A Phase I/II Trial of APG-115 in Patients With Salivary Gland Carcinoma

This is an open label multi-institution phase I/II study with an initial randomized component
then followed by a planned single-arm phase. Arms will be monitored using the time-to-event
continual reassessment method (TITE-CRM). In the initial randomized phase, patients will be
randomized to one of two arms: Arm A (APG115 alone) or Arm B (APG115 + Carboplatin) at a
ratio of 1:2. After 14 patients have been accrued in Arm A and 28 patients have been accrued
to Arm B, responses will be tabulated. The outcomes of the arms will be considered, and a
single arm will be selected for further study in part 2 of the study. Response rate (defined
as CR or PR after cycle 2) will be the foremost consideration for deciding on the most
promising arm; in addition, a comprehensive evaluation of the available data including
toxicity and PK data will also be considered. After an arm has been chosen to advance an
additional 20 patients will be accrued.

Inclusion Criteria:

- Histologically documented malignant salivary gland cancers 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.

- ECOG performance status of ≤ 1.

- Presence of measurable disease by CT scan per RECIST v1.1 with > 20% increase in tumor
burden in the preceding 12 months.

- 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.

- Adequate organ and marrow function 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 with platinum-based chemotherapy within the last 6 months.

- Patients with active brain metastases are excluded because of unknown penetration into
the 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.

- 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