Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Botensilimab · 9 trials · 20 indications
Tumor response will be evaluated by a qualified colorectal surgeon using flexible sigmoidoscopy (or equivalent), with biopsy as clinically indicated, and rectal MRI using standard response criteria. Response categories are clinical complete response, near-complete clinical response, no response, or progression. Participants with near-complete clinical response must have pathologic complete response at TES/local excision to meet the endpoint.
The Clinical Benefit Rate (CBR) among participants will be reported. CBR is the number of participants achieving complete response (CR), partial response (PR) or stable disease after start of study therapy. Response will be assessed using Immune-related Response Evaluation Criteria in Solid Tumors (iRECIST) 1.1 criteria.
Disease control rate is defined as the proportion of subjects who have a complete response, partial response, or stable disease at the time of a second restaging scan. Complete response is defined as disappearance of all target lesions. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable disease is defined as a decrease of less than 30% or an increase of less than 20%. Increases of 20% or greater must be confirmed 4-8 weeks later, and confirmation scans must also show an increase of at least 5 mm in the sum of lesion sizes or an increase in the number of lesions. Otherwise, the increase will be counted as stable disease.
The number of subjects who went on treatment and had a complete response or partial response sometime during the study (prior to progression) divided by the number of subjects who went on treatment.
Percentage of patients in which a major pathologic response (MPR) is reported, defined as \<10% residual viable tumor (RVT) in the resection specimen.
Progression-free survival will be defined as the time from the date of randomization to the date of the first objectively documented tumor progression, assessed by investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), or death, whichever occurs first.
Objective response rate will be determined using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
To determine the maximum tolerated dose (MTD) of botensilimab when given in combination with balstilimab + triplet chemotherapy regimen (consisting of nab-paclitaxel + gemcitabine + cisplatin) + chloroquine + celecoxib to be used in Part 2-Dose Expansion. MTD will be defined at the dose of botensilimab at which no more than 1 of 6 evaluable patients experiences a dose-limiting toxicity (DLT).
To evaluate the safety and tolerability of botensilimab in combination with balstilimab + triplet + chloroquine + celecoxib. Treatment-related toxicities as per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTC AE V5.0).
TEAEs will include adverse events of special interest, immune-related adverse events, and adverse drug reactions, according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
DLTs will include any Grade 2 or greater drug related toxicity for all dose groups, according to NCI CTCAE version 5.0 and protocol specifications.
MTD based on DLT occurrence at DLT period (28 days after first dose) and all TEAEs seen through 90 days following last study dose.
| Arm | Type | Description |
|---|---|---|
| Botensilimab + Balstilimab | EXPERIMENTAL | Participants receive: * Botensilimab: one IV infusion on Cycle 1 Day 1, over about 30 minutes * Balstilimab: IV infusion every 2 weeks on Day 1 of each treatment cycle, over about 30 minutes, for up to 6 months The protocol specifies: * Botensilimab dose: 75 mg IV once * Balstilimab dose: 240 mg IV every 2 weeks for up to 6 months |
| Radiation, Botensilimab Combined with Balstilimab Treatment Group | EXPERIMENTAL | Participants in this group will receive Stereotactic Body Radiation Therapy (SBRT), followed by Botensilimab immunotherapy (ImT) for up to 24 weeks, in combination with Balstilimab ImT for up to one year. Total participation duration is up to five years. |
| Treatment | EXPERIMENTAL | botensilimab + balstilimab until disease progression, then botensilimab + balstilimab + mFOLFOX6 (leucovorin, fluorouracil, oxaliplatin) + {bevacizumab or panitumumab} |
