A Study of Botensilimab and Balstilimab for the Treatment of Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT05608044
• Recruitment Status: Active, not recruiting
• First Posted: November 8, 2022
• Last Update Posted: March 25, 2024
• Sponsor: Agenus Inc.
• Information provided by (Responsible Party): Agenus Inc.

Tracking Information

• First Submitted Date: November 1, 2022
• First Posted Date: November 8, 2022
• Last Update Posted Date: March 25, 2024
• Actual Study Start Date: November 30, 2022
• Estimated Primary Completion Date: February 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 1, 2022)

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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 1, 2022)

• Duration of Response [ Time Frame: First dose through up to 2 years ]
  Duration of response is defined as the time from initial objective radiographic response until disease progression or death, whichever occurs first, as assessed using RECIST 1.1.
• Progression-free Survival [ Time Frame: First dose through up to 3 years ]
  Progression-free survival is defined as the time from randomization until disease progression or death, whichever occurs first, as assessed using RECIST 1.1.
• Overall Survival [ Time Frame: First dose through up to 3 years ]
  Overall survival is defined as the time from randomization until death due to any cause.
• Number of Participants Experiencing Treatment-emergent Adverse Events [ Time Frame: First dose through up to 2 years ]
• Serum Botensilimab Concentration [ Time Frame: First study dose (pre-dose and 1 hour post-dose) through up to 2 years ]
• Serum Balstilimab Concentration [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: First study dose (pre-dose and 1 hour post-dose) through up to 2 years ]

Original Secondary Outcome Measures (submitted: November 1, 2022)

• Duration of Response [ Time Frame: First dose through up to 2 years ]
  Duration of response is defined as the time from initial objective radiographic response until disease progression or death, whichever occurs first, as assessed using RECIST 1.1.
• Progression-free Survival [ Time Frame: First dose through up to 3 years ]
  Progression-free survival is defined as the time from randomization until disease progression or death, whichever occurs first, as assessed using RECIST 1.1.
• Overall Survival [ Time Frame: First dose through up to 3 years ]
  Overall survival is defined as the time from randomization until death due to any cause.
• Number of Participants Experiencing Treatment-emergent Adverse Events [ Time Frame: First dose through up to 2 years ]
• Serum Botensilimab Concentration [ Time Frame: First study dose (pre-dose and 1 hour post-dose) through up to 2 years ]
• Serum Balstilimab Concentration [ Time Frame: First study dose (pre-dose and 1 hour post-dose) through up to 2 years ]
• Botensilimab Anti-drug Antibodies [ Time Frame: First study dose (pre-dose and 1 hour post-dose) through up to 2 years ]
• Balstilimab Anti-drug Antibodies [ Time Frame: First study dose (pre-dose and 1 hour post-dose) through up to 2 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Botensilimab and Balstilimab for the Treatment of Colorectal Cancer
• Official Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Colorectal Cancer

Intervention

• Drug: Botensilimab
  An anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody.
  Other Name: AGEN1181
• Drug: Balstilimab
  An anti-programmed death (ligand) 1 [PD-(L)1] monoclonal antibody.
  Other Name: AGEN2034
• Drug: Standard of Care
  Regorafenib or trifluridine and tipiracil.

Study Arms

• Experimental: Combination Botensilimab Dose 1 plus Balstilimab
  Participants will receive botensilimab at dose 1 given IV and balstilimab given IV.
  Interventions:

  • Drug: Botensilimab
  • Drug: Balstilimab
• Experimental: Combination Botensilimab Dose 2 plus Balstilimab
  Participants will receive botensilimab at dose 2 given IV and balstilimab given IV.
  Interventions:

  • Drug: Botensilimab
  • Drug: Balstilimab
• Experimental: Monotherapy Botensilimab Dose 1
  Participants will receive botensilimab dose 1 given IV.
  Intervention: Drug: Botensilimab
• Experimental: Monotherapy Botensilimab Dose 2
  Participants will receive botensilimab dose 2 given IV.
  Intervention: Drug: Botensilimab
• Active Comparator: Standard of Care
  Participants will receive select standard of care as determined by the investigator.
  Intervention: Drug: Standard of Care

