Clinical trial NCT05275673: A Study of Sapanisertib in Relapsed/Refractory NFE2L2-Mutated and Wild-Type Squamous Non-Small Cell Lung Cancer
Official title: A Randomized, Open-Label Phase 2 Study of the TORC 1/2 Inhibitor Sapanisertib in Relapsed/Refractory NFE2L2 (NRF2)-Mutated and Wild-Type (WT) Squamous Non-Small Cell Lung Cancer (sqNSCLC)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Squamous Non-small-cell Lung Cancer
Squamous Non-Small Cell Neoplasm of Lung
NFE2L2 Gene Mutation
Keywords: NSCLC
sqNSCLC
NFE2L2
Next Generation Sequencing
NGS
Mutation
Relapsed
Refractory
Squamous
NRF2
Lung Cancer
Lead sponsor: Faeth Therapeutics
Sponsor class: INDUSTRY
First posted: 2022-03-11
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 2 dosing schedules: 3 mg once per day (3 mg total) OR 2 mg twice per day (4 mg total)

Group A: 30 participants randomized 1:1 to one of two dosing schedules

Group B: approximately 20 participants randomized 1:1 to one of two dosing schedules
Primary purpose: TREATMENT

Brief summary: This is a multicenter, randomized, open-label Phase 2 study of sapanisertib in biomarker-defined populations of sqNSCLC. Patients with NFE2L2 (the name for gene encoding the protein called NRF2)-mutated or wild-type sqNSCLC should have disease that has progressed on or after at least two prior systemic therapies for metastatic disease including platinum-doublet chemotherapy and a programmed cell death 1 ligand 1 (PD-L1) inhibitor. The study will evaluate sapanisertib monotherapy in patients with relapsed/refractory sqNSCLC as two separate groups: Group A: NFE2L2-mutated sqNSCLC and Group B: NFE2L2-WT sqNSCLC.

Detailed description: NFE2L2 mutation status for all patients will be identified using local or central next generation sequencing (NGS) testing on archival or fresh tissue or circulating tumor deoxyribonucleic acid (ctDNA), the results of which must be reviewed and approved by the Sponsor prior to enrollment. Each group will be randomized 1:1 to one of two doses/schedules of sapanisertib. Approximately 30 NFE2L2-mutant and 20 NFE2L2-wild type patients will be enrolled. Patients will be treated with sapanisertib until disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), unacceptable toxicity, withdrawal of consent, or death.

Eligibility criteria: Inclusion Criteria:

* Stage IV squamous NSCLC.
* Disease progression during or after prior systemic therapy for metastatic disease, which must include platinum-doublet chemotherapy and immune checkpoint inhibitor therapy (anti-PD-(L)1 +/-anti-CTLA-4), if approved and available, administered as separate lines of therapy or in combination.
* Has study-eligible mutation in NFE2L2 or wild-type NFE2L2 using NGS from a College of American Pathologists- (CAP)-accredited and/or a Clinical Laboratory Improvement Amendments- (CLIA)-certified laboratory
* Must have at least one radiographically measurable lesion per RECIST v1.1 defined as a lesion that is ≥ 10 mm in longest diameter or lymph node that is ≥ 15 mm in short axis imaged by computerized tomography (CT) scan or Magnetic Resonance Imaging (MRI).
* Target lesions situated in a previously irradiated area may be considered measurable if progression has been demonstrated subsequent to radiation therapy.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
* Adequate Organ Function Laboratory Findings: Absolute neutrophil count (ANC): ≥1,500/mm3, Hemoglobin: ≥9.0 g/dL \* Transfusions and growth factors must not be used within 2 weeks prior to randomization to meet these requirements, Platelets: ≥ 100,000/mm3, Calculated creatinine clearance (CrCl): ≥ 40mL/min, Serum total bilirubin: ≤ 1.5× upper limit of normal (ULN) OR ≤ 3 mg/dL for patients with Gilbert's disease, AST (SGOT) and ALT (SGPT): ≤ 2.5× ULN OR ≤ 5× ULN for patients with liver metastases, Fasting triglycerides: \< 300 mg/dL, Fasting serum glucose: \<160 mg/dL
* A female patient of childbearing potential must:

  1. Have a negative serum or urine pregnancy test within 7 days prior to the first dose of study treatment
  2. Agree to use acceptable methods of contraception(See Section 8.1.2) during the study and for a minimum of 14 days following the last dose of sapanisertib
  3. Post-menopausal females (no menses for \>1 year without an alternative medical cause) and surgically sterilized females are exempt from these requirements.
* Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential and refrain from donating sperm during the study and for a minimum of 14 days following the last dose of sapanisertib.

