Adagrasib for the Treatment of Patients with Unresectable or Metastatic Pancreatic Cancer with KRAS G12C Mutation

Inclusion Criteria

• Histologically confirmed diagnosis of a pancreatic cancer with KRAS G12C mutation. Patients are eligible based on detection of KRAS G12C mutation in tumor tissue or plasma circulating tumor deoxyribnucleic acid (DNA) (ctDNA) by any Clinical Laboratory Improvement Act (CLIA)-certified lab assay
• Unresectable or metastatic disease
• Presence of tumor lesions to be evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients must have measurable or evaluable disease
• Age >= 18 years old
• Life expectancy of at least 3 months
• No more than one prior therapy. Prior systemic therapy (e.g., chemotherapy, immunotherapy or, investigational agent) and radiation therapy discontinued at least 2 weeks before first dose date
• Recovery from the adverse effects of prior therapy at the time of enrollment to =< Grade 1 (excluding alopecia and neuropathy)
• Eastern Cooperative Oncology Group (ECOG) performance status in 0 to 2
• Absolute neutrophil count >= 1000/mm^3 (>= 1.0 x 10^9/L) (within the screening period)
• Platelet count >= 75,000/mm^3 (>= 75 x 10^9/L) (within the screening period)
• Hemoglobin >= 8 g/dL, in the absence of transfusions for at least 2 weeks (within the screening period)
• Total bilirubin =< 2 x Upper Limit of Normal (ULN) (if associated with liver metastases or Gilbert’s disease, =< 3 x ULN) (within the screening period)
• Aspartate transaminase (AST) and alanine transaminase (ALT) =< 5 x ULN (if associated with liver metastases, =< 5 x ULN) (within the screening period)
• Creatinine clearance >= 60 mL/min calculated using a validated prediction equation (e.g., Cockcroft-Gault, Modification of Diet in Renal Disease [MDRD], or 24-hour urine creatinine clearance [CrCl]) or serum creatinine =< 1.5 X ULN per institutional criterion (within the screening period)
• Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment
• Completed informed consent process, including signing Institutional Review Board/Independent Ethics Committee (IRB/EC)-approved informed consent form
• Willing to comply with clinical trial instructions and requirements
• Patients who are biologically capable of having children and sexually active must agree to use an acceptable method of contraception for the duration of the treatment period and for at least 6 months after the last dose of study treatment. The local Investigator will counsel the patient on selection of contraception method and instruct the patient in its consistent and correct use. Examples of acceptable forms of contraception include: * Oral, inserted, injected or implanted hormonal methods of contraception, provided it has been used for an adequate period of time to ensure effectiveness * Correctly placed copper containing intrauterine device (IUD) * Male condom or female condom used WITH a spermicide. * Male sterilization with confirmed absence of sperm in the post-vasectomy ejaculate * Bilateral tubal ligation or bilateral salpingectomy ** The local Investigator will instruct the patient to call immediately if the selected birth control method is discontinued or if pregnancy is known or suspected ** Note: Women are considered post-menopausal and/or not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 months ago. In case of any ambiguity, the reproductive status of the woman should be confirmed by hormone level assessment

Exclusion Criteria

• Active brain metastases. Patients are eligible if brain metastases are adequately treated and patients are neurologically stable (except for residual signs or symptoms related to the central nervous system (CNS) treatment) for at least 2 weeks prior to enrollment without the use of corticosteroids or are on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent)
• Carcinomatous meningitis
• History of significant hemoptysis or hemorrhage with hemoglobin dropped below 8 g/dL within 4 weeks of the first dose date
• Major surgery within 4 weeks of first dose date
• Inability to swallow oral medications
• Any of the following cardiac abnormalities: * Unstable angina pectoris or myocardial infarction within the previous 6 months * Congestive heart failure >= New York Heart Association (NYHA) Class 3 within the previous 6 months * Left ventricular ejection fraction (LVEF) < 50% * Corrected QT interval by Fridericia (QTcF) > 480 milliseconds or medical or immediate family history of congenital Long QT Syndrome
• Symptomatic or uncontrolled atrial fibrillation or other arrhythmia
• History of stroke or transient ischemic attack within the previous 6 months
• Ongoing need for a medication with any of the following characteristics that cannot be switched to alternative treatment prior to study entry: known risk of QT prolongation or Torsades de Pointes; substrate of CYP3A with narrow therapeutic index; strong inducer of CYP3A and/or P-gp; strong inhibitor of BCRP; and proton pump inhibitors
• Second malignancy that either requires active concurrent systemic therapy or involves a lesion that may confound assessment of the pancreatic cancer under study
• Known active human immunodeficiency virus (HIV) or Hepatitis B or C. Note that the following are permitted: * Patients treated for hepatitis C with no detectable viral load; * Patients treated for HIV with no detectable viral load for at least 1 month prior to enrollment while on a stable regimen of agents that are not strong inhibitors of CYP3A4; and * Patients with hepatitis B (HBV) receiving prophylaxis against reactivation of hepatitis B (either [hepatitis B surface antigen (HBsAg)-positive with normal ALT and hepatits B virus (HBV) DNA < 2,000 IU/mL or < 10,000 copies/mL] or [HBsAg-negative and hepatitis B core antibody (anti-HBc)positive])
• Pregnancy. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test documented within the screening period prior start of study drug
• Breast-feeding or planning to breast feed during the study or within 6 months after study treatment
• Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical history, including laboratory results, which, in the local Investigator’s opinion, would be likely to interfere with the patient’s participation in the study, or with the interpretation of the results
• Prior treatment with a therapy targeting KRAS G12C mutation is permitted