A Phase 1/2, Open-label Study of VS-7375, a KRAS G12D (ON/OFF) Inhibitor, as Monotherapy and in Combination, in Patients with Advanced KRAS G12D-Mutant Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Verastem Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-06-09

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Verastem, Inc.

External identifiers

EU CT number

2025-523432-39-01

ClinicalTrials.gov

NCT07020221

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic

Part A: VS-7375 Single-Agent Dose Escalation
To characterize the safety, tolerability, and AE profile of escalating doses of VS-7375 as monotherapy administered on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor.

To identify the MTD or MFD using a BOIN design and recommend a dose for subsequent studies of VS-7375 as monotherapy on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor.


Part B: VS-7375 Single-Agent Dose Expansion
To evaluate the efficacy of the optimal VS-7375 2L+ regimen identified from Part A in participants with advanced or metastatic KRAS G12D-mutated PDAC who have received 1 line of prior systemic therapy (cohort B1), NSCLC who have received 1 of 2 lines of prior system therapy (cohort B2), and other solid tumors who have received 1 of 2 lines of prior systemic therapy (cohort B3).


Part C: VS-7375 Combination Dose Escalation
To characterize the safety, tolerability, and AE profile of VS-7375:
• In combination with cetuximab in participants with any advanced or metastatic solid tumor harboring a KRAS G12D mutation who have received 1 to 3 lines of prior systemic therapy (cohort C1)
• In combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC (cohort 2)
• In combination with gemcitabine and nab-paclitaxel in participants with locally advanced or metastatic PDAC
• who have received 1 to 3 lines of prior systemic therapy (cohort C1)

To identify a recommended dose for subsequent studies of combination dosed VS-7375.


Part D: VS-7375 Combination Dose Expansion
To determine the efficacy of the optimal regimen of VS-7375 identified in Part C as:
• Monotherapy or in combination with cetuximab in participants with metastatic colorectal adenocarcinoma who have received 1 to 3 lines of prior systemic therapy (cohort C1)
• In combination with carboplatin, pembrolizumab, and pemetrexed in participants with previously untreated metastatic NSCLC (cohort D)
• In combination with gemcitabine and nab-paclitaxel in participants with previously untreated metastatic PDAC (cohort D3)


Part E: DDI
To determine the impact of VS-7375 (600 mg QD) on the PK of midazolam (CYP3A4 substrate) or repaglinide (CYP2C8 substrate) in participants with metastatic KRAS G12D-mutated PDAC who have received 2 or 3 prior lines of systemic therapy, NSCLC who have received 3 or 4 prior lines of systemic therapy, colorectal adenocarcinoma who have received 4 prior lines of systemic therapy, or other KRAS G12D-mutated solid tumor who have received 3 or more prior lines of systemic therapy

To characterize the safety, tolerability, and AE profile of VS-7375 administered in combination with CYP3A4 and CYP2C8 substrates

Secondary objectives 6

1. Part A: To characterize the PK of VS-7375 as monotherapy administered on a daily oral schedule in participants with any KRAS G12D-mutated solid tumor.
2. Part A: To evaluate the preliminary anticancer activity of VS-7375 as monotherapy in participants with any KRAS G12D-mutated solid tumor.
3. Parts B and D: To evaluate additional efficacy parameters of the recommended VS-7375 regimens from Part A (VS-7375 monotherapy) and Part C (VS-7375 in combination with other systemic therapies), administered on a daily oral schedule in participants with KRAS G12D-mutated solid tumors.
4. Parts B and D: To characterize the safety, tolerability of the recommended VS-7375 regimens from Part A (VS-7375 monotherapy) and Part C (VS-7375 in combination with other systemic therapies), administered on a daily oral schedule in participants with KRAS G12D-mutated solid tumors.
5. Parts B, C, and D: To continue to evaluate the PK of VS-7375 as monotherapy and in combination with other systemic therapies in participants with KRAS G12D-mutated advanced solid tumors.
6. Part C, Cohort C3: To evaluate the impact of VS-7375 on nab-paclitaxel PK in cohort C3.

