A Phase Ib Study of Botensilimab Plus Balstilimab and Fasting-Mimicking Diet (FMD) Plus Vitamin C in Patients With KRAS-Mutant Metastatic Colorectal Cancer
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 15
- Locations
- 5
- Primary Endpoint
- Proportion of patients who adhere to the fast mimicking diet
Overview
Brief Summary
This phase Ib trial tests the safety, side effects, and effectiveness of botensilimab, and balstilimab in combination with a fasting mimicking diet and high dose vitamin C in treating patients with KRAS-mutant metastatic colorectal cancer. Botensilimab and balstilimab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. KRAS is protein found on some tumor cells that is involved in the growth of tumor cells. KRAS mutant cells have been found to be more sensitive to vitamin C induced growth suppression in the presence of low-sugar (glucose). A fasting mimicking diet, a plant-based, calorie reduced, low-sugar diet alternating with refeeding periods, may positively change the way the body responds to cancer treatment. Vitamin C is a nutrient that the body needs in small amounts to function and stay healthy. It is an antioxidant that that can help prevent cell damage and may block growth and spread of tumor cells. Botensilimab and balstilimab in combination with a fasting mimicking diet and high dose vitamin C may be safe, tolerable and effective in treating patients with KRAS-mutant metastatic colorectal cancer.
Detailed Description
PRIMARY OBJECTIVES:
I. To evaluate the feasibility of the fasting mimicking diet (FMD) when combined with vitamin C and botensilimab plus balstilimab by determining the proportion of patients who adhere to the FMD ≥ 75% of the designated days and receive all doses of botensilimab, balstilimab and Vitamin C for at least any two cycles of therapy.
II. To characterize the safety and tolerability of FMD and vitamin C when combined with botensilimab and balstilimab by assessing any grade toxicities per Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
SECONDARY OBJECTIVES:
I. To obtain a preliminary assessment of anti-tumor activity of botensilimab plus balstilimab and FMD plus vitamin C by determining the overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
II. To estimate the progression-free and overall survival in patients with KRAS-mutant colorectal cancer (CRC) receiving botensilimab plus balstilimab and FMD plus vitamin C.
EXPLORATORY OBJECTIVES:
I. To characterize circulating tumor deoxyribonucleic acid (ctDNA) and ctDNA methylation (TET, Wnt, JAK/STAT, PI3K/AKT, CXCR, ALDH, AMPK) profiles at baseline, on treatment and at disease progression.
II. To examine metabolomic markers (IGF-1, GAPDH, DHA, GLUT-1, iron signaling) at baseline, on treatment and at disease progression.
OUTLINE:
Patients receive botensilimab intravenously (IV) over 30 minutes on day 1 of each cycle for up to 4 cycles. Patients receive balstilimab IV over 30 minutes and vitamin C IV over 30 minutes on days 1, 15 and 29 of each cycle. Patients undergo a FMD on days -4 to -1 of each cycle. Cycles repeat every 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, computed tomography (CT) scans and magnetic resonance imaging (MRI) throughout the study.
After completion of study intervention, patients are followed up at 30 days and every 3 months for up to 6 months.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histologically or cytologically confirmed microsatellite stable (MSS) metastatic colorectal adenocarcinoma with any KRAS mutation (as determined by a Clinical Laboratory Improvement Act \[CLIA\]-certified lab), including metastases to liver, lung, etc.
- •Disease progression, intolerance or contraindication to a fluoropyrimidine, oxaliplatin, irinotecan
- •≥ 18 years of age
- •Performance status Eastern Cooperative Oncology Group (ECOG) 0-1
- •Estimated life expectancy ≥ 3 months
- •Body mass index (BMI) ≥ 18.5
- •Absolute neutrophil count ≥ 1,500/mcL
- •Hemoglobin ≥ 8.0 g/dL
- •Platelets ≥ 75,000/mcL
- •Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (for patients with Gilbert syndrome ≤ 3.0 x ULN)
Exclusion Criteria
- •Patients with a current diagnosis of diabetes mellitus are not eligible for this study.
