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

Phase 2 Trial of CBX-12 for Metastatic Chemotherapy-Refractory Microsatellite Stable Colorectal Cancer

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 trifluridine-tipiracil, 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.

Study Overview

• Status: Withdrawn
• Conditions: Stage IV Colorectal Cancer AJCC v8; Metastatic Mismatch Repair Proficient Colorectal Carcinoma; Refractory Mismatch Repair Proficient Colorectal Carcinoma
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: pH Low Insertion Peptide-exatecan Conjugate CBX-12; Procedure: X-Ray Imaging; Procedure: Biopsy Procedure

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/mismatch repair proficient (MSS/pMMR) 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 computed tomography (CT), magnetic resonance imaging (MRI), and blood collection throughout the study and patients may undergo biopsy during screening and on 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 Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Irvine, California, United States, 92612
      • UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Orange, California, United States, 92868
      • UC Irvine Health/Chao Family Comprehensive Cancer Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Health Science Center - Gainesville
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
  • New York
    • The Bronx, New York, United States, 10461
      • Montefiore Medical Center-Einstein Campus
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Cancer Center-UC Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
    • West Chester, Ohio, United States, 45069
      • University of Cincinnati Cancer Center-West Chester
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center - University Hospital
    • Madison, Wisconsin, United States, 53718
      • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed metastatic colorectal cancer (mCRC) that is mismatch repair proficient (pMMR) 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, with no Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 toxicity of grade 3 or higher at the time of 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
• Hemoglobin >= 8.0 g/dL
• 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
• 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 (first 10 patients in 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 6 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (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 CT, MRI, and blood collection throughout the study and patients may undergo biopsy during screening and on study.

Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Drug: pH Low Insertion Peptide-exatecan Conjugate CBX-12; Given IV; Other Names: Alphalex Conjugate CBX-12; Alphalex-exatecan Conjugate CBX-12; CBX 12; CBX-12; CBX12; Low pH Targeting Alphalex-exatecan Conjugate CBX-12; pHLIP-exatecan Conjugate CBX-12; Procedure: X-Ray Imaging; Undergo chest x-rays; Other Names: Conventional X-Ray; Diagnostic Radiology; Medical Imaging, X-Ray; Radiographic Imaging; Radiography; RG; Static X-Ray; X-Ray; Plain film radiographs; Radiographic imaging procedure (procedure); Procedure: Biopsy Procedure; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicities (DLTs)	DLTs will be defined as any grade >= 3 non-hematologic toxicity irrespective of adequate supportive treatment, or grade >= 4 hematologic toxicity per Common Terminology Criteria for Adverse Events version 5.0 attributed as possibly, probably, or definitely related to drug. The ORR will be estimated along with the 95% confidence interval.	Baseline up to 12 months
Objective response rate (ORR)	Treatment response will be assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Objective response will be defined as either complete response or partial response. Simon's 2-stage optimal design will be used.	From registration to disease progression or death due to any cause, assessed up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	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).	From registration to disease progression or death due to any cause, assessed up to 12 months
Overall survival (OS)	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).	From registration to disease progression or death due to any cause, assessed up to 12 months
Pharmacodynamics of CBX-12 by DDR3 and apoptosis	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.	Baseline to 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variant allele frequencies (VAF) of tumor mutations in circulating tumor DNA (ctDNA)	VAF change will be assessed categorically for each patient (increased or decreased at cycle 3 as compared to baseline). VAF change will be compared to objective response or non-response using the Fisher's test, where p<0.05 will be considered statistically significant	Baseline and at cycle 3
Incidence and grades of adverse events	All patients who received at least one dose of CBX-12 will be considered evaluable for safety and toxicity. Continual toxicity monitoring will be used for all patients. Toxicity names, rates, and grades will be reported descriptively	Baseline up to 12 months
Expression of YH2AX	DNA damage, apoptosis, and TOP1-DNA complex markers will be measured in pre- and post-treatment samples, and a difference (increase) in expression post-treatment will also be measured on DNA damage multiplex assay. Regression analysis will be used to determine if the increase in these three biomarkers correlates with response to CBX-12.	Baseline to 12 months
Expression of apoptosis protein markers	DNA damage, apoptosis, and TOP1-DNA complex markers will be measured in pre- and post-treatment samples, and a difference (increase) in expression post-treatment will also be measured in Luminex assay. Regression analysis will be used to determine if the increase in these three biomarkers correlates with response to CBX-12	Baseline to 12 months
Expression of TOP1-DNA complex	DNA damage, apoptosis, and TOP1-DNA complex markers will be measured in pre- and post-treatment samples, and a difference (increase) in expression post-treatment will also be measured. Regression analysis will be used to determine if the increase in these three biomarkers correlates with response to CBX-12	Baseline to 12 months
Expression of SLFN11	On immunohistochemistry. SLFN11 tumor baseline expression will be measured in pre-treatment tumor tissue and regression analysis will be used to determine if baseline SLFN11 expression correlates with response to CBX-12.	At baseline
Tissue and plasma pharmacokinetics (PK) of CBX-12 and free exatecan	The maximum concentration and area under the plasma drug concentration-time curve of the plasma PK will be compared descriptively with historical data. The on-treatment tumor concentrations of free exatecan and CBX-12 will be used to calculate the free exatecan:CBX-12 ratio. The ratio of plasma free exatecan Cmax:CBX-12 Cmax will be calculated. These ratios in tumor and plasma will be compared using a two-sided paired t-test, where p<0.05 will be considered statistically significant. The ratio of free exatecan:CBX-12 from the tumor is expected to greater than the ratio of the same from plasma.	From baseline to 12 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Chaoyuan Kuang, UPMC Hillman Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Estimated): February 17, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: December 11, 2024
• First Submitted That Met QC Criteria: December 11, 2024
• First Posted (Actual): December 12, 2024

Study Record Updates

• Last Update Posted (Estimated): October 6, 2025
• Last Update Submitted That Met QC Criteria: October 3, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Physical Phenomena; Equipment and Supplies; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Spectrum Analysis; Electromagnetic Phenomena; Magnetic Phenomena; Electromagnetic Radiation; Radiation; Radiation, Ionizing; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; X-Rays; Phantoms, Imaging
• Other Study ID Numbers: NCI-2024-10048 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186690 (U.S. NIH Grant/Contract); 10707 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No