Exclusion Criteria:

* Non-squamous cell histology and mixed histology tumors with any small-cell/neuroendocrine component.
* Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment per investigator's discretion.
* Receipt before the first dose of study drug of any of the following:

  i. Any investigational agent within 4 weeks. ii. Chemotherapy with 3 weeks (6 weeks for nitrosoureas or mitomycin C) iii. Any radiotherapy within 2 weeks prior to randomization with the exception of palliative radiotherapy for isolated tumor lesions
* Major surgery or other anticancer therapy not previously specified within 4 weeks.
* Unable or unwilling to discontinue proton pump inhibitor (PPI) use ≥ 5 days prior to randomization.
* Interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoid treatment.
* Any condition including social, psychiatric or medical (including uncontrolled significant concurrent illness) that in the opinion of the Investigator could interfere with treatment or protocol-related procedures.
* Patients who are pregnant or lactating.
* Symptomatic ascites or pleural effusion. Exception: Patients who are clinically stable following treatment for these conditions (including therapeutic thoraco-or paracentesis) are eligible.
* Refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, significant small bowel resection or gastric bypass surgery, use of feeding tubes or other situation that may preclude adequate absorption of oral study medication.
* Infection requiring more than 5 days of parenteral antibiotics, antivirals, or antifungals within two weeks prior to randomization.
* Patients receiving systemic corticosteroids greater than prednisone 10 mg or equivalent (excluding inhalers or low-dose hormone replacement therapy) within the 7 days before treatment initiation.
* Previous intolerance to mammalian target of rapamycin (mTOR), AKT, or dual PI3K/mTOR inhibitors.
* Patients with symptomatic, active/untreated central nervous system metastasis and/or leptomeningeal disease are not eligible.
* Significant active cardiovascular disease
* Participants who are known to be HIV-positive, unless assessed to be healthy with a low risk of AIDS-related outcomes.
* Known active Hepatitis B or C infection.
* Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of the study drug.

Primary outcomes:
measure: Investigator-Assessed Overall Response Rate (ORR) Per RECIST v1.1.
timeFrame: 36 months
measure: Number of Participants With Adverse Events (AEs), Serious AEs, and Deaths
timeFrame: From the first dose through 28 days after the last dose of sapanisertib (up to a maximum of 124 days).
Secondary outcomes:
measure: Duration of Response (DOR)
timeFrame: 36 months
measure: Progression-Free Survival (PFS)
timeFrame: 36 months
measure: Overall Survival (OS) at 6 and 12 Months
timeFrame: Months 6 and 12
Other outcomes:
Locations:
city: Davis
country: United States
facility: UC Davis Comprehensive Cancer Center
state: California
city: Santa Rosa
country: United States
facility: Providence Medical Group Santa Rosa - Cancer Center
state: California
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Ocala
country: United States
facility: Ocala Oncology Center
state: Florida
city: Tallahassee
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Louisville
country: United States
facility: Norton Cancer Institute, Downtown
state: Kentucky
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Saint Louis
country: United States
facility: Washington University - Patient Care Coordinator Center
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - Thoracic
state: New York
city: Columbus
country: United States
facility: Zangmeister Cancer Center
state: Ohio
city: Portland
country: United States
facility: Providence Cancer Institute Franz Clinic
state: Oregon
city: Pittsburgh
country: United States
facility: UPMC Cancer Pavilion
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Fairfax
country: United States
facility: Virginia Cancer Specialist, PC
state: Virginia
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Paul Paik
role: PRINCIPAL_INVESTIGATOR
References: