A Phase II, Open-label Study of VS-7375, an Oral KRAS G12D (ON/OFF) Inhibitor, With and Without an Anti-EGFR Antibody, and With an Anti-EGFR Antibody and Chemotherapy, in Patients With Metastatic KRAS G12D-Mutated Colorectal Adenocarcinoma (TARGET-D 203)
Study Identifier:
VS-7375-203
CT.gov Identifier:
EudraCT Identifier:
N/A
EU Trial (CTIS) Number:
Study Contact Information:
Recruiting
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Study Summary
This study will assess the safety and efficacy of VS-7375 alone and in combination with cetuximab or panitumumab and cetuximab plus mFOLFOX in patients with metastatic KRAS G12D - mutated Colorectal Cancer
To evaluate VS-7375 at 900 mg once daily (QD) both as monotherapy and in combination with anti-EGFR therapies, including cetuximab or panitumumab, in previously treated KRAS G12D-mutated mCRC.
Main objective (English)
To evaluate the anti-tumor efficacy of 900 mg VS 7375 monotherapy administered on a daily oral schedule and 900 mg VS-7375 combination therapy with intravenous (IV) cetuximab or panitumumab, in participants with metastatic KRAS G12D-mutated colorectal adenocarcinoma (CRC). To characterize the safety and tolerability of VS-7375 monotherapy administered on a daily oral schedule and VS-7375 combination therapy with IV cetuximab or panitumumab in participants with metastatic KRAS G12D-mutated CRC.
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Bowel (Colorectal)
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase II
Sex
Female & Male
Age
18+ years
Study Drug
Drug: EXPERIMENTAL: VS-7375 + cetuximab and mFOLFOX in 1L CRC
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Drug: Drug: Cetuximab + mFOLFOX6
Drug: Intravenous infusion
Drug: EXPERIMENTAL: VS-7375 Monotherapy or Preferred Combination in 2L+ CRC
Drug: Participants randomized to a treatment in 2: 1 ratio
Drug: Drug: cetuximab
Drug: Drug: panitumumab
Drug: Drug: VS-7375
Drug: Taken by mouth
Drug: EXPERIMENTAL: VS-7375 with chosen regimen in 2L+ CRC
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting
Requirements information
Inclusion criteria
- * Histopathology confirmed metastatic CRC * Measurable disease per RECIST 1.1 * Local testing confirmed KRAS G12D mutation (tissue required for confirmatory central testing) * ECOG PS=0 or 1 2L+ patients: * Must have received at least 1 standard chemotherapy for metastatic colorectal adenocarcinoma * Have documented disease progression during or following their most recent prior line of therapy * Have either stable disease, partial response (PR), or complete response (CR) by RECIST v1.1 as the best overall response (BOR) during at least 1 prior systemic therapy. 1L patients: * Treatment-naïve or received no more than 1 cycle of standard systemic therapy for metastatic disease.
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KRAS G12D-mutated 2L+ metastatic CRC
Advanced colorectal cancer - 1. 1. Individuals ≥ 18 years of age.
- 2. 10. Have either stable disease, partial response (PR), or complete response (CR) by RECIST v1.1 as the best overall response (BOR) during at least 1 prior systemic therapy. Participants with progressive disease as the BOR for all prior systemic therapy are not eligible.
- 3. Participants in Part C Only: 11. Treatment-naïve or received no more than 1 cycle of standard systemic therapy for metastatic disease.
- 4. 12. Adequate organ function defined by the following laboratory parameters listed in the protocol.
- 5. 13. Recovered from all adverse events (AEs) due to previous therapies to Grade ≤ 1 or baseline, except for alopecia or Grade 2 neuropathy. Participants with endocrine-related AEs Grade ≤ 2 requiring treatment or hormone replacement are eligible. Prior toxicities that resulted in laboratory abnormalities should have resolved to Grade ≤ 1 unless a higher-grade abnormality is allowed by the inclusion criteria. If medical therapy is required for the treatment of a laboratory abnormality, the dose and laboratory value(s) should be stable.
- 6. Participants in Parts A or B Only: 14. Adequate organ function defined by the laboratory parameters outlined in the protocol
- 7. Participants in Part C Only: 15. Adequate organ function defined by laboratory parameters outlined in the protocol
- 8. 16. Female participants must: a. Not be a person of childbearing potential (POCBP) (eg, surgically sterilized or postmenopausal), or b. If a POCBP, the individual must have a negative serum pregnancy test at Screening and within 7 days prior to Study Day 1. The participant must agree not to attempt to become pregnant, must not donate ova, and must agree to use 2 forms of highly effective contraception upon signing consent, during the study, and for at least 6 months after the last dose of study drug (9 months after last dose of study drug for participants in Part C), OR use 1 form of highly effective contraception, plus an additional barrier method of contraception upon signing consent, during the study, and for at least 6 months after the last dose of study drug (9 months after last dose of study drug for participants in Part C). c. If a POCBP with same sex partners (abstinence from penile vaginal intercourse), the individual is eligible when this is their preferred and usual lifestyle.
