%) 11
    Platelet count decreased 1/4 (25%) 1 0/4 (0%) 0 5/32 (15.6%) 5
    CPK increased 1/4 (25%) 1 0/4 (0%) 0 3/32 (9.4%) 4
    Creatinine increased 2/4 (50%) 2 0/4 (0%) 0 2/32 (6.3%) 3
    Lipase increased 0/4 (0%) 0 0/4 (0%) 0 4/32 (12.5%) 4
    Lymphocyte count decreased 1/4 (25%) 2 1/4 (25%) 1 2/32 (6.3%) 3
    Serum amylase increased 0/4 (0%) 0 1/4 (25%) 1 2/32 (6.3%) 3
    Electrocardiogram QT corrected interval prolonged 1/4 (25%) 2 0/4 (0%) 0 1/32 (3.1%) 1
    INR increased 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Weight gain 1/4 (25%) 1 0/4 (0%) 0 1/32 (3.1%) 1
    Weight loss 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    GGT increased 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Investigations - Other 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 2
    Metabolism and nutrition disorders
    Hyponatremia 1/4 (25%) 1 0/4 (0%) 0 9/32 (28.1%) 12
    Anorexia 0/4 (0%) 0 1/4 (25%) 1 8/32 (25%) 8
    Hyperglycemia 1/4 (25%) 1 0/4 (0%) 0 7/32 (21.9%) 8
    Hypoalbuminemia 1/4 (25%) 2 1/4 (25%) 3 6/32 (18.8%) 6
    Dehydration 1/4 (25%) 1 0/4 (0%) 0 4/32 (12.5%) 5
    Hyperkalemia 2/4 (50%) 5 1/4 (25%) 1 2/32 (6.3%) 2
    Hypocalcemia 2/4 (50%) 4 0/4 (0%) 0 3/32 (9.4%) 3
    Hypokalemia 0/4 (0%) 0 1/4 (25%) 2 3/32 (9.4%) 3
    Hypomagnesemia 1/4 (25%) 1 1/4 (25%) 1 2/32 (6.3%) 2
    Hypercalcemia 0/4 (0%) 0 0/4 (0%) 0 3/32 (9.4%) 3
    Hypermagnesemia 0/4 (0%) 0 1/4 (25%) 1 1/32 (3.1%) 1
    Hypophosphatemia 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Hypoglycemia 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Musculoskeletal and connective tissue disorders
    Back pain 0/4 (0%) 0 1/4 (25%) 1 4/32 (12.5%) 4
    Myalgia 0/4 (0%) 0 1/4 (25%) 1 5/32 (15.6%) 8
    Arthralgia 0/4 (0%) 0 0/4 (0%) 0 4/32 (12.5%) 6
    Musculoskeletal and connective tissue disorders - Other 1/4 (25%) 1 2/4 (50%) 2 1/32 (3.1%) 4
    Pain in extremity 0/4 (0%) 0 0/4 (0%) 0 3/32 (9.4%) 3
    Arthritis 0/4 (0%) 0 1/4 (25%) 1 1/32 (3.1%) 1
    Flank pain 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Generalized muscle weakness 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Muscle weakness lower limb 1/4 (25%) 1 0/4 (0%) 0 0/32 (0%) 0
    Neck pain 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified -Other 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Nervous system disorders
    Headache 2/4 (50%) 4 1/4 (25%) 1 7/32 (21.9%) 10
    Dizziness 1/4 (25%) 2 0/4 (0%) 0 4/32 (12.5%) 4
    Peripheral sensory neuropathy 1/4 (25%) 1 0/4 (0%) 0 3/32 (9.4%) 3
    Parasthesia 1/4 (25%) 1 0/4 (0%) 0 1/32 (3.1%) 1
    Dysgeusia 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Encephalopathy 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Memory impairment 1/4 (25%) 1 0/4 (0%) 0 0/32 (0%) 0
    Nervous system disorders - Other 1/4 (25%) 1 0/4 (0%) 0 0/32 (0%) 0
    Peripheral motor neuropathy 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Seizure 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Psychiatric disorders
    Anxiety 1/4 (25%) 1 1/4 (25%) 1 1/32 (3.1%) 1
    Insomnia 0/4 (0%) 0 1/4 (25%) 1 2/32 (6.3%) 2
    Depression 0/4 (0%) 0 0/4 (0%) 0 2/32 (6.3%) 2
    Restlessness 0/4 (0%) 0 1/4 (25%) 1 1/32 (3.1%) 1
    Agitation 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 3
    Confusion 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Renal and urinary disorders
    Acute kidney injury 1/4 (25%) 1 1/4 (25%) 1 0/32 (0%) 0
    Renal and urinary disorders - Other 0/4 (0%) 0 2/4 (50%) 4 0/32 (0%) 0
    Cystitis noninfective 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Proteinuria 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Urinary frequency 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Urinary incontinence 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Urinary tract obstruction 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Urinary urgency 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Urine discoloration 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Reproductive system and breast disorders
    Female genital tract fistula 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Vaginal discharge 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Respiratory, thoracic and mediastinal disorders
    Cough 2/4 (50%) 2 1/4 (25%) 1 7/32 (21.9%) 7
    Dyspnea 1/4 (25%) 1 1/4 (25%) 2 5/32 (15.6%) 5
    Respiratory, thoracic and mediastinal disorders - Other 0/4 (0%) 0 0/4 (0%) 0 3/32 (9.4%) 3
    Hypoxia 0/4 (0%) 0 1/4 (25%) 1 1/32 (3.1%) 1
    Epistaxis 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Hiccups 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Pleural effusion 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Pulmonary edema 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Respiratory failure 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Sleep apnea 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 0/4 (0%) 0 0/4 (0%) 0 8/32 (25%) 11
    Pruritus 1/4 (25%) 1 0/4 (0%) 0 2/32 (6.3%) 2
    Skin and subcutaneous tissue disorders - Other 0/4 (0%) 0 0/4 (0%) 0 3/32 (9.4%) 3
    Bullous dermatitis 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Dry skin 0/4 (0%) 0 1/4 (25%) 1 0/32 (0%) 0
    Hyperhidrosis 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Rash acneiform 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1
    Vascular disorders
    Hypertension 1/4 (25%) 1 1/4 (25%) 2 8/32 (25%) 11
    Hypotension 1/4 (25%) 1 1/4 (25%) 1 3/32 (9.4%) 3
    Hot flashes 2/4 (50%) 3 0/4 (0%) 0 1/32 (3.1%) 1
    Thromboembolic event 0/4 (0%) 0 0/4 (0%) 0 1/32 (3.1%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Richard D. Kim, MD
    Organization Moffitt Cancer Center
    Phone 813-745-1277
    Email Richard.Kim@moffitt.org
    Responsible Party:
    H. Lee Moffitt Cancer Center and Research Institute
    ClinicalTrials.gov Identifier:
    NCT03332498
    Other Study ID Numbers:
    • MCC-19091
    First Posted:
    Nov 6, 2017
    Last Update Posted:
    Jun 3, 2022
    Last Verified:
    Jun 1, 2022