| Cohort 2: pMMR Safety run-in 1 - closed (accrual reached) | EXPERIMENTAL | 5 Patients will be included and will be treated with 2 cycles of neoadjuvant immunotherapy consisting of 450mg balstilimab and 25mg botensilimab in Cycle 1 and 450mg balstilimab in Cycle 2 followed by surgery Accrual was reached in June 2024, cohort is closed. |
| Cohort 4: pMMR Safety run-in 2 - closed (accrual reached) | EXPERIMENTAL | 5 Patients will be included and will be treated with 2 cycles of neoadjuvant immunotherapy consisting of 450mg balstilimab and 50mg botensilimab in Cycle 1 and 450mg balstilimab in Cycle 2 followed by surgery Accrual was reached in August 2024, cohort is closed. |
| Cohort 1: dMMR Safety run-in 1 - closed (accrual reached) | EXPERIMENTAL | 5 Patients will be included and will be treated with 2 cycles of neoadjuvant immunotherapy consisting of 450mg balstilimab and 25mg botensilimab in Cycle 1 and 450mg balstilimab in Cycle 2 followed by surgery Accrual was reached in June 2025, cohort is closed. |
| Cohort 3: dMMR Safety run-in 2 - closed (accrual reached) | EXPERIMENTAL | 5 Patients will be included and will be treated with 2 cycles of neoadjuvant immunotherapy consisting of 450mg balstilimab and 50mg botensilimab in Cycle 1 and 450mg balstilimab in Cycle 2 followed by surgery Acrrual was reached in August 2024, cohort is closed. |
| Cohort 6: dMMR Colorectal basket - closed (accrual reached) | EXPERIMENTAL | Patients with resectable colon and rectal cancer will be treated with the regimen assesses as safe and feasible in the dMMR safety run-in. Treatment will be administered at day 1 and day 22 followed by surgery 8 weeks after registration. Accrual will be temporarily halted after accrual of the first 8 patients. If \>2 major pathological responses are observed accrual will continue to a total of 18 patients. Accrual was reached in July 2025, cohort is closed. |
| Cohort 5: dMMR Upper gastro-intestinal cancer basket | EXPERIMENTAL | Patients with resectable oesophageal (adenocarcinoma), gastro-oesophageal junction, gastric and small bowel cancer will be treated with the regimen assessed as safe and feasible in the dMMR safety run-in. Treatment will be administered at day 1 and day 22 followed by surgery 8 weeks after registration. Accrual will be temporarily halted after accrual of the first 8 patients. If \>2 major pathological responses are observed accrual will continue to a total of 18 patients. |
| Cohort 7: dMMR "other cancers" basket | EXPERIMENTAL | Patients with resectable solid tumors of various origins such as but not limited to breast-, prostate-, bladder cancer, Head\&Neck SCC, oesophageal SCC and sarcoma will be treated with the regimen assessed as safe and feasible in the dMMR safety run-in. Treatment will be administered at day 1 and day 22 followed by surgery 8 weeks after registration. Accrual will be temporarily halted after accrual of the first 8 patients. If \>2 major pathological responses are observed accrual will continue to a total of 18 patients. |
| Cohort 8: pMMR TNBC cohort | EXPERIMENTAL | Patients with resectable Triple Negative Breast Cancer will be treated with the regimen assessed as safe and feasible in the pMMR safety run-in. Treatment will be administered at day 1 and day 22 followed by surgery 8 weeks after registration. Accrual will be temporarily halted after accrual of the first 8 patients. If \>2 major pathological responses are observed accrual will continue to a total of 18 patients. |
| Cohort 9: pMMR "other cancers" - cohort closed | EXPERIMENTAL | Patients with resectable pMMR tumors of various origins will be treated with the regimen assessed as safe and feasible in the pMMR safety run-in. Treatment will be administered at day 1 and day 22 followed by surgery 8 weeks after registration. Accrual will be temporarily halted after accrual of the first 8 patients. If \>2 major pathological responses are observed accrual will continue to a total of 18 patients. Accrual was halted after 8 patients in July 2025, not more then 2 major pathological responses were observed, cohort remains closed. |
