Phase 1/2 Open‑Label Study of VS‑7375, a KRAS G12D (ON/OFF) Inhibitor, as Monotherapy and Combination Therapy in Patients with Advanced KRAS G12D‑Mutant Solid Tumors
- Trial ID
- 2025-523432-39-01
- Protocol
- VS-7375-101
- Sponsor
- Verastem Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objectives of the study are to:
- Characterize the safety profile and tolerability of escalating oral doses of VS‑7375 as monotherapy, and to determine the maximum tolerated dose (MTD) or maximum feasible dose (MFD) using a Bayesian optimal interval (BOIN) design.
- Assess the efficacy of the optimal monotherapy regimen identified in dose escalation in patients with advanced KRAS G12D‑mutated pancreatic ductal adenocarcinoma, non‑small cell lung cancer, and other solid tumors who have received prior systemic therapy.
- Evaluate the safety and tolerability of VS‑7375 in combination with cetuximab, carboplatin + pembrolizumab + pemetrexed, or gemcitabine + nab‑paclitaxel, and to recommend a dose for subsequent combination studies.
- Investigate the impact of VS‑7375 on the pharmacokinetics of CYP3A4 (midazolam) and CYP2C8 (repaglinide) substrates, thereby addressing potential drug‑drug interaction concerns.
- Determine the pharmacokinetic profile of VS‑7375 as monotherapy.
- Evaluate preliminary anticancer activity of VS‑7375 monotherapy.
- Assess additional efficacy parameters of the recommended monotherapy and combination regimens in expansion cohorts.
- Characterize the safety and tolerability of the recommended regimens in expansion cohorts.
- Continue evaluation of VS‑7375 pharmacokinetics in monotherapy and combination settings.
- Examine the effect of VS‑7375 on the pharmacokinetics of nab‑paclitaxel in the relevant combination cohort.
Participants
The trial enrolled 594 adult participants of both sexes with advanced or metastatic solid tumors harboring a confirmed KRAS G12D mutation; eligibility required a histologic or cytologic diagnosis, measurable disease per RECIST v1.1, and an ECOG performance status of 0 or 1. All subjects were ≥18 years old and demonstrated adequate organ function, including specific hematologic, hepatic, renal, and cardiac criteria. Enrollment was limited to patients who had received a defined number of prior systemic therapy lines appropriate to their tumor type (e.g., 1–3 lines for colorectal adenocarcinoma, up to 2 lines for pancreatic ductal adenocarcinoma, and up to 4 lines for non‑small cell lung cancer) and who were not eligible for other study cohorts. Lifestyle considerations incorporated requirements for effective contraception in individuals of child‑bearing potential and exclusion of participants with uncontrolled comorbidities that could interfere with safety assessments. Selection was based on molecular testing using validated NGS or PCR methods, performance status, organ function, and prior treatment history, ensuring a population reflective of heavily pretreated patients with KRAS G12D‑mutated solid malignancies.
Plans and Procedures
The study is a phase 1/2, open‑label investigation of the KRAS G12D inhibitor VS‑7375 in adults with KRAS G12D‑mutant solid tumors. It incorporates a multi‑part design that includes a dose escalation segment to define the maximum tolerated or biologically effective dose, followed by dose‑expansion cohorts evaluating monotherapy and predefined combination regimens (e.g., with cetuximab, carboplatin‑pemetrexed‑pembrolizumab, or gemcitabine‑nab‑paclitaxel). Participants undergo an initial screening visit to confirm eligibility, including histologic verification of KRAS G12D status, performance‑status assessment, and baseline imaging per RECIST v1.1. After consent, a baseline visit initiates study treatment; subsequent visits are scheduled at regular intervals (typically every 3 weeks during combination therapy and monthly during monotherapy) to monitor safety, pharmacokinetics, and tumor response. An end‑of‑study visit is performed after the final treatment cycle, at disease progression, or upon discontinuation for safety or protocol reasons. Participants remain in the trial from screening through the end‑of‑study assessment, with follow‑up continuing until the last patient completes the final visit; the overall trial recruitment period spans from June 2026 to September 2029.
Treatment
The investigational product VS-7375 is supplied as a tablet for oral use. It is administered once daily on a continuous schedule. Dose levels are escalated according to a Bayesian optimal interval (BOIN) design in the dose‑escalation phase, with the selected dose carried forward to expansion cohorts. Pill counts and patient diaries are used to assess adherence.
Gemcitabine is provided as a solution for intravenous infusion. It is administered by infusion according to the protocol‑specified dose and schedule, typically on days 1 and 8 of each treatment cycle. Infusion records and nursing documentation are employed to verify administration.
Pembrolizumab is supplied as a 25 mg/mL concentrate for solution for infusion. The drug is given intravenously at the protocol‑defined interval, commonly every three weeks. Administration details are captured in the electronic case report form.
