Metastatic Colon Adenocarcinoma, Metastatic Colorectal Carcinoma, Metastatic Rectal Adenocarcinoma, Stage III Colon Cancer AJCC v8, Stage III Rectal Cancer AJCC v8, Stage IIIA Colon Cancer AJCC v8, Stage IIIA Rectal Cancer AJCC v8, Stage IIIB Colon Cancer AJCC v8, Stage IIIB Rectal Cancer AJCC v8, Stage IIIC Colon Cancer AJCC v8, Stage IIIC Rectal Cancer AJCC v8, Stage IV Colon Cancer AJCC v8, Stage IV Rectal Cancer AJCC v8, Stage IVA Colon Cancer AJCC v8, Stage IVA Rectal Cancer AJCC v8, Stage IVB Colon Cancer AJCC v8, Stage IVB Rectal Cancer AJCC v8, Stage IVC Colon Cancer AJCC v8, Stage IVC Rectal Cancer AJCC v8, Unresectable Colon Adenocarcinoma, Unresectable Rectal Adenocarcinoma
Conditions
Brief summary
This phase Ib/II trial studies the side effects and best dose of SX-682 that can be given alone and in combination with nivolumab in treating patients with RAS-Mutated, microsatellite stable (MSS) colorectal cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). SX-682 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving SX-682 alone and together with nivolumab may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVE: I. To determine the safety profile of CXCR1/2 Inhibitor SX-682 (SX-682) alone and in combination with nivolumab in subjects with refractory RAS mutated microsatellite stable (MSS) metastatic colorectal cancer (mCRC), including the maximum dose that can be administered until adverse effects prevent further dose increases (i.e., the maximum tolerated dose \[MTD\] or recommended phase 2 dose), and the dose-limiting toxicity (DLT). SECONDARY OBJECTIVES: I. Evaluate the efficacy of SX-682 in combination with nivolumab on the basis of the objective response rate (ORR), the duration of response, and the rate of progression. II. Characterize the single-dose and multidose pharmacokinetic (PK) profile of SX-682. EXPLORATORY OBJECTIVES: I. Assess overall survival (OS). II. Explore potential biomarkers associated with pharmacodynamic and clinical response to SX-682 alone and combined with nivolumab, where the biomarker measures include, but are not limited to, tumor CMS4, gene expression, deoxyribonucleic acid (DNA) mutations (KRAS, NRAS and BRAF mutation status via ribonucleic acid \[RNA\] and DNA sequencing), IRF2 (interferon regulatory factor 2) expression, lymphocyte clonality (via sequencing), myeloid-derived suppressor cell (MDSCs), regulatory T-cells (Tregs) and CD69/CD8 T cells, and in the circulation, circulating tumor DNA (ctDNA), T- and B-cell subpopulations, neutrophils, the neutrophil-to-lymphocyte ratio (NLR), MDSCs, Tregs, the CD4:CD8 ratio, chemokines and cytokines. OUTLINE: This is a phase I, dose-escalation study of CXCR1/2 Inhibitor SX-682, followed by a phase II study. MONOTHERAPY STAGE: Patients receive SX-682 orally (PO) twice daily (BID) on days 1-21 in the absence of disease progression or unacceptable toxicity. COMBINATION STAGE: Patients receive SX-682 PO BID on days 1-56 and nivolumab intravenously (IV) over 30 minutes on days 1 and 29. Treatment repeat every 56 days weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After completion of study, patients with no have tumor response are followed up every 3 weeks for 90 days, and patients with tumor response every 3 months for up to 6 months.
