NCT05608044
Active, not recruiting
Phase 2
A Randomized, Open-Label, Phase 2 Study of Botensilimab (AGEN1181) as Monotherapy and in Combination With Balstilimab (AGEN2034) or Investigator's Choice Standard of Care (Regorafenib or Trifluridine and Tipiracil) for the Treatment of Refractory Metastatic Colorectal Cancer
ConditionsMetastatic Colorectal Cancer
Overview
- Phase
- Phase 2
- Intervention
- Botensilimab
- Conditions
- Metastatic Colorectal Cancer
- Sponsor
- Agenus Inc.
- Enrollment
- 234
- Locations
- 65
- Primary Endpoint
- Objective Response Rate
- Status
- Active, not recruiting
- Last Updated
- 8 months ago
Overview
Brief Summary
This is an open-label, Phase 2, multicenter study to evaluate the efficacy, safety, tolerability, and pharmacokinetic profiles of botensilimab as monotherapy and in combination with balstilimab or standard-of-care treatments in participants with refractory metastatic colorectal cancer.
Detailed Description
This study will enroll adult participants with a confirmed diagnosis of unresectable metastatic colorectal adenocarcinoma (CRC) who have had prior chemotherapy for metastatic or recurrent CRC. This study will consist of 5 cohorts. In the first and second cohorts, participants will receive 1 of 2 different doses of botensilimab intravenously (IV) and balstilimab IV. In the third and fourth cohorts, participants will receive 1 of 2 different doses of botensilimab. In the fifth cohort, participants will receive standard of care consisting of the investigator's choice of regorafenib or trifluridine and tipiracil.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed diagnosis of unresectable and metastatic CRC adenocarcinoma.
- •The tumor must have been assessed for microsatellite instability high (MSI-H) or deficient mismatch repair (dMMR) status per a standard local testing method.
- •Voluntarily agree to participate by giving signed, dated, and written informed consent prior to any study-specific procedures.
- •Must have received at least 1 prior chemotherapy regimen for metastatic or recurrent CRC as follows where approved and locally available in the country of randomization:
- •Standard chemotherapy/therapy including all of the following agents (if eligible and no contraindication): a fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab or biosimilars, an anti-epidermal growth factor receptor antibody (cetuximab or panitumumab), and v-raf murine sarcoma viral oncogene homolog B1 inhibitor/BRAF (encorafenib), if applicable.
- •Participants must have progressed while receiving or within 3 months of the last administration of their last line of standard therapy or be unable to tolerate any of these standard treatments.
- •Participants who received adjuvant chemotherapy and had recurrence during or within 6 months of completion of the adjuvant chemotherapy can count this as a line of therapy.
- •Measurable disease on baseline imaging per RECIST 1.
- •Life expectancy ≥ 12 weeks.
- •Eastern Cooperative Oncology Group performance status of 0 or
Exclusion Criteria
- •Tumor is MSI-H/dMMR per a standard local testing method.
- •Received programmed cell death protein 1, PD-(L)1, or CTLA-4 therapies including any immune checkpoint inhibitor or experimental immunologic agents.
- •Received regorafenib or trifluridine/tipiracil as prior therapy(ies).
- •Partial or complete bowel obstruction within the last 3 months, signs/symptoms of bowel obstruction, or known radiologic evidence of impending obstruction.
- •Refractory ascites.
- •Liver metastases by computed tomography or magnetic resonance imaging. Note: Participants with definitively treated liver metastases (this includes surgical resection, including microwave or radiofrequency ablation, or stereotactic body radiation therapy, but not yttrium-90 or chemotherapy alone) may be eligible if they were treated at least 6 months prior to enrollment with no evidence of metastatic disease in the liver on subsequent imaging.
- •Clinically significant (that is, active) cardiovascular disease.
- •Active brain metastases or leptomeningeal metastases with certain exceptions.
- •Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study treatment. Participants with history of prior early-stage basal/squamous cell skin cancer, low-risk prostate cancer eligible for active surveillance, or noninvasive or in situ cancers who have undergone definitive treatment at any time are also eligible.
- •Treatment with one of the following classes of drugs within the delineated time window prior to Cycle 1 Day 1 (C1D1):
Arms & Interventions
Combination Botensilimab Dose 1 plus Balstilimab
Participants will receive botensilimab at dose 1 given IV and balstilimab given IV.
