Study of CBX-12 in Subjects With Advanced or Metastatic Refractory Solid Tumors

Study Overview
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Brief Summary
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This is a first-in-human, Phase 1/2 open-label, multicenter, dose-escalation, safety, pharmacokinetics (PK), and biomarker study of CBX-12 in subjects with advanced or metastatic refractory solid tumors.

Detailed Description
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Phase 1 is the dose-escalation portion of the study in which the safety and tolerability of two dosing schedules of CBX-12 will be evaluated. Subjects in Part A will be treated with CBX-12 on a daily x 5 every 3 weeks schedule (treatment in Part A was discontinued in October 2021). Subjects in Phase 1 Part B will be treated with CBX-12 on a daily x 3 every 3 weeks schedule. Subjects in Phase 1 Part C will be treated with CBX-12 once weekly. Subjects in Phase 1 Modified Part B will be treated with CBX-12 once every 3 weeks. For all parts in Phase 1, after all subjects in a cohort have completed treatment through the DLT period or discontinued treatment due to a DLT, the SRC, composed of the Investigators who have enrolled subjects in the current cohort(s), the study Medical Monitor and ad hoc members (e.g., other Investigators, a statistician) as needed, will review all available safety data, including DLTs and all available PK data for that cohort and make dose-level recommendations. Once the recommended phase 2 dose (RP2D) has been established in Part B, Part C and Modified Part B, Phase 2 expansion cohorts may open.

Official Title
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A Phase 1/2 Study of CBX-12 in Subjects With Advanced or Metastatic Refractory Solid Tumors

Conditions
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Solid Tumor, Adult, Epithelial Ovarian Cancer, Small Cell Lung Carcinoma, Breast Cancer, Colorectal Cancer, Pancreas Cancer, Appendix Cancer, Non-small Cell Lung Cancer, Gastric Cancer, Esophagus Cancer, Urothelial Carcinoma, Sarcoma

Intervention / Treatment
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* Drug: CBX-12