Cetuximab is presented as a 5 mg/mL solution for infusion. It is delivered intravenously on a weekly or bi‑weekly schedule as defined by the study protocol. Compliance is monitored through infusion logs.
Pemetrexed is available as both a concentrate for solution for infusion and a ready‑to‑use solution for infusion. It is administered intravenously on day 1 of each cycle, with dosing calculated per body surface area. Pharmacy dispensing records track each dose.
Carboplatin is supplied as a 10 mg/mL concentrate for infusion solution. It is given intravenously on day 1 of the cycle, with the dose calculated using the Calvert formula. Infusion documentation confirms correct dosing.
Nab‑paclitaxel (albumin‑bound paclitaxel) is provided as a powder for dispersion for infusion. The drug is reconstituted and administered intravenously on days 1 and 8 of each cycle, per protocol specifications. Administration is recorded in the infusion chart.
Combination regimens incorporate the oral investigational agent with the following agents according to cohort assignment:
- VS‑7375 + cetuximab for KRAS G12D‑mutated solid tumors.
- VS‑7375 + carboplatin + pembrolizumab + pemetrexed for previously untreated metastatic non‑small cell lung cancer.
- VS‑7375 + gemcitabine + nab‑paclitaxel for locally advanced or metastatic pancreatic ductal adenocarcinoma.
All study drugs are administered under controlled clinical settings, with dosing schedules and compliance monitored through electronic case report forms, pharmacy dispensing logs, and infusion documentation to ensure protocol adherence.
Efficacy
Efficacy will be evaluated primarily by the proportion of participants achieving a confirmed overall response rate (ORR) as determined by blinded independent central review (BICR) according to RECIST v1.1 criteria. Secondary efficacy assessments will include confirmed disease control rate (DCR), duration of response (DOR), progression‑free survival (PFS), and overall survival (OS). Tumor assessments will be performed using standard imaging modalities (e.g., CT or MRI) and interpreted by both BICR and investigator review per protocol‑specified visit windows.
All radiographic evaluations will be conducted at baseline and at subsequent study visits defined in the protocol, with response classifications (partial response, complete response, stable disease, progressive disease) recorded for each timepoint. The collected data will be analyzed using appropriate statistical methods to estimate response rates, time‑to‑event outcomes, and confidence intervals.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Individuals ≥18 years of age.
- Participants with metastatic colorectal adenocarcinoma must have received at least 1, but no more than 3 prior lines of therapy and must have previously received fluoropyrimidine, oxaliplatin, irinotecan, and an anti-vascular endothelial growth factor (VEGF) agent.
- Must have histologic or cytologic confirmation of metastatic PDAC and be an appropriate candidate for treatment with gemcitabine and nab-paclitaxel.
- Received prior treatment with a platinum-based chemotherapy regimen and an immune checkpoint inhibitor (if not contraindicated) in the advanced, non-resectable setting.
- Treatment naïve or received no more than 1 cycle of standard systemic therapy for metastatic disease.
- Received prior appropriate therapy for an activating mutation (except prior RAS inhibitors) for which a therapeutic has been approved (eg, rearranged during transfection [RET], rapidly accelerated fibrosarcoma [RAF], CMET exon 14 skipping, ROS) in the Stage 3B, C or 4 setting if indicated.
- Must have received 1 or 2 prior lines of standard systemic therapy for advanced or metastatic disease or, for PDAC, progressed during adjuvant therapy and have no available therapies with proven clinical benefit.
- Must have histologic or cytologic evidence of locally advanced unresectable or metastatic solid tumor harboring a KRAS G12D mutation, other than the tumor types being evaluated in other cohorts (eg, other than PDAC, NSCLC, or colorectal adenocarcinoma), including small bowel, biliary tract (including intrahepatic cholangiocarcinoma), appendiceal, endometrial, and ovarian tumors (except LGSOC).
- Must have histologic or cytologic confirmation of metastatic (Stage 4) NSCLC and be an appropriate candidate for treatment with carboplatin, pemetrexed, and pembrolizumab.
- 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.
- 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.
- Histologic or cytologic evidence of solid tumor harboring a KRAS G12D mutation. Mutation status should be determined using a validated next generation sequencing (NGS) or polymerase chain reaction (PCR) testing method as assessed using , fresh biopsy, if feasible. The results must be available prior to screening and consent.
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
- Must have histologic or cytologic confirmation of metastatic KRAS G12D-mutated solid tumor type.
- Must have received 2 or 3 prior lines of therapy or progressed during adjuvant therapy for PDAC, 3 or 4 prior lines of therapy for NSCLC, 4 prior lines of therapy for colorectal adenocarcinoma, or 4 or more prior lines of therapy for other tumor types.