| Cohort 10: pMMR GEA basket | EXPERIMENTAL | Patients with pMMR gastro-, esophageal or GE-junction tumors will receive study treatment that consists of cycle 1) botensilimab 50mg plus balstilimab 240mg 2) FLOT + bal 240mg 3) FLOT plus bot 50mg/bal 240mg 4-5) FLOT + bal 240mg. Surgery will take place a maximum of 6 weeks after start last treatment cycle. Patients will receive 8mg dexamethasone as premedication for docetaxel on the first day of infusion, and no additional doses of dexamethasone are allowed in the following days as an anti-emetic. Post-surgery, patients may receive 4 additional cycles of FLOT according to the standard of care. Evaluation will be performed after the first 3 patients are treated; if the proposed treatment is deemed feasible and all patients received the intended chemotherapy regimen, accrual may continue with the next 3 patients. If the first three patients undergo surgery according to plan without delays that are considered immune-related, accrual may continue beyond six patients (max 21). |
| Cohort 11: dMMR Rectal Organ Preservation basket | EXPERIMENTAL | Patients with stage I-III dMMR rectal adenocarcinoma who prefer organ preservation are eligible. The study treatment will consist of 1 cycle of combination therapy on day 1: botensilimab 50mg plus balstilimab 450mg, followed by 2 cycles of balstilimab 450mg monotherapy on day 22 and day 43. If at the 1st response evaluation at 10 weeks a limited response, no response or progressive disease is observed, treatment according to standard of care, which may consist of direct surgery or additional neoadjuvant therapy may be considered after discussion in the MDT and with the study team. |
| Part 1: Combination (Safety Lead-in Phase) | EXPERIMENTAL | Participants will receive botensilimab in combination with standard-of-care chemotherapy (nab-paclitaxel + gemcitabine). |
| Part 2: Combination | EXPERIMENTAL | Participants will receive botensilimab in combination standard-of-care chemotherapy (nab-paclitaxel + gemcitabine). |
| Part 2: Standard of Care | ACTIVE_COMPARATOR | Participants will receive standard-of-care chemotherapy (nab-paclitaxel + gemcitabine). |
| Part 1 Cohort A: Botensilimab | EXPERIMENTAL | Participants refractory to PD-(L)1 therapy will receive botensilimab intravenously (IV). |
| Part 1 Cohort B: Botensilimab | EXPERIMENTAL | Participants refractory to PD-(L)1 and anti-CTLA-4 therapies will receive botensilimab IV. |
| Part 2 Cohort A: Botensilimab + Balstilimab | EXPERIMENTAL | Participants refractory to PD-(L)1 will receive botensilimab IV in combination with balstilimab IV. |
| Part 2 Cohort B: Botensilimab + Balstilimab | EXPERIMENTAL | Participants refractory to PD-(L)1 and CTLA-4 will receive botensilimab IV in combination with balstilimab IV. |
| Combination Botensilimab Dose 1 plus Balstilimab | EXPERIMENTAL | Participants will receive botensilimab at dose 1 given IV and balstilimab given IV. |
| Combination Botensilimab Dose 2 plus Balstilimab | EXPERIMENTAL | Participants will receive botensilimab at dose 2 given IV and balstilimab given IV. |
| Monotherapy Botensilimab Dose 1 | EXPERIMENTAL | Participants will receive botensilimab dose 1 given IV. |
| Monotherapy Botensilimab Dose 2 | EXPERIMENTAL | Participants will receive botensilimab dose 2 given IV. |
| Standard of Care | ACTIVE_COMPARATOR | Participants will receive select standard of care as determined by the investigator. |
| DoseEscalationBotensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin +chloroquine + celecoxib | EXPERIMENTAL | Botensilimab 50 mg IV, Balstilimab 240 mg, nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 +cisplatin 25 mg/m2; Chloroquine phosphate 500 mg po (300 mg equivalent chloroquine base); Celecoxib 200 mg po twice daily (BID) on Famotidine 20 mg po BID Aspirin 81 mg |
| Expansion Cohort-Botensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin+chloroquine+celecoxib | EXPERIMENTAL | Botensilimab (MTD TBD), Balstilimab 240 mg IV, nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 +cisplatin 25 mg/m2 IV infusion ; Chloroquine phosphate 500 mg po (300 mg equivalent chloroquine base),Celecoxib 200 mg po twice daily (BID); Famotidine 20 mg po BID Aspirin 81 mg |
| 3-Week Monotherapy | EXPERIMENTAL | 3+3 Dose escalation: botensilimab, every 3 weeks, starting at dose level 0.1 milligrams/kilogram (mg/kg) up to 4 mg/kg, administered intravenously (IV) for up to 2 years. |
| 6-Week Monotherapy | EXPERIMENTAL | 3+3 Dose escalation: botensilimab, every 6 weeks, starting at dose level 1 mg/kg up to 4 mg/kg, administered IV for up to 2 years. |
