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
- Trial ID
- 2022-502065-23-00
- Protocol
- C-800-25
- Sponsor
- Agenus Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the clinical efficacy of **botensilimab** as monotherapy and in combination with **balstilimab** through the objective response rate (ORR) as assessed by the investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in the Intent-to-Treat (ITT) Analysis Set. This is clinically relevant as it aims to determine the potential of these treatments in improving response rates in patients with refractory metastatic colorectal cancer, a condition with limited treatment options.
Secondary objectives include:
- Evaluating the clinical efficacy of botensilimab as monotherapy and in combination with balstilimab as determined by the duration of response (DOR) in the ITT Analysis Set.
- Assessing the clinical efficacy of botensilimab as monotherapy and in combination with balstilimab as determined by progression-free survival (PFS) in the ITT Analysis Set.
- Evaluating the clinical efficacy of botensilimab as monotherapy and in combination with balstilimab as determined by overall survival (OS) in the ITT Analysis Set.
Participants
The clinical trial involves a total of **128 participants** diagnosed with **refractory metastatic colorectal cancer**. The study population includes both male and female subjects, aged 18 years and older, who have a histologically confirmed diagnosis of unresectable and metastatic colorectal adenocarcinoma. Participants were selected based on their prior treatment history, having received at least one prior chemotherapy regimen for metastatic or recurrent colorectal cancer. The trial includes individuals with a life expectancy of at least 12 weeks and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was chosen to include those with adequate organ function and measurable disease per RECIST 1.1 criteria. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with protocol requirements, including the use of effective contraception for those of childbearing potential. The trial does not exclude vulnerable populations, indicating a broad inclusion of eligible patients. The sponsor has not provided specific information regarding additional lifestyle factors or habits of the participants.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 2 study to evaluate the clinical efficacy of **botensilimab** as monotherapy and in combination with **balstilimab** or the investigator's choice of standard care, which includes **regorafenib** or **trifluridine** and **tipiracil**, for the treatment of refractory metastatic colorectal cancer. The trial aims to assess the objective response rate (ORR) as the primary endpoint, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The trial is expected to conclude by December 31, 2025, with recruitment having commenced on March 1, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis of unresectable and metastatic colorectal adenocarcinoma, measurable disease per RECIST 1.1, and adequate organ function. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments conducted according to the trial protocol. The end-of-study visit will occur upon completion of the treatment period or earlier if the participant experiences disease progression or unacceptable toxicity.
The expected length of participant involvement is up to 24 months, depending on the treatment arm and individual response to therapy. Conditions that may lead to early termination from the study include withdrawal of consent, non-compliance with study procedures, or adverse events that compromise participant safety. The trial will adhere to ethical standards and regulatory requirements, ensuring that all procedures are conducted with scientific rigor and integrity.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments for the management of refractory metastatic colorectal cancer. **Lonsurf** is one of the experimental medications used in this study. It is available in two formulations: 20 mg/8.19 mg and 15 mg/6.14 mg film-coated tablets. The active substances in Lonsurf are **trifluridine** and **tipiracil**, both of which are of chemical origin. The medication is administered orally, with a maximum daily dose of 70 mg and a total maximum dose of 8400 mg over a treatment period of 24 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
**Botensilimab** is another experimental treatment in the trial, provided as a solution for infusion. It is a human IgG1k monoclonal antibody against CTLA4, originating from protein sources. The maximum daily dose is 150 mg, with a total maximum dose of 600 mg over a 24-week period. The administration route is via intravenous infusion, and dosing schedules are strictly adhered to, with compliance monitored through infusion records and participant feedback.
**Stivarga**, containing the active substance **regorafenib**, is used as a comparator treatment in the study. It is available as 40 mg film-coated tablets and is administered orally. The maximum daily dose is 160 mg, with a total maximum dose of 80640 mg over the course of 24 weeks. Compliance is monitored through pill counts and patient diaries to ensure accurate adherence to the prescribed regimen.
**Balstilimab** is also included in the trial as a solution for infusion. It is a human IgG4 monoclonal antagonist antibody directed against programmed cell death protein 1 (PD-1). The maximum daily dose is 240 mg, with a total maximum dose of 12240 mg over a 24-week period. The administration is conducted intravenously, and compliance is tracked through infusion logs and participant reports.
Throughout the trial, participant compliance is a critical component, with regular monitoring and documentation to ensure adherence to the treatment protocols. The study aims to evaluate the clinical efficacy of these treatments, with a focus on objective response rates as assessed by the investigator per RECIST 1.1 criteria.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, which is defined as the proportion of patients achieving a complete or partial response as evaluated by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). This assessment will be conducted by the investigator within the Intent-to-Treat (ITT) Analysis Set. Secondary endpoints include the **Duration of Response (DOR)**, which measures the time from the initial objective radiographic response until disease progression or death, whichever occurs first. Additionally, **Progression-Free Survival (PFS)** will be evaluated, defined as the time from randomization until disease progression or death. **Overall Survival (OS)**, defined as the time from randomization until death from any cause, will also be assessed.