Conditions and MedDRA coding

Advanced KRAS G12D-Mutant Solid Tumors

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 27

1. 1. Individuals ≥18 years of age.
2. 5. 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.
3. 6. 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.
4. 7. Must have histologic or cytologic confirmation of advanced or metastatic PDAC.
5. 8. 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.
6. 9. One or 2 prior approved systemic lines of therapy for advanced (Stage 3B, 3C, or 4) NSCLC.
7. 15. Treatment naïve or received no more than 1 cycle of standard systemic therapy for metastatic disease.
8. 16. Must have histologic or cytologic confirmation of locally advanced or metastatic PDAC and be an appropriate candidate for treatment with gemcitabine and nab-paclitaxel.
9. 17. 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.
10. 18. 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.
11. 19. Must have histologic or cytologic confirmation of metastatic PDAC and be an appropriate candidate for treatment with gemcitabine and nab-paclitaxel.
12. 10. Received prior treatment with a platinum-based chemotherapy regimen and an immune checkpoint inhibitor (if not contraindicated) in the advanced, non-resectable setting.
13. 20. Treatment naïve or received no more than 1 cycle of standard systemic therapy for metastatic disease.
14. 11. 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.
15. 12. 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.
16. 13. 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).
17. 14. Must have histologic or cytologic confirmation of metastatic (Stage 4) NSCLC and be an appropriate candidate for treatment with carboplatin, pemetrexed, and pembrolizumab.
18. 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.
19. 3. 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.
20. 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
21. 21. Must have histologic or cytologic confirmation of metastatic KRAS G12D-mutated solid tumor type.
22. 22. 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.
23. 23. 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.
24. 24. 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.
25. 25. 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.
26. 26. 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.
27. 27. 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.

Exclusion criteria 28

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. 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.
2. 10. 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.
3. 11. 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.
4. 12. Receipt of an allogeneic tissue/solid organ transplant.
5. 13. 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.
6. 14. 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.
7. 2. 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.
8. 3. 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.
9. 4. History of treatment with direct RAS inhibitors are prohibited in all parts of this study.
10. 5. 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.
11. 6. 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.
12. 7. 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.
13. 8. 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.
14. 9. 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.
15. 15. 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.
16. 16. 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.
17. 17. Individuals who are pregnant or breastfeeding.
18. 18. 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.
19. 19. Individuals with LGSOC
20. Cohort B2 (Advanced or Metastatic KRAS G12D-mutated NSCLC) Only: 20. NSCLC tumors harboring ALK mutations, or EGFR-mutant NSCLC.
21. 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.
22. Cohort E only 22. Heterozygous or homozygous carriers of the CYP2C8*3 allele (eg, *1/*3 or *3/*3).
23. 23. 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.
24. 24. 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.
25. 25. 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).
26. 26. 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.
27. 27. 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.
28. 28. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, and DLTs; and abnormal vital signs, physical examination, ECG parameters, ECOG PS, clinical laboratory results; and dose interruptions/reductions.
2. Proportion/number of participants with DLTs during the DLT assessment period (C1D1 through C1D21).
3. Confirmed ORR by blinded independent central review (BICR) per RECIST v1.1.
4. Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, and DLTs; and abnormal vital signs, physical examination, ECG parameters, ECOG PS, clinical laboratory results; and dose interruptions/reductions.
5. Proportion/number of participants with DLTs during the DLT assessment period (through C1).
6. Confirmed ORRby BICR, per RECIST v1.1.
7. AUC0-t, AUC0-inf, and Cmax of midazolam, repaglinide and relative metabolites.
8. Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs; and abnormal vital signs, physical examination, ECG parameters, ECOG PS, clinical laboratory results; and dose interruptions/reductions.

Secondary endpoints 6

1. PK parameters derived from plasma concentrations of VS-7375 including Cmax and AUC.
2. Confirmed ORR, DCR, and DOR per RECIST v1.1. Unless otherwise specified, all tumor response-based endpoints will be analyzed using both BICR and Investigator assessments.
3. Confirmed ORR by Investigator-assessed DOR, BoR, DCR, PFS per RECIST 1.1 and OS.
4. Proportion/number of participants with AEs, TEAEs, TRAEs, SAEs, and abnormal vital signs, physical examination, ECG parameters, ECOG PS, clinical laboratory results; and dose interruptions/reductions.
5. PK parameters derived from plasma concentrations of VS-7375 including Cmax and AUC
6. Change in nab-paclitaxel exposures in the presence and absence of VS-7375.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Verastem Inc.

Sponsor organisation

Verastem Inc.

Address

117 Kendrick Street Suite 500

City

Needham

Postcode

02494-2730

Country

United States

Scientific contact point

Organisation

Verastem Inc.

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

Verastem Inc.

Contact name

Clinical Trial Information Desk

Third parties 13

Locations

6 EU/EEA countries · 18 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 87 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications