Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib in G12C NSCLC Patients (RAMP203)

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] - Cardiovascular Diseases [C14]

Trial duration

14 Nov 2023 → ongoing

Decision date (initial)

2023-11-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Verastem, Inc.

External identifiers

EU CT number

2023-505107-24-00

ClinicalTrials.gov

NCT05074810

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Dose response, Safety

-Part A Dose Evaluation: To determine the Recommended Phase 2 Dose (RP2D) (avutometinib + sotorasib), for subsequent evaluation for efficacy in the expansion phase (Part B)
-Part B Dose Expansion: To determine the efficacy of the RP2D identified from Part A

Secondary objectives 3

1. To characterize the safety of avutometinib in combination with sotorasib in KRAS G12C mutant NSCLC
2. To evaluate additional efficacy parameters for the optimal regimen identified in Part A.
3. To determine the PK of avutometinib, sotorasib, defactinib, and relevant metabolites.

Conditions and MedDRA coding

Non-small cell lung cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Male or female patients ≥ 18 years of age.
2. 2. Histologic or cytologic evidence of NSCLC without histological evidence of a small cell or neuroendocrine components that are either metastatic (Stage 4) or locally advanced (Stage 3B-C) and unresectable (IASLC 8th edition).
3. 3. Patients must have a known KRAS G12C mutation determined using a validated test prior to enrollment. Adequate material (as defined in the lab manual) must be available prior to study therapy to be used for central confirmation of KRAS mutation status. Central confirmation does not need to be completed prior to enrollment.
4. 4. The patient must have received, in any setting, anti-programmed cell death protein 1 or anti-programmed death-ligand 1 immunotherapy (unless not indicated) AND/OR platinum-based combination chemotherapy; AND targeted therapy for actionable oncogenic driver mutations (ie, EGFR, ALK, and ROS1), excluding KRAS G12C.
5. 5. The patient must have received appropriate treatment with at least 1 prior systemic regimen, but no more than 2 prior systemic regimens, for Stage 3B-C or 4 NSCLC.
6. 6. The patient may have previously received adjuvant chemotherapy for early-stage disease. Adjuvant or neoadjuvant chemotherapy-based regimens in early stages will not count as prior regimen unless disease progression occurred during or within 3 months following the last dose of therapy.
7. 7. For prior G12C inhibitor use: a). Part A (avutometinib + sotorasib): Either prior G12C inhibitor exposure or no exposure is allowed. If prior G12C inhibitor use, must have had a best response to prior G12C inhibitor of confirmed response (CR or PR) by RECIST 1.1 or SD for ≥4 cycles. b). Part B, Cohort 1: No prior therapy with G12C inhibitor. c). Part B, Cohort 2: Must have received prior G12C inhibitor for at least 12 weeks
8. 8. Measurable disease according to RECIST 1.1.
9. 9. An Eastern Cooperative Group (ECOG) performance status ≤ 1.
10. 10. Must have adequate organ function defined by the following laboratory parameters: a). Adequate hematologic function including: hemoglobin (Hb) ≥ 9.0 g/dL; platelets ≥ 100,000/mm3; and absolute neutrophil count (ANC) ≥ 1500/mm3. If a red blood cell transfusion has been administered the Hb must remain stable and ≥9 g/dL for at least 1 week prior to first dose of study therapy. b). Adequate hepatic function: (i) total bilirubin ≤ 1.5 × upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin < 3.0 mg/dL (51 μmol/L) upon discussion with Medical Monitor; (ii) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (or < 5 x ULN in patients with liver metastases). c). Adequate renal function with creatinine clearance rate of ≥ 50 mL/min as calculated by the Cockcroft-Gault formula or serum creatinine of ≤ 1.5 ULN. d). International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation. e). Albumin ≥3.0 g/dL (451 μmol/L). f). Creatine phosphokinase (CPK) ≤ 2.5 x ULN. g). Adequate cardiac function with left ventricular ejection fraction ≥ 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
11. 11. Baseline corrected QT interval (QTc) interval < 470 ms for females and ≤450 ms for males (average of triplicate readings) (CTCAE Grade 1) using Fredericia’s QT correction formula. NOTE: This criterion does not apply to patients with a right or left bundle branch block.
12. 12. Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v5.0. Exceptions include alopecia and peripheral neuropathy Grade ≤ 2. Patients with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval by the Sponsor.
13. 13. Male and female patients with reproductive potential agree to use a highly effective method of contraceptive (per Clinical Trial Facilitation Group [CTFG] recommendations in Section 11.3.1) during the trial and for 3 months following the last dose of study intervention for male patients, and 1 month following the last dose of study intervention for female patients.