- •Note: Patients with pre-diabetes or previous diabetes or glucose intolerance and who are currently not taking any diabetes medications are eligible
- •Patients taking medications that cannot be safely stopped during the fasting periods or which may not be safely taken without food are not eligible for this study
- •Received prior systemic cytotoxic chemotherapy, biological therapy, radiotherapy, or major surgery within 3 weeks prior to first dose of study drug. A 1-week washout is permitted for palliative radiation to non-central nervous system (CNS) disease, with approval from the principal investigator
- •History of syncope with caloric restriction or another medical comorbidity which would make fasting potentially dangerous
- •Current use of oral vitamin C supplements
- •Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 3 weeks of first dose of current study drug
- •Expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent, radiation therapy, and/or surgical resection)
- •History of anti-PD1 or anti-CTLA4 therapy
- •Unresolved toxicity ≥ CTCAE grade 2 except for neuropathy, alopecia
Arms & Interventions
Treatment (botensilimab, balstilimab, FMD, vitamin C)
Patients receive botensilimab IV over 30 minutes on day 1 of each cycle for up to 4 cycles. Patients receive balstilimab IV over 30 minutes and vitamin C IV over 30 minutes on days 1, 15 and 29 of each cycle. Patients undergo a FMD on days -4 to -1 of each cycle. Cycles repeat every 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT scans and MRI throughout the study.
Intervention: Balstilimab (Biological)
Treatment (botensilimab, balstilimab, FMD, vitamin C)
Patients receive botensilimab IV over 30 minutes on day 1 of each cycle for up to 4 cycles. Patients receive balstilimab IV over 30 minutes and vitamin C IV over 30 minutes on days 1, 15 and 29 of each cycle. Patients undergo a FMD on days -4 to -1 of each cycle. Cycles repeat every 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT scans and MRI throughout the study.
Intervention: Biospecimen Collection (Procedure)
Treatment (botensilimab, balstilimab, FMD, vitamin C)
Patients receive botensilimab IV over 30 minutes on day 1 of each cycle for up to 4 cycles. Patients receive balstilimab IV over 30 minutes and vitamin C IV over 30 minutes on days 1, 15 and 29 of each cycle. Patients undergo a FMD on days -4 to -1 of each cycle. Cycles repeat every 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT scans and MRI throughout the study.
Intervention: Botensilimab (Biological)
Treatment (botensilimab, balstilimab, FMD, vitamin C)
Patients receive botensilimab IV over 30 minutes on day 1 of each cycle for up to 4 cycles. Patients receive balstilimab IV over 30 minutes and vitamin C IV over 30 minutes on days 1, 15 and 29 of each cycle. Patients undergo a FMD on days -4 to -1 of each cycle. Cycles repeat every 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT scans and MRI throughout the study.
Intervention: Computed Tomography (Procedure)
Treatment (botensilimab, balstilimab, FMD, vitamin C)
Patients receive botensilimab IV over 30 minutes on day 1 of each cycle for up to 4 cycles. Patients receive balstilimab IV over 30 minutes and vitamin C IV over 30 minutes on days 1, 15 and 29 of each cycle. Patients undergo a FMD on days -4 to -1 of each cycle. Cycles repeat every 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT scans and MRI throughout the study.
Intervention: Dietary Intervention (Other)
Treatment (botensilimab, balstilimab, FMD, vitamin C)
Patients receive botensilimab IV over 30 minutes on day 1 of each cycle for up to 4 cycles. Patients receive balstilimab IV over 30 minutes and vitamin C IV over 30 minutes on days 1, 15 and 29 of each cycle. Patients undergo a FMD on days -4 to -1 of each cycle. Cycles repeat every 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT scans and MRI throughout the study.
Intervention: Magnetic Resonance Imaging (Procedure)
Treatment (botensilimab, balstilimab, FMD, vitamin C)
Patients receive botensilimab IV over 30 minutes on day 1 of each cycle for up to 4 cycles. Patients receive balstilimab IV over 30 minutes and vitamin C IV over 30 minutes on days 1, 15 and 29 of each cycle. Patients undergo a FMD on days -4 to -1 of each cycle. Cycles repeat every 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT scans and MRI throughout the study.
Intervention: Vitamin C (Dietary Supplement)
Outcomes
Primary Outcomes
Proportion of patients who adhere to the fast mimicking diet
Time Frame: Up to 30 months
Adherence will be defined as the percentage of patients who adhere to the fasting-mimicking diet ≥ 75% of the designated days and receive all doses of study drugs for at least any 2 cycles of therapy during the course of the study. Adherence will be reported overall and by cycle started.
Incidence of adverse events (AEs)
Time Frame: Up to 30 months
The frequency and severity of treatment-related events will be assessed using Common Terminology Criteria for Adverse Events version 5.0. Descriptive statistics will be used to summarize AEs including counts for categorical measures and means for continuous measures. Incidence of AEs will be reported overall and by cycle started.
Secondary Outcomes
- Overall survival (OS)(Up to 30 months)
- Overall response rate (ORR)(Up to 30 months)
- Progression-free survival (PFS)(Up to 30 months)