| 6-Week Combination Therapy | EXPERIMENTAL | 3+3 Dose escalation: balstilimab, every 2 weeks, at dose level 3 mg/kg in combination with botensilimab, every 6 weeks, starting at dose level 0.1 mg/kg up to 4 mg/kg, administered IV for up to 2 years. Participants enrolled at sites in the United Kingdom (UK) may have the option for extended treatment. An additional cohort will investigate balstilimab, every 3 weeks, at 450 mg in combination with botensilimab every 6 weeks, at 150 mg, administered IV for up to 2 years. |
| Name | Type | Description |
|---|---|---|
| Botensilimab | DRUG | one IV infusion on Cycle 1 Day 1, over about 30 minutes |
| Balstilimab | DRUG | IV infusion every 2 weeks on Day 1 of each treatment cycle, over about 30 minutes, for up to 6 months |
| Stereotactic Body Radiation Therapy | RADIATION | The radiation therapy (RT) prescription biologically effective dose (BED10) goal for tumor (α/β=10) aims to achieve at least BED10= 60 Gy for a single fraction plan and at least BED10=100 Gy for a multi-fraction plan. This equates to a prescription dose of at least 20 Gy in a single fraction, 42 Gy over 3 fractions, 50 Gy over 5 fractions, and 62 Gy over 10 fractions. Radiation therapy must be completed for up to 10 daily treatments within a 15-day course. |
| Oxaliplatin | DRUG | 85 mg/m2 IV every 2 weeks |
| Leucovorin | DRUG | 400 mg/m2 IV every 2 weeks |
| Fluorouracil | DRUG | 400 mg/m2 IV bolus + 2,400 mg/m2 IV (over 46 hours) every 2 weeks |
| Bevacizumab | DRUG | 5 mg/kg IV every 2 weeks |
| Panitumumab | DRUG | 6 mg/kg IV every 2 weeks |
| FLOT (Fluorouracil+Leucovorin+Oxaliplatin+Docetaxel) | DRUG | 5-Fluorouracil (2400mg/m2), leucovorin (200mg/m2), oxaliplatin (85mg/m2), docetaxel (50mg/m2). |
| Gemcitabine | DRUG | Standard-of-care chemotherapy administered intravenously. |
| Nab-paclitaxel | DRUG | Standard-of-care chemotherapy administered intravenously. |
| Standard of Care | DRUG | Regorafenib or trifluridine and tipiracil. |
| Chloroquine Phosphate | DRUG | an antimalarial agent, that is being used in this patient population to sensitize cancer cells to chemotherapy and leads to anticancer effects through inhibiting autophagy |
| Celecoxib | DRUG | a second-generation selective Cyclooxygenase 2 (COX-2) inhibitor, is being used in this patient population to enhance the therapeutic effect of cisplatin by inhibiting the expression of COX-2 as well as inhibit anti-apoptotic gene BCL-2 (B-cell lymphoma 2) |
| Nab paclitaxel | DRUG | microtubule inhibitor indicated for the treatment of Metastatic adenocarcinoma of the pancreas as first-line treatment, in combination with gemcitabine |
| Cisplatin | DRUG | platinum-based drug indicated for the treatment of advanced cancers |
Inclusion Criteria: * Histologically confirmed diagnosis of early-rectal cancer clinically staged T1-T2 N0 M0 by MRI (American Joint Committee on Cancer (AJCC) staging 8th edition, 2017). * The tumor must confirmed to be MSS/MMRp by local testing. * The tumor must be evaluable by endoscopy. * Volun...
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Botensilimab is an investigational antibody being studied for the treatment of several cancers, including non-small cell lung cancer, metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma, early rectal cancer, and advanced cancer. It is being developed by Agenus Inc. and is currently in Phase 1 clinical trials.
Botensilimab is a monoclonal antibody, indicated by its -mab suffix. As an antibody, it is designed to bind to specific targets involved in cancer. However, the specific molecular target has not been disclosed in the available information.
Botensilimab is being developed by Agenus Inc., a biopharmaceutical company. Agenus is publicly traded under the ticker symbol AGEN. The company is conducting clinical trials to evaluate Botensilimab for various oncology indications.
Botensilimab is currently in Phase 1 clinical development. It has received Fast Track designation from the FDA. Botensilimab is investigational and has not been approved by the FDA for any indication.
Botensilimab is being studied in several clinical trials, including NCT05529316 for advanced melanoma, NCT05608044 for metastatic colorectal cancer, NCT06076837 for metastatic pancreatic cancer, and NCT06268015 for colorectal cancer. These trials are in Phase 1 or Phase 2 and are active but not recruiting.
Botensilimab is sometimes studied in combination with balstilimab, another investigational antibody. The combination is referred to as Botensilimab plus Balstilimab. Clinical trials such as NCT05608044 and NCT06268015 are evaluating this combination for colorectal cancer.