Clinical study to investigate efficacy of Botensilimab (AGEN1181) as Monotherapy and in Combination with Balstilimab (AGEN2034) or Investigator’s Choice Standard of Care in patients of Refractory Metastatic Colorectal Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Agenus Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Jun 2023 → ongoing

Decision date (initial)

2023-03-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Agenus, Inc.

External identifiers

EU CT number

2022-502065-23-00

WHO UTN

U1111-1280-0708

ClinicalTrials.gov

NCT05608044

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Others, Safety, Efficacy, Pharmacokinetic

To evaluate the clinical efficacy of botensilimab as monotherapy and in combination with balstilimab through 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.

Secondary objectives 3

1. 01. To evaluate the clinical efficacy of botensilimab as monotherapy and in combination with balstilimab as determined by duration of DOR in the ITT Analysis Set.
2. 02. To evaluate the clinical efficacy of botensilimab as monotherapy and in combination with balstilimab as determined by progression-free survival (PFS) in the ITT Analysis Set.
3. 03. To evaluate the clinical efficacy of botensilimab as monotherapy and in combination with balstilimab as determined by overall survival (OS) in the ITT Analysis Set.

Conditions and MedDRA coding

Refractory Metastatic Colorectal Cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 01. Histologically confirmed diagnosis of unresectable and metastatic colorectal adenocarcinoma
2. 10. 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.
3. 11. 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).
4. 12. 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.
5. 13. Willing and able to comply with the requirements of the protocol.
6. 02. The tumor must have been assessed for microsatellite high (MSI-H) or deficient mismatch repair (dMMR) status per a standard local testing method.
7. 03. 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.
8. 04. ≥ 18 years of age
9. 05. 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.
10. 06. Measurable disease on baseline imaging per RECIST 1.1.
11. 07. Life expectancy ≥ 12 weeks
12. 08. ECOG performance status of 0 or 1.
13. 09. 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.
14. 14. No growth factor support, transfusions, or albumin administration within 14 days of randomization of study treatment

Exclusion criteria 27

1. 01. Tumor is MSI-H/dMMR per a standard local testing method.
2. 10. 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.
3. 12. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
4. 13. Any evidence of current interstitial lung disease (ILD) or pneumonitis, or prior history of ILD or non-infectious pneumonitis requiring glucocorticoids
5. 14. History of allogeneic organ transplant, stem cell transplant or bone marrow transplant.
6. 15. Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
7. 16. 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
8. 17. 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)
9. 18. 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
10. 19. Previous SARS-CoV-2 infection within 10 days for mild or asymptomatic infections or 20 days for severe/critical illness prior to C1D1
11. 02. Received PD-1, PD-L1, or CTLA-4 therapy including any ICI or experimental or immunologic agents
12. 20. 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
13. 21. 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
14. 22. 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
15. 23. Has urine protein ≥1 gram/24 hour.
16. 24. 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).
17. 25. Patients who require treatment with strong CYP3A4 inducers or inhibitors
18. 26. Has presence of gastrointestinal condition, e.g., malabsorption, that might affect the absorption of study drug.
19. 27. Non-healing wound(s).
20. 28. Symptomatic active bleeding
21. 03. Received regorafenib or trifluridine-tipiracil as prior therapy(ies)
22. 04. Partial or complete bowel obstruction within the last 3 months, signs/symptoms of bowel obstruction, or known radiologic evidence of impending obstruction
23. 05. 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.
24. 06. 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
25. 07. 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.
26. 08. 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.
27. 09. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ORR, defined as the proportion of patients with a complete response or partial response as assessed by RECIST 1.1 criteria.

Secondary endpoints 3

1. 01. DOR, defined as the time from initial objective radiographic response until disease progression or death, whichever occurs first.
2. 02. PFS, defined as the time from randomization until disease progression or death, whichever occurs first.
3. 03. OS, defined as the time from randomization until death due to any cause.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 10

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Agenus Inc.

Sponsor organisation

Agenus Inc.

Address

3 Forbes Road

City

Lexington

Postcode

02421-7305

Country

United States

Scientific contact point

Organisation

Agenus Inc.

Contact name

Agenus, Inc. Clinical Trial Information

Public contact point

Organisation

Agenus Inc.

Contact name

Agenus, Inc. Clinical Trial Information

Third parties 10

Locations

4 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 68 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications