A Phase 2 Study of Botensilimab, Balstilimab and Regorafenib in Patients With Microsatellite Stable Colorectal Cancer
Overview
- Phase
- Phase 2
- Status
- Withdrawn
- Sponsor
- City of Hope Medical Center
- Enrollment
- 84
- Primary Endpoint
- Incidence of dose limiting toxicities (Safety lead in)
Overview
Brief Summary
This phase II trial studies how well the combination of botensilimab, balstilimab and regorafenib works compared to botensilimab and balstilimab in treating patients with microsatellite stable colorectal cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as botensilimab and balstilimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Regorafenib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps to slow or stop the spread of tumor cells. The combination of botensilimab, balstilimab and regorafenib or botensilimab and balstilimab may be a safe and effective treatment for advanced or metastatic microsatellite stable colorectal cancer.
Detailed Description
COPRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of botensilimab, balstilimab and regorafenib (BBR) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients without metastatic liver lesions in the safety run-in. (Safety lead-in) II. Compare the overall response rate in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients without metastatic liver lesions receiving botensilimab, balstilimab and regorafenib (BBR) versus botensilimab and balstilimab (BB), by treatment arm. (Phase II)
SECONDARY OBJECTIVES:
I. Estimate the overall survival in MSS mCRC patients without metastatic liver lesions receiving BBR and BB, by treatment arm.
II. Estimate the progression free survival in MSS mCRC patients without metastatic liver lesions receiving BBR and BB, by treatment arm.
III. Estimate the duration of response (DOR) in MSS mCRC patients without metastatic liver lesions receiving BBR and BB that experience a response to therapy, by treatment arm.
IV. Describe the safety of giving to BBR and BB to patients with MSS mCRC without metastatic liver lesions, by treatment arm.
EXPLORATORY OBJECTIVE:
I. Through the performance of baseline and on treatment biopsies and serial blood work (cytokines and flow cytometry), explore potential biomarkers of response to BBR and BB therapy given to MSS mCRC patients without metastatic liver lesions, by treatment arm.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM BBR: Patients receive botensilimab intravenously (IV) over 60 minutes on day 1 of each cycle, balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle, and regorafenib orally (PO) once daily (QD) on days 1-7, 15-21, and 29-35 of each cycle or on days 1-5, 15-19, and 29-33 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab and regorafenib in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
ARM BB: Patients receive botensilimab IV over 60 minutes on day 1 of each cycle and balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
After completion of study treatment, patients are followed up at 30 and 90 days and then every 2-3 months for 5 years.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Documented informed consent of the participant
- •In the phase II randomized portion of the study only, until two biopsies are obtained on ten patients receiving BBR and ten patients receiving BB: Agreement to biopsy of the same tumor at baseline and at 4 weeks
- •Agreement to biopsy of the same tumor at baseline and at 4 weeks
- •This applies only to patients with easily accessible tumors, where the risk of a biopsy is deemed acceptable. If a biopsy is determined to be unsafe patients will be exempt from this requirement
- •Agreement to allow the collection of blood for correlatives at baseline, 1 week, 2 weeks, 4 weeks, 8 weeks, and at the time progressive disease
- •Age: ≥ 18 years
- •Eastern Cooperative Oncology Group (ECOG) ≤ 1
- •Histologically or cytologically confirmed advanced or metastatic progressive proficient mismatch repair (pMMR)/MSS adenocarcinoma of the colon or rectum
- •No active brain metastases or leptomeningeal metastases, except for patients who underwent definitive surgery or radiation without progression following repeat imaging (at least 4 weeks after the intervention) and were systemic steroids have been discontinued at least 2 weeks prior study treatment
- •Known extended RAS and BRAF status, as per local standard of practice. Tumor mutation burden (TMB) and PD-L1 status will be collected when available but are not mandated for enrollment
Exclusion Criteria
- •Prior allogeneic organ transplantation
- •Prior immunotherapy with PD-1 or PD-L1 or CTLA-4 targeting agents
- •Prior regorafenib
- •Surgical intervention within 4 weeks prior to study treatment, except for minor procedures such as port placement
- •Patients with a condition requiring systemic treatment with corticosteroids (\> 10 mg daily prednisone equivalent) within 14 days or another immunosuppressive medication within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
- •Chemotherapy, radiation therapy, biological therapy, immunotherapy within 14 days or five half-lives (whichever is shorter for non-radiation therapy) prior to day 1 of protocol therapy
- •Strong CYP3A4 inducers or CYP3A4 inhibitors within 14 days prior to day 1 of protocol therapy
- •Patients unwilling to refrain from drinking grapefruit juice and taking St. John's Wort while on study
- •Herbal medications other than cannabidiol (CBD) unless reviewed by the principal investigator (PI) and deemed to unlikely interact with study drugs
- •Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 12 months of enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication
Arms & Interventions
Arm BB (botensilimab, balstilimab)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle and balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Balstilimab (Biological)
