IRB Study Number 23-174
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
Part A Dose Evaluation:
To determine the Recommended Phase 2 Dose (RP2D) optimal combination regimen) for avutometinib in combination with 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
To characterize the safety and toxicity profile of avutometinib in combination with sotorasib in KRAS G12C mutant NSCLC
To evaluate additional efficacy parameters for the optimal regimen identified in Part A
To characterize the PK of avutometinib, sotorasib, and relevant metabolites
Inclusion Criteria
Male or female patients ≥ 18 years of age.
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).
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.
The patient must have received in any setting anti-programmed cell death protein 1 or anti programmed death-ligand 1 immunotherapy (unless contraindicated) AND/OR platinum-based combination chemotherapy AND targeted therapy for actionable oncogenic driver mutations (i.e., EGFR, ALK, and ROS1).
The patient must have received appropriate treatment with at least one prior systemic regimen, but no more than 2 prior systemic regimens, for Stage 3B-C or 4 NSCLC.
The patient may have previously received adjuvant chemotherapy for early-stage disease. Adjuvant or neoadjuvant chemotherapy-based regimes in early stages will not count as a prior regimen unless disease progression occurred during or within 3 months following the last dose of the adjunct therapy.
For prior G12C inhibitor use:
a. Part A: 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 had a best response to prior G12C inhibitor of confirmed response (CR or PR) by RECIST 1.1 or SD for ≥4 cycles.
Measurable disease according to RECIST 1.1.
An Eastern Cooperative Group (ECOG) performance status ≤1.
Must have adequate organ function defined by the following laboratory parameters:
a. Adequate hematologic function including: 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 < 5x ULN in patients with liver metastases).
c. Adequate renal function with creatinine clearance rate of ≥ 50 mL/min as calculated by the co*ckcroft-Gault formula or serum creatinine ≤ 1.5 x 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.
Baseline QTc interval < 460 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.
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.
Male and female patients with reproductive potential agree to use a highly effective method of contraceptive (per Clinical Trial Facilitation Group [CTGG] recommendations in Section 11.4.1) during the trial and for at least 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
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.
History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression.
Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of study therapy.
Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism can be converted to low-molecular-weight heparin or direct oral anticoagulants.
History of treatment with a direct and specific inhibitor of MEK.
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).
Use of proton pump inhibitors (PPIs) within 3 days and H2 receptor antagonists within 1 day prior to Study Day 1.
Exposure to strong CYP3A4 inhibitors, inducers, or sensitive substrates with narrow therapeutic index within 14 days prior to the first dose and during the course of therapy. See Table 20, Table 21, and Table 24 for representative lists of CYP inhibitors inducers, and substrates. For additional guidance, see https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.
Exposure to strong P-glycoprotein (P-gp) inhibitors or inducers or sensitive substrates with narrow therapeutic index within 14 days prior to the first dose and during the course of therapy.
Exposure to strong Breast Cancer Resistance Protein (BCRP) inhibitors or inducers within 14 days prior to the first dose and during the course of therapy.
Part A: Leptomeningeal metastases or any central nervous system (CNS) metastases. Part B: Leptomeningeal metastases or active CNS metastases <4 weeks prior to first dose of study therapy. “Active” is defined as any symptomatic, <4-week washout from any therapy such as radiation, surgery or corticosteroids, neurological instability attributable to such metastases, or evidence of interim progression. Patients with new asymptomatic brain metastases must receive radiation therapy and/or surgery for brain metastases. Following treatment, these patients may then be eligible if all other criteria are met.
Weight loss >10% within 4 weeks prior to first dose of study therapy.
Known severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection (clinical symptoms) ≤ 28 days prior to first dose of study therapy.
Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active and/or requires therapy.
Active skin disorder that has required systemic therapy within the past 1 year.
History of rhabdomyolysis.
History of interstitial lung disease (ILD).
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.
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.
Patients with the inability to swallow oral medications or with impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
Patients with a history of hypersensitivity to any of the active (avutometinib, sotorasib) or inactive (croscarmellose sodium, hydroxypropyl methylcellulose, lactose monohydrate, mannitol, magnesium stearate, microcrystalline cellulose) ingredients of the investigational products.
Female patients who are pregnant or breastfeeding.
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.