Interventions
Given PO
BIOLOGICALNivolumab
Given IV
Sponsors
M.D. Anderson Cancer Center
Bristol-Myers Squibb
Syntrix Biosystems, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written Informed Consent and HIPAA Authorization 1. Subjects must have the nature of the study explained to them. 2. Non-English speaking patients will be eligible for participation with involvement of the MD Anderson Language Assistance department in the informed consent process (per MD Anderson SOP 04\_Informed Consent Process). 3. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, pharmacokinetic collections, and other requirements of the study. 4. Subjects must provide a signed and dated IRB approved written informed consent form (ICF) in accordance with regulatory and institutional guidelines for both the study and exploratory biomarker analyses (e.g., CMS4 and others) on archival tissue. 5. Subjects must provide a signed and dated Health Insurance Portability and Accountability Act (HIPAA) authorization. 6. The ICF and HIPAA authorization must be obtained before conducting any procedures that do not form a part of the subject's normal care. 7. After signing the ICF and HIPAA Authorization, subjects will be evaluated for study eligibility during the Screening Period (no more than 28 days before study drug administration) according to the following further inclusion/
Exclusion criteria
2. Target Population 1. Men and women, ages \> 18 years of age. Both men and women of all races and ethnic groups, regardless of preferred language, are eligible for this trial. 2. Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum that is metastatic or unresectable. 3. Tumor is determined to be RAS-mutated (KRAS or NRAS) and microsatellite stable/proficient in mismatch repair, as assessed by IHC and/or PCR/NGS in a CLIA environment. 4. Received at least two prior regimens of therapy for unresectable or metastatic CRC including fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. Patients who relapse within 6 months of adjuvant chemotherapy composed of oxaliplatin and a fluoropyrimidine will have their adjuvant therapy count as one prior regimen. 5. For the expansion cohort, pre-treatment primary tumor tissue (i.e., archived paraffin-embedded) or from an unresectable metastatic site must be available for biomarker analyses. Biopsy should be excisional or core needle. Fine needle aspirates or other cytology samples are insufficient. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix 1). 7. Must have measurable disease with at least 1 unidimensional measurable lesion per RECIST v1.1 (see Appendix 2). 8. Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration. 9. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to first dose: WBC \> 3000/µL Neutrophils \> 1500/ µL Platelets \> 100,000/µL Hemoglobin \> 9.0 g/dL (may have been transfused) Creatinine \< 1.5 mg/dL AST/ALT \< 2.5 X ULN for subject with no liver metastases \< 5 X ULN for subjects with liver metastases Bilirubin \< 1.5 mg/dL (unless diagnosed with Gilbert's syndrome, who can have total bilirubin \< 3.0 mg/dL) INR or PT \< 1.5 X ULN unless the subject is receiving anticoagulant therapy aPTT or PTT \< 1.5 X ULN unless the subject is receiving anticoagulant therapy 10. Glomerular filtration rate (GFR) calculated by Cockcroft-Gault formula \>60 ml/min. 11. Life expectancy \> 12 weeks as judged by the treating physician. 12. Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (i.e., subject has not been treated with SX-682). If re-enrolled, the subject must be re-consented.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events (AEs) | Up to 2 years | For each system organ class and preferred term, summaries will be made with respect to the number and proportion of subjects having at least 1 occurrence of an adverse event during the study. The incidence of AEs will be presented overall, by system organ class and preferred term, intensity (based on National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0), immune-related adverse events, treatment-emergent adverse events, and additional grouping by severity and relationship to study drug. Individual listings of adverse events will be provided. Dose limiting toxicities and study drug-related grade \>= 2 adverse events will be listed individually. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) | Up to 2 years | Patient response will be determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Unconfirmed responses will not be used in the final analysis. ORR is defined by the number of (partial response + complete response)/ (total number of treated patients) in the cohort. Will estimate the response rate along with the two-sided exact 95% confidence interval. |
| Progression-free survival (PFS) | Up to 104 weeks | Assessed according to RECIST 1.1. Median PFS and 95% confidence intervals will be estimated using the Kaplan-Meier method. |
| Overall survival (OS) | Up to 104 weeks | OS time will be presented using the Kaplan-Meier method. Median OS with 95% confidence interval will be estimated using the Kaplan-Meier method. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAlisha Bent, MD
M.D. Anderson Cancer Center
Outcome results
None listed