Arm BB (botensilimab, balstilimab)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle and balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Biopsy (Procedure)
Arm BB (botensilimab, balstilimab)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle and balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Biospecimen Collection (Procedure)
Arm BB (botensilimab, balstilimab)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle and balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Botensilimab (Biological)
Arm BB (botensilimab, balstilimab)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle and balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Computed Tomography (Procedure)
Arm BB (botensilimab, balstilimab)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle and balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Magnetic Resonance Imaging (Procedure)
Arm BBR (botensilimab, balstilimab, regorafenib)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle, balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle, and regorafenib PO QD on days 1-7, 15-21, and 29-35 of each cycle or on days 1-5, 15-19, and 29-33 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab and regorafenib in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Balstilimab (Biological)
Arm BBR (botensilimab, balstilimab, regorafenib)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle, balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle, and regorafenib PO QD on days 1-7, 15-21, and 29-35 of each cycle or on days 1-5, 15-19, and 29-33 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab and regorafenib in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Biopsy (Procedure)
Arm BBR (botensilimab, balstilimab, regorafenib)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle, balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle, and regorafenib PO QD on days 1-7, 15-21, and 29-35 of each cycle or on days 1-5, 15-19, and 29-33 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab and regorafenib in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Biospecimen Collection (Procedure)
Arm BBR (botensilimab, balstilimab, regorafenib)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle, balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle, and regorafenib PO QD on days 1-7, 15-21, and 29-35 of each cycle or on days 1-5, 15-19, and 29-33 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab and regorafenib in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Botensilimab (Biological)
Arm BBR (botensilimab, balstilimab, regorafenib)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle, balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle, and regorafenib PO QD on days 1-7, 15-21, and 29-35 of each cycle or on days 1-5, 15-19, and 29-33 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab and regorafenib in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Computed Tomography (Procedure)
Arm BBR (botensilimab, balstilimab, regorafenib)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle, balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle, and regorafenib PO QD on days 1-7, 15-21, and 29-35 of each cycle or on days 1-5, 15-19, and 29-33 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab and regorafenib in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Magnetic Resonance Imaging (Procedure)
Arm BBR (botensilimab, balstilimab, regorafenib)
Patients receive botensilimab IV over 60 minutes on day 1 of each cycle, balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle, and regorafenib PO QD on days 1-7, 15-21, and 29-35 of each cycle or on days 1-5, 15-19, and 29-33 of each cycle. Cycles repeat every 42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab and regorafenib in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and blood sample collection throughout the trial. Patients also undergo tumor biopsy during screening and on study.
Intervention: Regorafenib (Drug)
Outcomes
Primary Outcomes
Incidence of dose limiting toxicities (Safety lead in)
Time Frame: During cycle 1 (42 days)
Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Treatment related adverse event rates (Safety lead in)
Time Frame: During cycle 1 (42 days)
Assessed by NCI CTCAE version 5.0.
Response rate (Phase II) RECIST
Time Frame: Up to 5 years after completion of study treatment
Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (primary) in microsatellite stable metastatic colorectal cancer patients without metastatic liver lesions receiving botensilimab, balstilimab and regorafenib versus botensilimab and balstilimab, by treatment arm. Will be summarized by number, and percentage, along with Clopper-Pearson exact binomial confidence intervals.
Response rate (Phase II) Immune-Modified RECIST
Time Frame: Up to 5 years after completion of study treatment
Assessed by Immune-Modified RECIST (secondary) in microsatellite stable metastatic colorectal cancer patients without metastatic liver lesions receiving botensilimab, balstilimab and regorafenib versus botensilimab and balstilimab, by treatment arm. Will be summarized by number, and percentage, along with Clopper-Pearson exact binomial confidence intervals.
Secondary Outcomes
- Progression free survival(From enrollment to disease progression/relapse or death as a result of any cause, whichever occurs first, assessed up to 5 years after completion of study treatment)
- Incidence of adverse events(Up to 90 days after completion of study treatment)
- Overall survival(From enrollment to death as a result of any cause or being censored at their last contact, assessed up to 5 years after completion of study treatment)
- Duration of treatment response(Up to 5 years after completion of study treatment)