The trial will involve the administration of botensilimab as monotherapy and in combination with balstilimab, or the investigator’s choice of standard care, which includes regorafenib or trifluridine and tipiracil. The efficacy parameters will be measured at various timepoints throughout the study, with the trial estimated to conclude by December 31, 2025. The study is designed to evaluate the clinical efficacy of these treatments in patients with refractory metastatic colorectal cancer, following the guidelines set by the European Medicines Agency (EMA) for a Phase II trial.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed diagnosis of unresectable and metastatic colorectal adenocarcinoma
- The most recent biopsy of a tumor lesion that is available as a formalin-fixed paraffin-embedded (FFPE) tumor tissue block is required. If recent tumor tissue is unavailable or inadequate, patient must be willing to provide a fresh biopsy if deemed safe and feasible. The sponsor may waive the requirement for screening biopsies once a sufficient number has been collected.
- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at the screening and prior to study drug administration. Non-childbearing potential is defined as: a. ≥ 50 years of age and has not had menses for greater than 1 year. b. Amenorrheic for ≥ 2 years without a hysterectomy and bilateral oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation. c. Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation. WOCBP must agree to use highly effective contraceptive measures starting with the Screening Visit through 3 months after the last dose of study treatment (if randomized to monotherapy [Arms C or D] or 5 months after the last dose of study treatment (if randomized to combination therapy [Arms A or B]) or 2 months after the last dose of study treatment (if randomized to Arm E and taking regorafenib) or 6 months after the last dose of study treatment (if randomized to Arm E and taking trifluridine and tipiracil). Highly effective contraception is defined in Appendix B, Guidance on Contraception, or as stipulated in national or local guidelines. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient. WOCBP must agree not to donate eggs (ova, oocytes) during the treatment period and for at least 3 months after the last dose of study treatment (if randomized to monotherapy [Arms C or D] or 5 months after the last dose of study treatment (if randomized to combination therapy [Arms A or B]) or 2 months after the last dose of study treatment (if randomized to Arm E and taking regorafenib) or 6 months after the last dose of study treatment (if randomized to Arm E and taking trifluridine and tipiracil).
- Male patients 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 3 months after the last dose of study treatment (if randomized to monotherapy [Arms C or D] or 5 months after the last dose of study treatment (if randomized to combination therapy [Arms A or B]) or 2 months after the last dose of study treatment (if randomized to Arm E and taking regorafenib) or 6 months after the last dose of study treatment (if randomized to Arm E and taking trifluridine and tipiracil). Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
- Willing and able to comply with the requirements of the protocol.
- The tumor must have been assessed for microsatellite high (MSI-H) or deficient mismatch repair (dMMR) status per a standard local testing method.
- Patient, or Legally Authorized Representative if patient is unable to do so, voluntarily agree to participate by giving signed, dated, and written informed consent prior to any study-specific procedures.
- ≥ 18 years of age
- 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: a. Standard chemotherapy/therapy including all of the following agents (if eligible and no contraindication): a fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab or biosimilars, an anti-EGFR antibody (cetuximab or panitumumab) and BRAF inhibitor (encorafenib). These agents may have been in combination, e.g., FOLFOXIRI/bevacizumab may be given first line in which case a RAS mutant patient who does not have a BRAF V600E mutation may be eligible for this study in the second line, or more commonly, agents will be sequenced, and most patients will be eligible in the third line and beyond. b. Patients 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 due to toxicity, which warrants discontinuation of treatment and precludes retreatment with the same agent. c. Patients 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 1.1.
- Life expectancy ≥ 12 weeks
- ECOG performance status of 0 or 1.
- Adequate organ function defined as the following laboratory values within 7 days of Cycle 1 Day 1 (C1D1): a. Neutrophils ≥ 1500/μL. b. Platelets ≥ 100 × 103 /μL . c. Hemoglobin ≥ 8.0 g/dL . d. Creatinine clearance ≥ 30 mL/min as measured or calculated per local institutional standards. e. Aspartate aminotransferase/alanine aminotransferase ≤ 2.5 × upper limit of normal (ULN). f. Total bilirubin ≤ 1.5 × ULN (except patients with Gilbert syndrome who must have a total bilirubin level of ≤ 3.0 × ULN). g. Albumin ≥ 3.0 g/dL.
- No growth factor support, transfusions, or albumin administration within 14 days of randomization of study treatment
Exclusion Criteria
- Tumor is MSI-H/dMMR per a standard local testing method.