Intervention: Botensilimab
Combination Botensilimab Dose 1 plus Balstilimab
Participants will receive botensilimab at dose 1 given IV and balstilimab given IV.
Intervention: Balstilimab
Combination Botensilimab Dose 2 plus Balstilimab
Participants will receive botensilimab at dose 2 given IV and balstilimab given IV.
Intervention: Botensilimab
Combination Botensilimab Dose 2 plus Balstilimab
Participants will receive botensilimab at dose 2 given IV and balstilimab given IV.
Intervention: Balstilimab
Monotherapy Botensilimab Dose 1
Participants will receive botensilimab dose 1 given IV.
Intervention: Botensilimab
Monotherapy Botensilimab Dose 2
Participants will receive botensilimab dose 2 given IV.
Intervention: Botensilimab
Standard of Care
Participants will receive select standard of care as determined by the investigator.
Intervention: Standard of Care
Outcomes
Primary Outcomes
Objective Response Rate
Time Frame: First dose through up to 2 years
Objective response rate is defined as the proportion of participants with complete response or partial response, as assessed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
Secondary Outcomes
- Duration of Response(First dose through up to 2 years)
- Progression-free Survival(First dose through up to 3 years)
- Overall Survival(First dose through up to 3 years)
- Number of Participants Experiencing Treatment-emergent Adverse Events(First dose through up to 2 years)
- Serum Botensilimab Concentration(First study dose (pre-dose and 1 hour post-dose) through up to 2 years)
- Serum Balstilimab Concentration(First study dose (pre-dose and 1 hour post-dose) through up to 2 years)
- Number of Participants Positive for Botensilimab Anti-drug Antibodies Following Treatment with Botensilimab(First study dose (pre-dose and 1 hour post-dose) through up to 2 years)
- Number of Participants Positive for Balstilimab Anti-drug Antibodies Following Treatment with Balstilimab(First study dose (pre-dose and 1 hour post-dose) through up to 2 years)
Study Sites (65)
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Related News
Balstilimab Plus Botensilimab Shows Enhanced Response in MSS mCRC Without Liver Metastases- Preliminary phase 2 data shows balstilimab combined with botensilimab yields a higher objective response rate in MSS mCRC patients without liver metastases.
- The combination of botensilimab 75 mg Q6W plus balstilimab showed a confirmed ORR of 19% and a disease control rate of 55%.
- The median duration of response has not been reached, with 70% of responses ongoing, indicating durable efficacy of the combination therapy.
- A phase 3 trial is planned using botensilimab 75 mg with balstilimab 240 mg, based on the favorable safety and efficacy profile observed.FDA Advises Against Accelerated Approval for Botensilimab/Balstilimab in MSS Colorectal Cancer Despite Phase 3 Advancement- The FDA advised against accelerated approval of botensilimab plus balstilimab for relapsed/refractory microsatellite stable metastatic colorectal cancer without liver metastases, citing concerns that objective response rates may not translate to survival benefit.
- Phase 2 trial data showed the combination achieved a 19.4% objective response rate with the 75 mg botensilimab dose, significantly higher than the 0% response rate seen with standard of care treatment.
- Despite the regulatory setback, Agenus and the FDA agreed on dosing for a phase 3 study, with botensilimab 75 mg every 6 weeks for up to 4 doses plus balstilimab 240 mg every 2 weeks for up to 2 years.
- The company remains committed to advancing the combination therapy and is exploring partnership opportunities to conduct the phase 3 trial in the United States.FDA Grants Fast Track Designation to Botensilimab Plus Balstilimab for Non-MSI-H/dMMR mCRC- The FDA has granted Fast Track designation to botensilimab plus balstilimab for treating non-MSI-H/dMMR metastatic colorectal cancer (mCRC).
- The designation targets heavily pretreated patients resistant or intolerant to standard therapies, including fluoropyrimidine, oxaliplatin, irinotecan, VEGF inhibitors, EGFR inhibitors, and BRAF inhibitors.
- Phase 1a/b trial data showed an overall response rate of 23% and a disease control rate of 76% in patients with microsatellite stable, refractory mCRC treated with the combination.
- The median overall survival was not reached in the overall population, with a 12-month overall survival rate of 63%, highlighting the potential of this combination in a high unmet need setting.