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Subject has a histologically- or cytologically-diagnosed solid tumor which is advanced or metastatic and which has progressed on or following at least one systemic therapy regimen administered for advanced or metastatic disease or for which no approved therapy exists. Subject's prior treatment should include all approved regimens that have demonstrated a survival advantage for the subject's disease, stage, and line of therapy. Has measurable disease per RECIST 1.1. An adequate tumor sample must be available from core needle biopsies obtained during the Screening Period and following the subject's most recent systemic therapy. Agrees to an on-treatment biopsy preferably of the same lesion from which the pre-CBX-12 treatment sample was obtained as long as the Investigator determines such biopsy can be performed with acceptable safety. (Removed Amd 4, date 31-Mar-2023) Exclusion Criteria: Cytotoxic chemotherapy, biologic agent, investigational agent, or radiation therapy less than or equal to 3 weeks prior to the first dose of CBX-12. The interval may be reduced to 2 weeks for bone only radiation therapy or investigational agents not expected to be associated with adverse events (AEs) after 2 weeks of last administration, with Medical Monitor approval. Small-molecule kinase inhibitors or hormonal agents less than or equal to 14 days prior to the first dose of CBX-12. Subjects who are currently receiving any other anti cancer or investigational agent(s). Clinically significant intercurrent disease. Subjects with primary central nervous system (CNS) tumors or clinically active CNS metastases or carcinomatous meningitis. Subjects with stable brain metastasis may be enrolled with Medical Monitor approval.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Parts B, C & Modified Part B will follow a 3 + 3 design, enrolling 3 subjects in each cohort. (De)escalation rules: DLT period for each subject in Phase 1 Part B & Modified Part B will be 3 weeks & 4 weeks in Part C (i.e., 1 cycle). If none of the 3 subjects experience a DLT, dose will be escalated to next highest dose level. If 1 of 3 subjects in cohort experiences a DLT, up to 3 additional subjects will be enrolled/treated at same dose. If none of the additional 3 subjects experience a DLT (i.e., only 1 of 6 subjects in cohort has a DLT), dose will be escalated to next highest level. If 2 or more of up to 6 subjects at dose level have DLTs, enrollment to that cohort will stop, dose will be considered above MTD. Dose will be decreased to previous dose level or to a level intermediate to those previously evaluated. MTD will be highest dose evaluated at which ≤ 1 of 6 have a DLT. A minimum of 6 DLT-evaluable subjects will be enrolled to any dose level being evaluated as possible MTD.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Schedule B Dose Escalation (Daily Dosing x 3)<br>CBX-12 administered on a daily x 3, 3 week schedule | Drug: CBX-12<br>* CBX-12 is an alphalex construct which consists of a low-pH insertion peptide, a self-immolating linker, and exatecan as the pharmacologically active moiety<br>|
| Experimental: Phase 1 Schedule C Dose Escalation (Once Weekly Dosing )<br>CBX-12 administered once weekly, 4 week schedule | Drug: CBX-12<br>* CBX-12 is an alphalex construct which consists of a low-pH insertion peptide, a self-immolating linker, and exatecan as the pharmacologically active moiety<br>|
| Experimental: Phase 2 Ovarian Cancer Expansion Cohort<br>CBX-12 administered once every 3 weeks | Drug: CBX-12<br>* CBX-12 is an alphalex construct which consists of a low-pH insertion peptide, a self-immolating linker, and exatecan as the pharmacologically active moiety<br>|
| Experimental: Phase 2 Metastatic Breast Expansion Cohort<br>CBX-12 administered once every 3 weeks | Drug: CBX-12<br>* CBX-12 is an alphalex construct which consists of a low-pH insertion peptide, a self-immolating linker, and exatecan as the pharmacologically active moiety<br>|
| Experimental: Phase 1 Schedule A Dose Escalation (Daily Dosing x 5)<br>CBX-12 administered on a daily x 5, 3 week schedule | Drug: CBX-12<br>* CBX-12 is an alphalex construct which consists of a low-pH insertion peptide, a self-immolating linker, and exatecan as the pharmacologically active moiety<br>|
| Experimental: Phase 1 Modified Schedule B Dose Escalation (Once Every 3 weeks)<br>CBX-12 administered once every 3 weeks | Drug: CBX-12<br>* CBX-12 is an alphalex construct which consists of a low-pH insertion peptide, a self-immolating linker, and exatecan as the pharmacologically active moiety<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Incidence of treatment-emergent adverse events (TEAEs) | NCI CTCAE v5.0 | Through the end of study, estimated as 6 months | 
| Phase 1: Recommended Phase 2 Dose for Daily x 3 every 3 weeks schedule of CBX-12 (Schedule B) | Safety Review Committee Analysis of Safety and PK Data | 15 months | 
| Phase 1: Recommended Phase 2 Dose for Once Weekly schedule of CBX-12 (Schedule C) | Safety Review Committee Analysis of Safety and PK Data | 15 months | 
| Phase 1: Recommended Phase 2 Dose for Once Every 3 Weeks schedule of CBX-12 (Modified Schedule B) | Safety Review Committee Analysis of Safety and PK Data | 15 months | 
| Phase 2: Overall response rate (ORR) | ORR Based on RECIST v1.1 | Through the end of study, estimated as 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration of CBX-12 | PK Analysis | 5 days | 
| Area under the curve from 0-24 hours of CBX-12 | PK Analysis | 5 days | 
| Time to maximum concentration of CBX-12 | PK Analysis | 5 days | 
| Half-life of CBX-12 | PK Analysis | 5 days | 
| Clearance (CL) of CBX-12 | PK Analysis | 5 days | 
| Apparent Volume of Distribution at Steady State (Vss) CBX-12 | PK Analysis | 5 days | 
| Phase 1: ORR | Based on RECIST v1.1 | Through the end of study, estimated as 6 months | 
| Duration of Response (DoR) | Based on RECIST v1.1 | Through the end of study, estimated as 6 months | 
| Progression-free Survival (PFS) | Based on RECIST v1.1 | Through the end of study, estimated as 6 months | 
| Phase 2: Incidence of TEAEs | NCI CTCAE v5.0 | Through the end of study, estimated as 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SCLC, small cell lung cancer, ovarian, breast, appendix, colorectal, pancreatic, NSCLC, Sarcoma