- Treatment with one of the following classes of drugs within the delineated time window prior to C1D1: a. Cytotoxic, targeted therapy or other investigational therapy within 3 weeks. b. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or similar therapy, within 4 weeks, or 5 half-lives, whichever is shorter. c. Small molecule/tyrosine kinase inhibitors within 2 weeks or less than 5 circulating half lives of investigational drug.
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- Any evidence of current interstitial lung disease (ILD) or pneumonitis, or prior history of ILD or non-infectious pneumonitis requiring glucocorticoids
- History of allogeneic organ transplant, stem cell transplant or bone marrow transplant.
- Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
- Patients with a condition requiring systemic treatment with either 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
- Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years of the start of study treatment (i.e., with use of disease-modifying agents or immunosuppressive drugs)
- 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 patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator
- Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to C1D1
- Received PD-1, PD-L1, or CTLA-4 therapy including any ICI or experimental or immunologic agents
- Uncontrolled infection with human immunodeficiency virus (HIV). Patients on stable highly active antiretroviral therapy (HAART) with undetectable viral load and normal CD4 counts for at least 6 months prior to study entry are eligible. Serological testing for HIV at screening is not required
- Known to be positive for hepatitis B virus (HBV) surface antigen, or any other positive test for HBV indicating acute or chronic infection. Patients who are receiving or who have received anti-HBV therapy and have undetectable HBV DNA for at least 6 months prior to study entry are eligible. Serological testing for HBV at screening is not required
- Known active hepatitis C virus (HCV) as determined by positive serology and confirmed by polymerase chain reaction (PCR). Patients on or who have received antiretroviral therapy are eligible provided they are virus-free by PCR for at least 6 months prior to study entry. Serological testing for HCV at screening is not required
- Has urine protein ≥1 gram/24 hour.
- Uncontrolled hypertension: systolic pressure ≥ 150 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).
- Patients who require treatment with strong CYP3A4 inducers or inhibitors
- Has presence of gastrointestinal condition, e.g., malabsorption, that might affect the absorption of study drug.
- Non-healing wound(s).
- Symptomatic active bleeding
- 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 defined as requiring 2 or more therapeutic paracenteses within the last 4 weeks or ≥ 4 times within the last 90 days or ≥ 1 time within the last 2 weeks prior to study entry or requiring diuretics within 2 weeks of study entry.
- Liver metastases by CT or MRI. NOTE: Patients with definitively treated liver metastases (this includes surgical resection, including microwave or radiofrequency ablation, or stereotactic body radiation therapy [SBRT], but not Y-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, however they must be excluded if they have: a. Received > 1 SBRT field to the liver. b. Undergone major hepatic resection (right, extended right, or extended left) and the remnant liver was subject to SBRT. c. Stigmata of hepatic decompensation including a history of variceal bleeding, a history of ascites related to hepatic cirrhosis, or severe portal hypertension
- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication a. QTcF (QTc interval corrected using Fridericia’s formula) of > 480 ms.
- Active brain metastases or leptomeningeal metastases with the following exceptions: a. Treated brain metastases require a) surgical resection, or b) stereotactic radiosurgery. These patients must have discontinued steroid treatment ≥ 28 days prior to randomization for the purpose of managing their brain metastases. Repeat brain imaging following surgical resection or stereotactic radiosurgery is not required if their patient’s last brain MRI is within screening window. Whole-brain radiation is not allowed. b. Untreated isolated brain metastases that are too small for treatment by surgical resection or stereotactic radiosurgery (e.g., 1-2 mm) and/or of uncertain etiology are potentially eligible but need to be discussed with and approved by the study Medical Monitor.
- Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study treatment, i.e., patients with a history of prior malignancy are eligible if treatment was completed at least 2 years before the first dose of study treatment and the patient has no evidence of disease. Patients 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Mar 2023 | 12 |
 France | Not Recruiting | 01 Mar 2023 | 36 |
 Italy | Not Recruiting | 01 Mar 2023 | 30 |
 Spain | Not Recruiting | 01 Mar 2023 | 24 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lonsurf 15 mg/6.14 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 70 | 24 | PRD4021653 |
Lonsurf 20 mg/8.19 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 70 | 24 | PRD4021874 |
Stivarga 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 160 | 24 | PRD1714052 |
BOTENSILIMAB | Test | SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 150 | 24 | PRD7271002 |
Lonsurf 15 mg/6.14 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 70 | 24 | PRD5621636 |
BALSTILIMAB | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 240 | 24 | PRD8723398 |
Lonsurf 20 mg/8.19 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 70 | 24 | PRD4021876 |
Stivarga 40 mg film-coated tablets. | Test | FILM-COATED TABLETS | ORAL | 160 | 24 | PRD1713388 |
Lonsurf 20 mg/8.19 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 70 | 24 | PRD4021877 |
Lonsurf 15 mg/6.14 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 70 | 24 | PRD4106910 |