Exclusion criteria 22

1. 1. Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy except sotorasib or another KRAS G12C inhibitor for Part A or Cohort 2 in Part B which must be discontinued at least 6 days prior to Day 1 of study therapy.
2. 13. Active skin disorder that has required systemic therapy within the past 1 year.
3. 14. History of rhabdomyolysis.
4. 17. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina, or severe obstructive pulmonary disease.
5. 15. History of interstitial lung disease (ILD).
6. 16. Concurrent ocular disorders: a). Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes. b). Patient with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO. c). Patients with active or chronic visually significant corneal disorders, other active ocular conditions requiring ongoing therapy or clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy. Examples of visually significant corneal disorders include corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. Visually significant corneal disorders do NOT include dry eyes, blepharitis, and uncomplicated corneal erosions.
7. 2. History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression.
8. 18. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
9. 19. Patients with a history of hypersensitivity to any of the active (avutometinib or sotorasib as applicable) or inactive (croscarmellose sodium, hydroxypropyl methylcellulose, lactose monohydrate, mannitol, magnesium stearate, microcrystalline cellulose) ingredients of the investigational products.
10. 20. Female patients who are pregnant or breastfeeding.
11. 21. Any other medical condition (e.g. cardiac, gastrointestinal, pulmonary, psychiatric, neurological, genetic, etc.) that in the opinion of the investigator would place the patient at unacceptably high risk for toxicity.
12. 5. History of treatment with a direct and specific inhibitor of MEK.
13. 3. Major surgery within 4 weeks, minor surgery within 2 weeks, (excluding placement of vascular access), or palliative radiotherapy within 1 week of the first dose of study therapy.
14. 4. Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism can be converted to low-molecular-weight heparin or direct oral anticoagulants.
15. 6. History of treatment with a KRAS G12C inhibitor in order to be enrolled in the cohort evaluating the combination in those patients who are G12C inhibitor treatment naive (Cohort 1).
16. 9. Part A and Part B: Leptomeningeal metastases or active CNS metastases are excluded. However, subjects who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to Study Day 1 are eligible if they meet all of the following criteria: a. residual neurological symptoms grade ≤ 2; b. on stable doses of corticosteroids, if applicable; and c. follow-up MRI shows no new lesions appearing.
17. 7. Use of proton pump inhibitors (PPIs) within 3 days and H2 receptor antagonists within 1 day prior to Study Day 1 and during time on study.
18. 8. Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with study interventions within 14 days prior to the first dose of study intervention and during the course of therapy, including: a. Strong CYP3A4 inducers, due to potential drug-drug interactions with sotorasib. See Table 22, and Table 23 for representative lists of CYP3A4 inhibitors, inducers, and substrates. b. Sensitive substrates with narrow therapeutic index within 14 days prior to the first dose and during the course of therapy.
19. 10. Weight loss >10% within 4 weeks prior to first dose of study therapy.
20. 11. Known severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection (clinical symptoms) ≤ 28 days prior to first dose of study therapy.
21. 12. Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active and/or requires therapy.
22. 22. Patients that were previously treated with sotorasib and were dose reduced due to toxicity.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Part A Dose Evaluation: Dose-limiting toxicities (DLTs), adverse events (AEs), serious AEs (s), physical examinations, clinical laboratory values, and tolerability (dose interruptions/reductions). -Part B Dose Expansion: Confirmed ORR (partial response [PR] + complete response [CR] defined according to Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1])

Secondary endpoints 7

1. Adverse events, SAEs, physical examinations, clinical laboratory values, and tolerability (dose interruptions/reductions).
2. Duration of response (DOR)
3. Disease control rate (DCR), defined as Complete response (CR) + Partial response (PR) + Stable disease (SD)
4. Clinical benefit rate (CBR), defined as complete response (CR) + partial response (PR) + stable disease (SD) ≥ 6 months
5. Progression-free survival (PFS) defined as the time from first dose of study treatment to the first documentation of progressive disease (PD), or death from any cause
6. Overall survival (OS)
7. PK parameters derived from plasma concentrations of avutometinib, sotorasib, defactinib, and relevant metabolites

Investigational products

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

Test 3

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 8

Locations

4 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 83 files

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

Application history

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