Colon CancerPhase 1/2NCT03332498
Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers
A Phase 1/2 study testing Pembrolizumab and Ibrutinib in people with Colon Cancer and Colorectal Cancer, run by H. Lee Moffitt Cancer Center and Research Institute at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colon Cancer, Colorectal Cancer, Colorectal Carcinoma
- What is being tested?
- Pembrolizumab and Ibrutinib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Jan 2018to 9 Sep 2021
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
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- 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.
Who cannot join
- 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)].
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, 33612
About this study
Official title: A Phase I/II Study of 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.
Read the 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.
- Conditions
- Colon Cancer, Colorectal Cancer, Colorectal Carcinoma, Colon Disease
- Being tested
- Pembrolizumab, Ibrutinib
- Keywords
- colon, rectum, advanced, refractory
- Medical subject headings
- Colonic Neoplasms, Colorectal Neoplasms, Colonic Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PembrolizumabDrug
Also called Keytruda®
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.
IbrutinibDrug
Also called Imbruvica®
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.
| Study group | Role | What they receive |
|---|---|---|
| Pembrolizumab and Ibrutinib | Experimental | 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. Receives: Drug: Pembrolizumab; Drug: Ibrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase I - Recommended Phase II Dose (RP2D)
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.
Measured: 42 days post first dose
Phase II - Disease Control Rate at 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).
Measured: 4 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Nov 2017
- Study start24 Jan 2018
- Primary completion5 Dec 2019
- Study completion9 Sep 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Colon CancerStudies of the same condition, open and under way.
- More trials run by H. Lee Moffitt Cancer Center and Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Janssen Scientific Affairs, LLC, Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
- Investigators
- Richard Kim, M.D., Principal investigator, H. Lee Moffitt Cancer Center and Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03332498
- Sponsor's protocol ID
- MCC-19091
- Status last verified
- Jun 2022
- First submitted
- 2 Nov 2017
- Last updated
- 3 Jun 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
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.
PubMed 33828254
Study at a glance
From the registry record, last updated by the sponsor on 3 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Study of Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers
- ClinicalTrials.gov ID
- NCT03332498
- Acronym / sponsor ID
- MCC-19091
- Conditions
- Colon Cancer, Colorectal Cancer, Colorectal Carcinoma, Colon Disease
- Keywords
- colon, rectum, advanced, refractory
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- H. Lee Moffitt Cancer Center and Research InstituteUniversity, hospital or other
- Collaborators
- Janssen Scientific Affairs, LLC, Merck Sharp & Dohme LLC
- Study start
- 24 Jan 2018 (actual)
- Primary completion
- 5 Dec 2019 (actual)
- Study completion
- 9 Sep 2021 (actual)
- First posted
- 6 Nov 2017 (actual)
- Results
- Posted 22 Jan 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pembrolizumab and Ibrutinib | Experimental | Drug: Pembrolizumab, Drug: IbrutinibPembrolizumab 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- 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.
Key exclusion criteria (22 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PembrolizumabAlso: Keytruda®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. | Drug | Pembrolizumab and Ibrutinib |
| IbrutinibAlso: Imbruvica®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. | Drug | Pembrolizumab and Ibrutinib |
Primary outcome
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).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jun 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33828254Kim 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.
- Moffitt Cancer Center Clinical Trials websiteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Richard Kim, M.D. principal investigator
H. Lee Moffitt Cancer Center and Research Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Pembrolizumab and Ibrutinib in people with Colon Cancer and Colorectal Cancer, run by H. Lee Moffitt Cancer Center and Research Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Jan 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase I - Recommended Phase II Dose (RP2D) (time frame: 42 days post first dose). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03332498, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jun 2022.