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: December 1, 2022): 230
• Original Estimated Enrollment (submitted: November 1, 2022): 120
• Estimated Study Completion Date: July 2025
• Estimated Primary Completion Date: February 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologically confirmed diagnosis of unresectable and metastatic CRC adenocarcinoma.
2. The tumor must have been assessed for microsatellite instability high (MSI-H) or deficient mismatch repair (dMMR) status per a standard local testing method.
3. Voluntarily agree to participate by giving signed, dated, and written informed consent prior to any study-specific procedures.

4. 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:

   1. 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.
   2. 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.
   3. 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.
5. Measurable disease on baseline imaging per RECIST 1.1.
6. Life expectancy ≥ 12 weeks.
7. Eastern Cooperative Oncology Group performance status of 0 or 1.
8. Adequate organ function.
9. Women of childbearing potential must have a negative serum pregnancy test at screening and prior to study drug administration.
10. Male participants with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study, starting with the Screening visit through 2-6 months, depending upon assigned study treatment. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
11. No growth factor support, transfusions, or albumin administration within 14 days of randomization of study treatment.

Exclusion Criteria:

1. Tumor is MSI-H/dMMR per a standard local testing method.
2. Received programmed cell death protein 1, PD-(L)1, or CTLA-4 therapies including any immune checkpoint inhibitor or experimental immunologic agents.
3. Received regorafenib or trifluridine/tipiracil as prior therapy(ies).
4. Partial or complete bowel obstruction within the last 3 months, signs/symptoms of bowel obstruction, or known radiologic evidence of impending obstruction.
5. Refractory ascites.
6. 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.
7. Clinically significant (that is, active) cardiovascular disease.
8. Active brain metastases or leptomeningeal metastases with certain exceptions.
9. 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.

10. Treatment with one of the following classes of drugs within the delineated time window prior to Cycle 1 Day 1 (C1D1):

    1. Cytotoxic, targeted therapy or other investigational therapy within 3 weeks.
    2. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or similar therapy, within 4 weeks, or 5 half-lives, whichever is shorter.
    3. Small molecule/tyrosine kinase inhibitors within 2 weeks or less than 5 circulating half-lives of investigational drug.
11. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
12. Any evidence of current interstitial lung disease (ILD) or pneumonitis, or prior history of ILD or non-infectious pneumonitis requiring glucocorticoids.
13. History of allogeneic organ transplant, stem cell transplant, or bone marrow transplant.
14. Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
15. Participants with a condition requiring systemic treatment with either corticosteroids (> 10 milligrams [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.
16. Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years of the start of study treatment (that is, with use of disease-modifying agents or immunosuppressive drugs).
17. History or current evidence of any condition, co-morbidity, therapy, any active infections, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating Investigator.
18. Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to C1D1.
19. Uncontrolled infection with human immunodeficiency virus.
20. Known to be positive for hepatitis B virus (HBV) surface antigen, or any other positive test for HBV indicating acute or chronic infection.
21. Known active hepatitis C virus as determined by positive serology and confirmed by polymerase chain reaction.
22. Has urine protein ≥ 1 gram/24 hour.
23. Uncontrolled hypertension: systolic pressure ≥ 150 millimeters of mercury (mmHg) or diastolic pressure ≥ 90 mmHg on repeated measurements that cannot be managed by standard antihypertension medications ≤ 28 days before the first dose of study drug(s).
24. Participants who require treatment with strong cytochrome P450 3A4 inducers or inhibitors.
25. Has presence of gastrointestinal condition, for example, malabsorption, that might affect the absorption of study drug(s).
26. Non-healing wound(s).
27. Symptomatic active bleeding.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Brazil, France, Italy, Russian Federation, Spain, United States

Administrative Information

• NCT Number: NCT05608044
• Other Study ID Numbers: C-800-25; 2022-501546-29 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Agenus Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Agenus Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Agenus Inc.

• PRS Account: Agenus Inc.
• Verification Date: March 2024