This is a single-arm pilot feasibility study evaluating the combination of Botensilimab and Balstilimab with Radiation Therapy (RT) in Non-Microsatellite Instability High (MSI-H) or Proficient Mismatch Repair (pMMR) chemorefractory colorectal cancer (CRC) with liver metastasis.
In this open-label study, the investigators propose to use standard of care (SOC) radiation (Stereotactic Body Radiation Therapy (SBRT)) to control the liver lesions in combination with investigational dual checkpoint inhibitors, botensilimab (AGEN1181) and balstilimab (AGEN2034). Initially, 5 patients will be enrolled in a lead-in cohort and assessed for dose-limiting toxicity (DLT) related to radiation during Cycle 1. If DLT are observed in 2 or more of the first 5 patients, the protocol will be stopped early. If DLT were observed in 0 or 1 of the first 5 patients during the lead-in, enrollment will be expanded to a total of 15 patients. After screening, participants will receive SOC SBRT for 2-3 weeks, and botensilimab + balstilimab for up to 24 weeks followed by balstilimab alone for 14 additional 6-week cycles, for a total treatment time of up to 108 weeks. Participants will be followed for 1 year.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
15
Starting on Day 1 participants will have 2-4 treatments per week for about 2 weeks, with no more than 2 days in a row. This is expected to last about 2 weeks but could last up to 3 weeks.
Administered once every 6 weeks by intravenous infusion over about 30 minutes, on Day 1 of Cycles 1-4 (six-week cycles). Administered 30 minutes after balstilimab.
Administered once every 2 weeks by intravenous infusion over about 30 minutes, starting on Day 1 of Cycle 1 and continuing for 4 six-week cycles (with botensilimab) followed by up to 14 six-week cycles of balstilimab alone. Participants will receive balstilimab for a total of 18 six-week cycles.
Massachusetts General Hospital
Boston, Massachusetts, United States
Incidence of dose limiting radiation-related toxicities
Dose limiting radiation-related toxicities will be assessed by CTCAE v6.0. A dose limiting toxicity (DLT) will be defined as any patient who can't complete all radiation therapy (RT) fractions within 2-3 weeks for pre-specified toxicity or lab values attributable to radiation therapy, or development of RT-related toxicities within 30 days of completion of RT. Participants will be evaluable for DLT once they start protocol therapy.
Time frame: Day 1 of treatment through 30 days after completion of radiation therapy (radiation therapy is 2-3 weeks), up to 60 days.
Response rate of in-field radiated hepatic lesion(s)
The response rate (Complete Response (CR), Partial Response (PR)) of irradiated hepatic lesions by RECIST 1.1 will be estimated as a proportion with 95% confidence intervals based on the exact binomial distribution by RECIST.
Time frame: Screening through end of Cycle 18 (each cycle is 6 weeks), up to 108 weeks.
Response rate of extrahepatic lesion(s)
The response rate (Complete Response (CR), Partial Response (PR)) of unirradiated extrahepatic lesions by RECIST 1.1 will be estimated with 95% confidence intervals based on the exact binomial distribution.
Time frame: Screening through end of Cycle 18 (each cycle is 6 weeks), up to 108 weeks.
Overall Survival (OS)
OS is defined as time from registration to death due to any cause or censored at date last known alive. OS rates will be estimated using the Kaplan-Meier method with 95% confidence intervals based on the complementary log-log transformation.
Time frame: Registration through 160 weeks (108 weeks of treatment + 1 year follow-up)
Progression-Free Survival (PFS)
PFS is defined as time from registration to the earlier of progression (per RECIST 1.1) or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. PFS rates will be estimated using the Kaplan-Meier method with 95% confidence intervals based on the complementary log-log transformation.
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Time frame: Registration through up to 108 weeks of treatment
Disease Control Rate (DCR)
Disease control is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. Response is measured by RECIST 1.1. The cumulative incidence will be estimated with patients still alive with disease control censored at the date of last disease assessment and death without disease analyzed as a competing risk.
Time frame: Day 1 through up to 108 weeks.