- Must be ineligible for enrollment into any other cohort in the study. If other monotherapy expansion cohorts complete enrollment (eg, B1, B2, or B3) and Part E has not yet completed enrollment, patients fulfilling those enrollment criteria may then be allowed to enroll into Part E.
- Adequate organ function defined by the following laboratory parameters: a. Absolute neutrophil count ≥1.0×103/µL without G-CSF support b. Platelets ≥100×103/µL (transfusion support is allowed, but count must be stable for at least 72 hours post-transfusion to qualify) c. Hemoglobin ≥9 g/dL (transfusion support is allowed, but count must remain consistently ≥9 g/dL for at least 72 hours post-transfusion to qualify) d. Adequate hepatic function: i. Total bilirubin ≤1.5×upper limit of normal (ULN) for the institution; participants with Gilbert syndrome may enroll if total bilirubin <3.0 mg/dL. ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN (or <5× ULN in participants with liver metastases). e. Adequate renal function with a creatinine clearance rate of ≥ 60 mL/min as calculated by at least one method using either the Cockcroft-Gault formula, CKD-EPI equations, or measured by a 24-hour urine collection. f. International normalized ratio (INR) ≤1.5 and partial thromboplastin time (PTT) ≤1.5×ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation. g. Albumin ≥3.0 g/dL (451 μmol/L). h. Adequate cardiac function with left ventricular ejection fraction ≥50% by echocardiography or multi-gated acquisition (MUGA) scan. i. Baseline QTc interval <470 msec (average of triplicate readings) using Fredericia’s QT correction formula (QTcF). NOTE: This criterion does not apply to participants with a right or left bundle branch block.
- Recovered from all AEs due to previous therapies to Grade ≤1 or baseline. Individuals with Grade ≤2 alopecia or neuropathy may be eligible. Individuals 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.
- Participants must: a. Not be a person of child-bearing 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 the planned start of study treatment. 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, 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. 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.
- 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 90 days after the last dose of study drug.
- Must have received ≥1 but no more than 3 prior lines of standard systemic therapy for advanced or metastatic disease or for PDAC, progressed during adjuvant therapy.
- Must have histologic or cytologic confirmation of advanced or metastatic PDAC.
- Must have received only 1 prior standard of care lines of therapy in the advanced or metastatic disease setting (eg, FOLFIRINOX or gemcitabine/nab-paclitaxel) or progressed during adjuvant therapy.
- One or 2 prior approved systemic lines of therapy for advanced (Stage 3B, 3C, or 4) NSCLC.
- Treatment naïve or received no more than 1 cycle of standard systemic therapy for metastatic disease.
- Must have histologic or cytologic confirmation of locally advanced or metastatic PDAC and be an appropriate candidate for treatment with gemcitabine and nab-paclitaxel.
- Must have had 1 prior standard of care regimen in the advanced disease setting (eg, FOLFIRINOX or gemcitabine/nab-paclitaxel) or progressed during adjuvant therapy.
- No remaining standard of care therapy is expected to provide meaningful clinical benefit in the Investigator’s opinion.
Exclusion Criteria
- 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. Medical Monitor or Sponsor may be consulted during Screening to discuss significance of recent/planned surgical procedures. 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 for diagnostic purposes. Eligibility of participants requiring persistent or repeated procedures for therapeutic intent (eg, pleural/peritoneal catheter placement or repeat paracentesis for ascites) must be discussed with the Medical Monitor or Sponsor.
- History of severe COVID-19 infection resulting in current need of supplemental O2 therapy to maintain resting oxygen saturations ≥90%. Note: Participants who had asymptomatic, mild, or moderate disease and are fully recovered are eligible for enrollment.
- Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active and/or requires therapy. For chronic hepatitis or indeterminate testing, must discuss with Medical Monitor prior to enrollment.
- Receipt of an allogeneic tissue/solid organ transplant.
- Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), myocardial infarction within the last 6 months prior to Study Day 1, unstable arrhythmias, unstable angina, or severe obstructive pulmonary disease.
- Evidence or history of uncontrolled, clinically significant hematological (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.
- Receipt of chemotherapy, targeted 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. Note: Palliative radiation will be allowed closer to the planned start of study treatment, but the timespan between the last dose of radiation and Study Day 1 should be discussed with the Medical Monitor or Sponsor. Steroids administered post-radiation therapy must be tapered to ≤ 10 mg prednisone (or equivalent) before starting study treatment.
- Treatment with any investigational drug at least 4 weeks or 5 half-lives, whichever is shorter, prior to Study Day 1 or concurrent participation in another interventional study.
- History of treatment with direct RAS inhibitors are prohibited in all parts of this study.
