APG-115 in Salivary Gland Cancer Trial

Study Overview
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Brief Summary
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This is a phase I/II trial to evaluate the efficacy of APG-115 +/- Carboplatin for the treatment p53 wild-type malignant salivary gland cancer. Part 1 consisted of 2 arms, arm A (APG-115 monotherapy) and arm B (APG-115 + Carboplatin) and was terminated early. Part 2 is a single arm study (APG-115 monotherapy).

Detailed Description
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The current single arm study design was originally part of a study with a parallel arm given combination APG-115 + Carboplatin. In the initial phase of that previous iteration, the combination arm was closed early for issues related to tolerability of the combination therapy. This study will continue as a single arm, monotherapy alone, Phase I/II study as approved by the UM Institutional Review Board as of June 2021.

Official Title
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A Multicenter Phase I/II Trial of a Novel MDM2 Inhibitor (APG-115) in p53 Wild-type Salivary Gland Carcinoma

Conditions
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Malignant Salivary Gland Cancer, Salivary Gland Cancer

Intervention / Treatment
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* Drug: APG-115
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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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 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 Patients must be able to take oral medication without breaking/opening, crushing, dissolving, or chewing capsules 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 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 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 Women who are pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part 1 -- Parallel assignment [terminated early]: Arm A: APG-115 Monotherapy Arm B: APG-115 + Carboplatin Part 2 -- Single arm (Arm A only): APG-115 Monotherapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APG-115 monotherapy<br>APG-115 will be administered in an open label fashion until progression, intolerance, or patient preference. | Drug: APG-115<br>* APG-115 at 150mg (or lower, if dose is reduced) is taken orally every other day through day 13 of each cycle. Cycle length 21 days.<br>|
| Experimental: APG-115 + Carboplatin [terminated]<br>APG-115 and Carboplatin will be administered in an open label fashion until progression, intolerance, or patient preference. [Phase 1 was terminated early and this arm was discontinued. An MTD was not established during Phase 1.] | Drug: APG-115<br>* APG-115 at 150mg (or lower, if dose is reduced) is taken orally every other day through day 13 of each cycle. Cycle length 21 days.<br>Drug: Carboplatin<br>* Carboplatin is given IV at AUC=4.5 on day 1 of each cycle. Cycle length 21 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Toxicity Endpoint: dose-limiting toxicity (DLT) | DLT will be defined based on the rate of drug-related grade 3-5 adverse events experienced within the first 6 weeks (2 cycles) of study treatment. These will be assessed via CTCAE version 5.0 | 42 days | 
| Maximally tolerated dose (MTD) | MTD will be determined based on DLTs observed during the first 6 weeks (2 cycles) of study treatment. | 42 days | 
| Overall response rate | Overall response rate will be defined as the proportion of patients achieving either complete response (CR) or partial response (PR). Response will be assessed via RECIST v1.1. | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate by tumor histology | Overall response rate will be defined as the proportion of patients achieving either complete response (CR) or partial response (PR), assessed via RECIST v1.1 and reported separately for those with histologically confirmed adenoid cystic carcinoma (ACC) versus other malignant salivary gland tumors (non-ACC) | Until death or end of study; up to approximately 5 years | 
| Duration of response | The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started. | Until death or end of study; up to approximately 5 years | 
| Progression-free survival | Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever is earlier. | Until death or end of study; up to approximately 5 years | 
| Overall survival | Overall survival (OS) is defined as the duration of time from start of treatment to time of death or end of study. | Until death or end of study; up to approximately 5 years | 
| Disease control rate | Defined as the proportion of patients achieving complete response (CR), partial response (PR), or stable disease (SD). Response will be assessed via RECIST v1.1 | Until death or end of study; up to approximately 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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p53 wild-type, Adenoid cystic carcinoma