CBX-12 for the Treatment of Metastatic Chemotherapy-Refractory Microsatellite Stable Colorectal Cancer

Phase 2

Not yet recruiting

• Conditions: Metastatic Microsatellite Stable Colorectal Carcinoma; Refractory Microsatellite Stable Colorectal Carcinoma; Stage IV Colorectal Cancer AJCC v8
• Interventions: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: pH Low Insertion Peptide-exatecan Conjugate CBX-12; Procedure: X-Ray Imaging

• Registration Number: NCT06730100
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase II trial studies how well CBX-12 works in treating patients with microsatellite stable colorectal cancer that has spread to other parts of the body (metastatic) and is no longer responding to chemotherapy treatment (chemotherapy-refractory). The usual approach to treating colorectal cancer includes treatment with surgery, radiation, or Food and Drug Administration (FDA)-approved drugs such as trifluoridine-tiparacil, bevacizumab, regorafenib, or fruquintinib. However, most metastatic colorectal patients progress through all approved treatments and eventually succumb to their disease. CBX-12 is a drug that contains a peptide (a substance that contains many amino acids \[molecules that join together to form proteins\]) called pHLIP, linked to an anticancer substance called exatecan. Upon administration, pHLIP gets inserted into the cellular membrane of tumor cells, delivering exatecan to kill them. Giving CBX-12 may work better than the usual approach in treating patients with metastatic chemotherapy-refractory microsatellite stable colorectal cancer.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the clinical activity, as determined by response rate, of pH low insertion peptide-exatecan conjugate CBX-12 (CBX-12) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients.

SECONDARY OBJECTIVES:

I. To evaluate the pharmacodynamics of CBX-12 (DDR3 and apoptosis). II. To determine the effect of CBX-12 on progression-free survival (PFS).

EXPLORATORY OBJECTIVES:

I. To evaluate the tissue and plasma pharmacokinetics (PK) of CBX-12 and free exatecan.

II. To evaluate circulating tumor deoxyribonucleic acid (DNA) (ctDNA) as a predictor for treatment response to CBX-12.

III. To evaluate the safety and tolerability of CBX-12 dosed every 21 days. IV. To evaluate biomarkers of response to CBX-12 (DNA damage response, apoptosis, SLFN11 expression, TOP1-DNA complex).

OUTLINE:

Patients receive CXB-12 intravenously (IV) over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo x-rays during screening and biopsy, computed tomography (CT), magnetic resonance imaging (MRI), and blood collection throughout the study.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for 12 months or until death.

Study Timeline

• Status Verified: 2024-12
• Study First Submitted: 2024-12-11
• Study First Submitted QC: 2024-12-11
• Study First Posted: 2024-12-12
• Last Update Submitted: 2025-04-08
• Last Update Posted: 2025-04-09
• Study Start: 2025-05-23
• Primary Completion: 2026-06-30
• Study Completion: 2026-06-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 35

Inclusion Criteria

• Patients must have histologically or cytologically confirmed metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS) or mismatch repair proficient based on local testing performed in a Clinical Laboratory Improvement Act (CLIA) lab

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical exam

• Potential trial participants should have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment

• Availability of archival tumor tissue at the time of patient enrollment for molecular profiling studies

• Patients must have progressed on or been intolerant to at least 2 lines of prior therapies:

  • Have progressed on or intolerant of standard therapies, including a fluoropyrimidine (5-fluorouracil or capecitabine), oxaliplatin, irinotecan, and VEGF inhibitor (bevacizumab or biosimilar).
  • If left-sided primary and RAS/RAF wild-type, then have progressed on or intolerant of EGFR inhibitor (cetuximab or panitumumab).
  • If BRAF V600 mutation, then have progressed on or intolerant of BRAF inhibitor (encorafenib).

• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of CBX-12 in patients <18 years of age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 3 × institutional ULN

• Creatinine =< 1.5 x institutional ULN OR

• Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression for at least 4 weeks

• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better

• Patients are willing and able to undergo pre- and on-treatment biopsies (stage 1 only)

• The effects of CBX-12 on the developing human fetus are unknown. For this reason and because topoisomerase 1 inhibitors are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after the last dose of study medication. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of CBX-12 administration

• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to CBX-12
• Patients with concurrent administration of medication expected to cause drug interactions with CBX-12, including strong inducers and strong inhibitors of CYP3A4/1A2 isoenzymes or sensitive substrates of CYP3A4/2B6, OATP1B1, OATP1B3, OAT1, and MATE-2k
• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
• Pregnant women are excluded from this study because CBX-12 is a topoisomerase 1 inhibitors agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with CBX-12, breastfeeding should be discontinued if the mother during treatment with CBX-12 and for at least 4 months after the last dose of CBX-12. Male patients treated with CBX-12 should use effective contraception and avoid fathering a child during and up to 4 months after treatment

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Treatment (CBX-12)	Biopsy Procedure	Patients receive CXB-12 IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo x-rays during screening and biopsy, CT, MRI, and blood collection throughout the study.
Treatment (CBX-12)	Biospecimen Collection	Patients receive CXB-12 IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo x-rays during screening and biopsy, CT, MRI, and blood collection throughout the study.
Treatment (CBX-12)	Computed Tomography	Patients receive CXB-12 IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo x-rays during screening and biopsy, CT, MRI, and blood collection throughout the study.
Treatment (CBX-12)	Magnetic Resonance Imaging	Patients receive CXB-12 IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo x-rays during screening and biopsy, CT, MRI, and blood collection throughout the study.
Treatment (CBX-12)	pH Low Insertion Peptide-exatecan Conjugate CBX-12	Patients receive CXB-12 IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo x-rays during screening and biopsy, CT, MRI, and blood collection throughout the study.
Treatment (CBX-12)	X-Ray Imaging	Patients receive CXB-12 IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo x-rays during screening and biopsy, CT, MRI, and blood collection throughout the study.

Primary Outcome Measures

Name	Time	Method
Objective response rate (ORR)	From registration to disease progression or death due to any cause, assessed up to 12 months	Treatment response will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Objective response will be defined as either complete response (CR) or partial response (PR). Simon's 2-stage optimal design will be used

Secondary Outcome Measures

Name	Time	Method
Pharmacodynamics (PD) of CBX-12 by DDR3 and apoptosis	Baseline to 12 months	Percent of tumor cells positive for deoxyribonucleic acid (DNA) damage marker γH2AX and percent of tumor cells positive for apoptosis marker cleaved caspase 3. Pre- and on-treatment comparisons will be made within patients who provide evaluable paired biopsies, using a paired t-test. A nonparametric method will be pursued as needed. Assuming an 80% evaluable biopsy rate out of 17 patients, we would obtain 14 evaluable pre-treatment and 14 evaluable post-treatment biopsies. Using a one-sided paired t-test at a type I error rate of 0.05, this study achieves 80% power to detect a mean paired difference of 0.6 standard deviation of differences, which is deemed to be a medium effect size (Cohen, 1992). In addition, will fit a logistic regression on objective response with increase in %γH2AX-positive tumor cells and increase in %caspase 3-positive tumor cells, separately as well as simultaneously.
Progression-free survival (PFS)	From registration to disease progression or death due to any cause, assessed up to 12 months	PFS and OS will be estimated by the Kaplan-Meier method, along with 95% confidence regions. The median time will be estimated and compared with 5.6 months of PFS and 10.8 months (Prager et al., 2023). One-sample log-rank tests will be performed against the reference curves from Prager et al. (Prager et al., 2023).
Overall survival (OS)	From registration to disease progression or death due to any cause, assessed up to 12 months	PFS and OS will be estimated by the Kaplan-Meier method, along with 95% confidence regions. The median time will be estimated and compared with 5.6 months of PFS and 10.8 months (Prager et al., 2023). One-sample log-rank tests will be performed against the reference curves from Prager et al. (Prager et al., 2023).