IPI-549 for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma

Inclusion Criteria

• Patients must have locally advanced, previously untreated HNSCC (unknown primary or any primary site except cutaneous or Epstein-Barr virus [EBV]-related nasopharynx cancer) that is amenable to surgical resection
• Patients must be able to administer IPI-549 by mouth and have no evidence of malabsorption
• Patients must be able to undergo a core tumor biopsy with tissue available for analytics
• There must be at least 3 weeks between initiation of IPI-549 and surgical resection
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count >= 1.0 x 10^9/L
• Platelet count >= 75 x 10^9/L (transfusion independent for > 7 days)
• Hemoglobin >= 8.0 g/dL (may receive transfusions)
• Total bilirubin =< 1.5 x institution’s upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal
• Serum creatinine =< 1.5 x institution’s ULN, or creatinine clearance >= 60 ml/min
• Female patient of childbearing potential has a negative serum or urine pregnancy within 7 days prior to receiving the first dose of study medication
• Female patient of childbearing potential agrees to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication * Note: Females of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male patient with a partner of childbearing potential agrees to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria

• Cutaneous squamous cell carcinoma (SCC) or Epstein-Barr virus (EBV) related nasopharynx cancer
• Severe allergic or anaphylactic reaction to IPI-549 * NOTE: Subjects with a history of anaphylaxis to other agents are eligible for study participation. Subjects who have received alternative therapies, including prior IPI-549, are eligible for study participation
• Major surgery within 4 weeks prior to initiation of study drug
• Subjects who have been treated with chemotherapy, biologic therapy, or other investigational agent within < 5 times the half-life of the agent or < 28 days (whichever is shorter) of starting study drug
• Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C virus (HCV)
• Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine) or systemic steroids
• Ongoing systemic bacterial, fungal, or viral infections at screening * NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not specifically excluded if all other inclusion/exclusion criteria are met
• Administration of a live vaccine within 6 weeks of first dose of study drug
• Administration of any of the following within 2 weeks prior to the administration of study drug: * Strong inhibitors or inducers of CYP3A4, including grapefruit, grapefruit juice and herbal supplements * P-glycoprotein (P-gp) inhibitors * Warfarin, phenytoin, or other substrates of CYP2C8 or CYP2C9 with a narrow therapeutic range * Medications associated with corrected QT (QTc) interval prolongation or Torsades de Pointes
• Baseline QT interval corrected with Fridericia’s method (QTcF) > 480 ms (average of triplicate readings)
• Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g. gastric bypass surgery, gastrectomy)
• Female subjects who are pregnant or breastfeeding
• Concurrent active malignancy other than nonmelanoma skin cancer, carcinoma in situ of the cervix, or prostate intraepithelial neoplasia
• History of peptic ulcer and/or gastrointestinal bleed that have not resolved
• Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the investigator’s judgment, increase the risk to the subject associated with his or her participation in the study