A Novel MDM2 Inhibitor (APG-115) for the Treatment of p53 Wild-Type Salivary Gland Cancer

Inclusion Criteria

• Histologically documented malignant salivary gland cancers (including secretory glands of the aerodigestive tract) with or without metastases, not amenable to curative treatment; or there is documentation of patient refusal of curative treatment.
• Previous mutational testing with no evidence of a p53 mutation.
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 1.
• Presence of measurable disease by CT scan per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 with >= 20% increase in tumor burden in the preceding 12 months.
• Age >= 18 years.
• Life expectancy of >= 12 weeks.
• Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment.
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
• Patients must be able to take oral medication without breaking/opening, crushing, dissolving or chewing capsules.
• White blood cells (WBC) >= 3 x 10^9 cells/mL (obtained =< 2 weeks prior to enrollment).
• Absolute neutrophil count (ANC) >= 1.5 x 10^9 cells/mL (obtained =< 2 weeks prior to enrollment).
• Hemoglobin >= 9 g/dL (obtained =< 2 weeks prior to enrollment).
• Platelets >= 100,000 cells/mm^3 (obtained =< 2 weeks prior to enrollment).
• Total serum bilirubin within 1.5 x upper limit of normal (ULN) (obtained =< 2 weeks prior to enrollment), unless the patient has documented Gilberts syndrome.
• Aspartate aminotransferase (AST) within 2.5 x ULN (obtained =< 2 weeks prior to enrollment) unless there are liver metastases in which case, AST within 5 x ULN.
• Alanine aminotransferase (ALT) within 2.5 x ULN (obtained =< 2 weeks prior to enrollment) unless there are liver metastases in which case, ALT within 5 x ULN.
• Serum creatinine clearance >= 30 mL/min (obtained =< 2 weeks prior to enrollment).
• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN or partial thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder) (obtained =< 2 weeks prior to enrollment). When treated with warfarin or other vitamin K antagonists, then INR =< 3.0.
• Fridericia corrected QT interval (QTc) =< 450 milliseconds in male and =< 470 milliseconds in female on screening electrocardiogram (ECG) (obtained =< 2 weeks prior to enrollment).

Exclusion Criteria

• Prior treatment with MDM2 inhibitors.
• Patients are not eligible if they have received any systemic anti-cancer therapy (including chemotherapy and/or hormone therapy) for salivary gland cancer within 4 weeks of the start of study therapy.
• Patients are not eligible if they have received any of the following within 4 weeks of the start of study therapy: live vaccines, antiretroviral drugs.
• Progressive disease within 6 months of the last dose of platinum-based chemotherapy.
• Patients with active brain metastases are excluded because of unknown penetration into the central nervous system (CNS). A confirmatory scan for asymptomatic patients is not required. Patients with a history of treated central nervous system (CNS) metastases are eligible provided they meet all of the following criteria: disease outside the CNS is present, no clinical evidence of progression since completion of CNS-directed therapy, minimum 4 weeks between completion of radiotherapy and enrollment and recovery from significant (grade >= 3) acute toxicity.
• Patients have received the following within 7 days prior to the first dose of the study drug: * CYP3A4 inhibitor such as clarithromycin, itraconazole, ketoconazole, grapefruit juice, indinavir, nelfinavir, ritonavir, nefazodone, saquinavir, and telithromycin * P-gp inhibitor such as amiodarone, carvedilol, propafenone, quinidine, verapamil, ranolazine and ritonavir
• Patients have received any of the following within 25 days of the start of study therapy: CYP3A4 inducer such as rifampin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John's wort. The Sponsor-Investigator should be contacted if there are any questions regarding concomitant or prior therapy; concomitant medication may be considered on a case-by-case basis by the investigator in consultation with the sponsor-investigator.
• A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment.
• Patients (male and female) having procreative potential who are not willing or not able to use 2 adequate methods of contraception or practicing abstinence during the study and for 90 days following their last dose of treatment. Adequate contraception is defined as: * Total abstinence or * Male or female sterilization or * Combination of any two of the following: ** Use of oral, injected or implanted hormonal methods of contraception ** Placement of an intrauterine device (IUD) or intrauterine system (IUS) ** Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
• Women who are pregnant or breast-feeding.
• Patients residing in prison.
• Availability of curative treatment option for the patient’s cancer, whether surgery, chemotherapy, radiation, or combination thereof, unless there is documentation of patient refusal of curative treatment.