- 9. 17. Male participants must be willing to not donate sperm and, if engaging in sexual intercourse with a partner who could become pregnant, be willing to use a condom in addition to having the partner use a highly effective contraceptive method upon signing consent, during the study, and for at least 100 days after the last dose of study drug (6 months after last dose of study drug for participants in Part C).
- 10. 2. Must be willing to sign and date an informed consent form (ICF) approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC), as appropriate, indicating that they understand the purpose of, and procedures required for, the study and are willing to comply. Consent is to be obtained prior to the performance of any study specific procedures or tests that are not part of the standard of care for the participant’s disease.
- 11. 3. Diagnosis of metastatic colorectal adenocarcinoma based on histopathology.
- 12. 4. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. All radiology Screening tests must be performed within 28 days prior to initiation of study treatment.
- 13. 5. Have a known KRAS G12D mutation. Mutation status should be determined using a validated next generation sequencing (NGS) or polymerase chain reaction (PCR) testing method assessed using fresh biopsy, if feasible. If fresh biopsy is not feasible, KRAS determination from archival tissue or blood will be accepted.
- 14. 6. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
- 15. 7. Must have received at least 1 standard chemotherapy for metastatic colorectal adenocarcinoma. Standard chemotherapies must include all of the following agents unless contraindicated: a. Fluoropyrimidines, irinotecan, and oxaliplatin. b. An anti-vascular endothelial growth factor (VEGF) agent (for 1 prior treatment, exposure to VEGF inhibitor is optional). NOTE: participants may not have received trifluridine/tipiracil (TAS-102), regorafenib, or fruquintinib, or more than 1 experimental therapy.
- 16. 8. Participants who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within 6 months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting. Participants who developed metastatic disease more than 6 months after completion of oxaliplatin-containing adjuvant treatment must have been treated with oxaliplatin-based therapy in the metastatic setting to be eligible.
- 17. 9. Have documented disease progression during or following their most recent prior line of therapy.
Exclusion criteria
- Have any other documented co-existing common RAS mutation(s) * Prior anti-cancer Tx within 4 weeks or drug-specific timeline within first treatment dose, whichever shorter * Major surgery within 4 weeks of first treatment dose * Radiation therapy (RT) within 1 week of first treatment dose * Receipt of prior direct RAS inhibitor * Receipt of more than 1 investigational therapy * Untreated or symptomatic CNS metastasis * Receipt of strong CYP3A4 inhibitor/inducer or CYP3A4 sensitive substrates with narrow therapeutic index within 14 days or drug-specific timeline within first treatment dose, whichever is shorter * Receipt of PPI or H2 blocker within 5 days * Inability to swallow oral medication * Other protocol-defined inclusion/exclusion criteria may apply
- 1. 1. Underwent major surgical procedure as defined by the Investigator, other than for diagnosis, within 4 weeks prior to Study Day 1, or anticipation of the need for a major surgical procedure during the study. Requires non-major but persistent or repeated procedures for therapeutic or palliative intent (eg, pleural/peritoneal catheter placement or repeat paracentesis for ascites). NOTE: The following procedures are permitted up to 7 days prior to Study Day 1: thoracentesis, paracentesis, laparoscopy, thoracoscopy, tube thoracostomy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, and imaging-guided biopsy.
- 2. 10. Use of proton pump inhibitors (PPIs) within 5 days and H2 receptor antagonists within 1 day prior to Study Day 1. Refer to Section 6.7 for use of PPI and H2 receptor antagonists after Study Day 1.
- 3. 11. Symptomatic, untreated, or actively progressing known central nervous system metastases. Participants with previously diagnosed brain metastases are eligible if they have completed their treatment for brain metastases and have recovered from the acute effects of radiation therapy or surgery prior to study entry, are neurologically stable, and have steroids administered post-radiation therapy be tapered to ≤ 10 mg prednisone (or equivalent) and stable for at least 2 weeks before Study Day 1.
- 4. 12. Inability to swallow oral medications or participants with gastrointestinal conditions or comorbidities (eg, significant gastric surgery) that may negatively impact oral medication absorption.
- 5. 13. In current need of supplemental O2 therapy to maintain resting oxygen saturation ≥ 90%.
- 6. 14. Known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection. Participants with HIV may be enrolled if in chronic suppression with stable viral load, no clinical symptoms, and lymphocyte count > 500 cells/µL.
- 7. 15. Receipt of an allogeneic tissue/solid organ or hematopoietic transplant.
- 8. 16. Concurrent symptomatic congestive heart failure, prior history of New York Heart Association (NYHA) class III/IV cardiac disease, myocardial infarction within 3 months prior to Study Day 1, current unstable arrhythmias, current unstable angina, or current severe obstructive pulmonary disease.
- 9. 17. Evidence or history of uncontrolled, clinically significant hematologic (clinically significant hemorrhage or bleeding diathesis), renal, hepatic, endocrine, pulmonary, gastrointestinal, cardiovascular, psychiatric, coagulation, neurologic, dermatologic, autoimmune, or allergic disease (including drug allergies, exclusive of untreated, asymptomatic, seasonal allergies at the time of study drug treatment), which would place the participant at an unacceptably high risk for toxicity.
- 10. 18. Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection requiring therapy, drug abuse, or a social situation that would limit compliance with study requirements.
- 11. 19. History of prior malignancy, except for having undergone potentially curative therapy with no evidence of disease recurrence for 3 years since initiation of that therapy. NOTE: Participants with any of the following additional malignancies are not excluded: Malignancies with negligible risk of metastases or death (eg, risk of death or metastases < 5% at 5 years) that were treated with curative intent and have not recurred within 2 years prior to Study Day 1, completely resected basal cell or squamous cell skin cancers, carcinoma in situ (CIS) of the cervix, or ductal CIS of the breast; malignancies considered to be indolent and never having required therapy; participants with early stage, low Gleason grade prostate cancer who otherwise qualify are permitted onto the study. Hormonal therapy for purposes of maintenance therapy is allowed (eg, prostate and breast cancer).
- 12. 2. Receipt of chemotherapy, targeted anti-cancer therapy, or radiotherapy (excluding palliative radiation) within 4 weeks or 5 half-lives, whichever is shorter, or immunotherapy within 4 weeks prior to Study Day 1. Palliative radiation of non-target lesions will be allowed up to 7 days prior to Study Day 1, with the exception of radiation to the lung or brain which requires a 2-week washout period prior to Study Day 1. NOTE: Steroids administered post-radiation therapy must be tapered to ≤ 10 mg prednisone (or equivalent) prior to Study Day 1.
- 13. 21. Individuals with a history of allergy or known hypersensitivity to any of the study treatments or any of their excipients, or contraindication to any of the study treatments as outlined in the respective local prescribing information.
- 14. 8. Tumors that are locally confirmed Microsatellite Instability-High (MSI-H) or deficient Mismatch Repair (dMMR).
- 15. 9. Have received a strong inhibitor of cytochrome P450 (CYP) 3A4 within 14 days prior to Study Day 1 or within 3 half-lives of the drug (whichever is shorter). Have received a strong inducer of CYP3A4 within 14 days prior to Study Day 1. Have received a sensitive CYP3A4, organic anion transporter 1 (OAT1), CYP2C8, or P-glycoprotein (P gp; oral dose only for P-gp) substrate with narrow therapeutic windows within 14 days prior to Study Day 1 or within 3 half-lives of the drug (whichever is shorter). As grapefruit juice can be a moderate to strong CYP3A4 inhibitor, participants must refrain from consuming grapefruit or grapefruit juice from 1 week prior to Study Day 1.
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Los Angeles
Los Angeles, CA, United States, 90025
Investigator
Navid Hafez
Status
Recruiting
Condition(s) Treated at Site
Bowel (Colorectal)
Location
START Dallas Fort Worth
Fort Worth, TX, United States, 76104
Investigator
Salwan Al Mutar
Status
Recruiting
Condition(s) Treated at Site
Bowel (Colorectal)
Location
START New Jersey
East Brunswick, NJ, United States, 08816
Investigator
Bruno Fang
Status
Recruiting
Condition(s) Treated at Site
Bowel (Colorectal)
Location
START Mountain Region
West Valley City, UT, United States, 84119
Investigator
Jose Pacheco
Status
Recruiting
Condition(s) Treated at Site
Bowel (Colorectal)
Location
START Midwest
Grand Rapids, MI, United States, 49546
Investigator
Sreenivasa Chandana
Status
Recruiting
Condition(s) Treated at Site
Bowel (Colorectal)