- Have received a strong inhibitor of CYP3A4 within 14 days prior to Study Day 1 or within 5 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, OAT1, CYP2C8, or P-gp (oral dose only for P-gp)substrates with narrow therapeutic windows within 14 days prior to Study Day 1 or within 5 half-lives of the drug (whichever is shorter). These participants can only be enrolled after being reviewed and approved by the Investigator and the Sponsor. 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.
- Use of proton pump inhibitors (PPIs) within 7 days and H2 receptor antagonists within 1 day prior to Study Day 1. Use of PPIs and H2 receptor antagonists after Study Day 1 should be referred to Section 6.8.
- Symptomatic, untreated, or actively progressing known central nervous system (CNS) metastases. Participants with previously diagnosed brain metastases are eligible if they have completed their treatment 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) before Study Day 1.
- Active flare of autoimmune disease that currently requires systemic treatment (eg, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) during the Screening period. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. Note: Low-dose, intermittent, or inhaled/topical corticosteroids are allowed.
- Inability to swallow oral medications. Note: Participants with gastrointestinal conditions or comorbidities (eg, significant gastric surgery) that may negatively impact oral medication absorption may be eligible for enrollment with Medical Monitor approval.
- 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.
- 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 the past 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 prostate cancer who otherwise qualify are permitted onto the study. If participant requires hormonal therapy, this must be discussed with the Medical Monitor prior to enrollment.
- Individuals who are pregnant or breastfeeding.
- 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.
- Individuals with LGSOC
- Cohort B2 (Advanced or Metastatic KRAS G12D-mutated NSCLC) Only: 20. NSCLC tumors harboring ALK mutations, or EGFR-mutant NSCLC.
- Cohorts C1 (Advanced or Metastatic KRAS G12D-mutated Solid Tumors) C2 (Metastatic KRAS G12D-mutated NSCLC), C3 (Advanced or Metastatic KRAS G12D-mutated PDAC), D1/D1R (Metastatic KRAS G12D-mutated Colorectal Adenocarcinoma), D2 (Metastatic KRAS G12D-mutated NSCLC), and D3 (Metastatic KRAS G12D-mutated PDAC) Only: 21. Individuals with a history or current diagnosis of interstitial lung disease (ILD) or pneumonitis.
- Cohort E only 22. Heterozygous or homozygous carriers of the CYP2C8*3 allele (eg, *1/*3 or *3/*3).
- Total bilirubin ≥1.5×upper limit of normal (ULN) for the institution (participants with Gilbert syndrome may enroll if total bilirubin >3.0 mg/dL); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≥2.5×ULN.
- Use of any drugs known to be inhibitors or inducers of CYP3A4 or CYP2C8, including St. John’s Wort, for 14 days prior to the first dose of midazolam + repaglinide in the run-in period and throughout the first cycle of the study.
- History of any GI surgery that could impact the absorption of the study drug, including partial gastrectomy, bariatric surgery, or cholecystectomy (except for uncomplicated appendectomy).
- Inability to abstain from all alcohol-containing products for at least 72 hours prior to the first dose of midazolam + repaglinide in the run-in period and throughout the first cycle of the study.
- Inability to abstain from all tobacco products (including cigarettes, cigars, heated tobacco products, and vaping products containing tobacco) for at least 7 days prior to the first dose of midazolam + repaglinide in the run-in period and throughout the first cycle of the study.
- Inability to abstain from all recreational drugs, including cannabis-containing products (THC or CBD), for at least 30 days prior to the first dose of midazolam + repaglinide in the run-in period and throughout the first cycle of the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Yet Recruiting | 01 Jun 2026 | 30 |
 France | Not Yet Recruiting | 01 Jun 2026 | 40 |
 Germany | Not Yet Recruiting | 01 Jun 2026 | 30 |
 Italy | Not Yet Recruiting | 01 Jun 2026 | 20 |
 The Netherlands | Not Yet Recruiting | 01 Jun 2026 | — |
 Spain | Not Yet Recruiting | 01 Jun 2026 | 60 |
| Netherlands | — | — | 30 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Carboplatin Hikma 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | — | — | PRD10240124 |
Pemetrexed STADA 25 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | — | — | PRD7905952 |
Ribozar 1 g Pulver zur Herstellung einer Infusionslösung | Test | PULVER ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS INFUSION | — | — | PRD7119324 |
VS-7375/GFH375 | Test | TABLET | ORAL USE | — | — | PRD12935268 |
Erbitux 5 mg/mL solution for infusion | Test | SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD327543 |
PEMETREXED VIATRIS 25 mg/ml, solution à diluer pour perfusion | Test | SOLUTION À DILUER POUR PERFUSION | INTRAVENOUS INFUSION | — | — | PRD11525067 |
Abraxane 5 mg/ml powder for dispersion for infusion. | Test | POWDER FOR DISPERSION FOR INFUSION | INTRAVENOUS | — | — | PRD9254303 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD12081132 |