Sotorasib in Previously Treated Locally Advanced or Metastatic NSCLC Subjects With Mutated KRAS p.G12C

An Interventional and Translational Study Investigating Sotorasib in Previously Treated Locally Advanced or Metastatic NSCLC Subjects With Mutated KRAS p.G12C

This study aims to provide a comprehensive understanding of sotorasib's mechanisms of action and resistance in NSCLC patients.

Inclusion Criteria:

• Age higher than 18 years;
• ECOG less or equal to 1 at the time of screening;
• Pathologically documented, previously treated, locally-advanced and unresectable or metastatic NSCLC with KRAS p.G12C mutation confirmed through molecular testing (results of both tissue and liquid biopsy are accepted);
• Subjects will have progressed or experienced disease recurrence on or after receiving at least 1 prior systemic therapy for locally advanced and unresectable or metastatic disease.
• Life expectancy of longer than 3 months from the time of screening, in the opinion of the investigator;
• Patients must have lesions easily accessible to biopsy and must have accepted to perform pre-treatment, on-treatment and end-of-treatment biopsies;
• Have adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to registration
• Patients must understand, sign and date the written informed consent from prior to any protocol-specific procedures performed.
• Patients should be able and willing to comply with study visits and procedures as per protocol.
• Patients must be affiliated to a Social Security System or beneficiary of the same.

Exclusion Criteria:

• Patient unwilling to participate to the biological investigations and to perform biopsies and blood sample collection as required in the protocol;

• Use of known cytochrome P450 (CYP) 3A4 or P-gp sensitive substrates (with a narrow therapeutic window), within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to registration, that was not reviewed and approved by the principal investigator.

• Use of strong inducers of CYP3A4 (including herbal supplements such as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior to registration, that was not reviewed and approved by the principal investigator.

• Inadequate washout period prior to registration, defined as: Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study shorter than 14 days or 5 half-lives;

• Prior treatment with a KRAS inhibitor.

• Major surgery within 28 days of registration.

• Significant gastrointestinal disorder that results in significant malabsorption, requirement for intravenous alimentation, or inability to take oral medication.

• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 6 months prior to registration, unstable arrhythmias or unstable angina.

• Severe infections within 2 weeks prior to registration, but not limited to hospitalization for complications of infection, bacteremia or severe pneumonia. Prophylactic antibiotics are allowed.

• Baseline or unresolved pneumonitis from prior treatment;

• Current CTCAE version 5.0 grade higher or equal to 2 peripheral neuropathy.

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures at a frequency greater than monthly. Subjects with PleurX catheters in place may be considered for the study with Principal Investigator approval.

• Known history of Human Immunodeficiency Virus (HIV) infection

• Exclusion of hepatitis infection based on the following results and/or criteria:

  1. Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic Hepatitis B or recent acute hepatitis B)

  2. Negative HepBsAg with a positive for hepatitis B core antibody (Hepatitis B core antibody testing is not required for screening, however if this is done and is positive, then hepatitis B surface antibody [Anti-HBs] testing is necessary.

     Undetectable anti-HBs in this setting would suggest unclear and possible infection, and needs exclusion).

  3. Positive Hepatitis C virus antibody: Hepatitis C virus RNA by polymerase chain reaction is necessary. Detectable Hepatitis C virus RNA renders the subject ineligible.

• Leptomeningeal disease and active brain metastases. Subjects who have had brain metastases resected or have received whole brain radiation therapy or stereotactic radiosurgery ending at least 2 weeks prior to registration are eligible if they meet all of the following criteria:

  1. residual neurological symptoms grade less or equal to 2;
  2. on stable doses of dexamethasone or equivalent for at least 2 weeks, if applicable; and
  3. follow-up brain imaging performed within 30 days of enrollment shows no progression or new lesions appearing.

• Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 7 days after the last dose of sotorasib or during treatment if planning to become pregnant.

• Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 7 days after the last dose of sotorasib

• Female subjects of childbearing potential with a positive pregnancy test assessed at Screening or day 1 by a serum pregnancy test and/or urine pregnancy test.

• Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 7 days after the last dose of sotorasib

• Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 7 days after the last dose of sotorasib

• Male subjects unwilling to abstain from donating sperm during treatment and for an additional 7 days after the last dose of investigational product.

• Any evidence of primary malignancy other than locally advanced or metastatic lung cancer at within 3 years of registration, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated;

• Participation in another clinical trial evaluating an experimental drug (except non-interventional research).

• Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.

• Hypersensitivity to the active substance or to any excipient

• Patients with hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption