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Phase 1/2 Multicenter Study of the Safety, Pharmacokinetics, and Preliminary Efficacy of APL-101 in Subjects with Non-Small Cell Lung Cancer with c-MET EXON 14 Skip Mutations and c-MET Dysregulation Advanced Solid Tumors


Trial ID:NCT03175224

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Protocol #:20-084

877-DF-TRIAL (877-338-7425)

Condition(s):Advanced Cancer, Brain Tumor, Gastric Cancer, Gastroesophageal Junction Adenocarcinoma, Glioblastoma Multiforme, Lung Cancer, NSCLC, Renal Cancer, Solid Tumor


Principal Investigator:Awad, Mark

Site Investigator(s):Costa, Daniel,

Site Research Nurse(s):Aspinwall, Sheridan,
Burke, Millicent,
Drevers, Dawn,
Janell, Samantha,
Kelley, Elaine,
Kelley, Kristina,
Lam, Ethan,
MacLeod, Taylor, H.
Souza, Joseph,

Trial Description:
The primary Phase 1 purpose of this study was to assess overall safety, tolerability and recommended Phase 2 dose (RP2D) of APL-101.

The Phase 2 portion will assess efficacy of the dose determined in Phase 1 in individuals with Non-Small Cell Lung Cancer with c-Met EXON 14 Skip Mutations; individuals with cancers associated with c-Met amplifications; individuals with cancers associated with c-Met fusion

Eligibility Requirements:
Major - Able to understand and comply with study procedures, understand the risks involved, and provide written informed consent.
- For Phase 1, histologically and / or cytological confirmed unresectable or metastatic solid malignancy, refractory to standard therapies with no more than three prior lines of therapy (Completed).
- For Phase 2, seven cohorts will be enrolled:
Cohort A-1: NSCLC EXON 14 skip mutation (c-Met naïve) for first line treatment, Cohort A-2: NSCLC EXON 14 skip mutation (c-Met naïve) pretreated subjects with no more than 3 lines of prior therapy, Cohort B: NSCLC EXON 14 skip mutation (c-Met experienced; radiographic progression on prior c-Met inhibitor), Cohort C: basket of tumor types with c-Met high level amplification (except Primary CNS tumors), Cohort C-1: NSCLC harboring MET amplification and wild-type epidermal growth factor receptor (EGFR) with no more than 3 lines of prior therapy (MET Naive), Cohort D: basket of tumor types except for primary CNS tumors harboring MET gene fusions (e.g., NSCLC, upper GI, colorectal, hepatobiliary cancer). Previously treated; or previously untreated but refused standard treatment, or if treatment was unavailable or unfeasible (≤ 3 prior lines in unresectable or metastatic setting). Met naive, Cohort E: Primary CNS tumors with MET alterations (single or co-occurred MET fusion including PTPRZ1-MET [ZM] fusion, MET Exon 14 skipping mutation, or MET amplification).Previously treated or previously untreated but refused standard treatment, or if treatment was unavailable or unfeasible (≤ 3 prior lines), Met naive.
- Local/archival result (tissue and/or plasma) of a positive c-Met dysregulation is required (except in Cohort A-1 in the US and Cohort C-1).
In Phase 2, provision of either archival or a fresh tumor biopsy sample (if safe and feasible) either from the primary or a metastatic site is required for study entry for Cohorts A-1, A-2, C, C-1, and D.
- Measurable disease according to relevant criteria (RECIST v1.1, RANO for CNS tumors, or other relevant criteria per tumor type).
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and/or Karnofsky Performance Scale (KPS) score.
- For all prior anticancer treatment, including radiotherapy, chemotherapy or targeted agents or hormonal therapy, a duration of more than 30 days or 5 half-lives of the agents used, whichever is shorter, must have elapsed, and any encountered toxicity must have resolved to levels meeting all the other eligibility criteria prior to the first dose of study treatment. Palliative radiotherapy to non-target lesions should be completed within 2 weeks prior to APL-101 administration.
- No planned major surgery within 4 weeks of first dose of APL-101
- Expected survival (life expectancy) ≥ 3 months from C1D1.
Major Exclusion Criteria:
- Hypersensitivity to APL-101, excipients of the drug product, or other components of the study treatment regimen.
- Known actionable mutation/gene rearrangement of EGFR (except for Cohort C), ALK, ROS1, RET, NTRK, KRAS, and BRAF.
- Unstable angina or myocardial infarction within 1 year prior to first dose of APL-101, symptomatic or unstable arrhythmia requiring medical therapy, history of congenital prolonged QT syndrome, prolonged QT interval corrected by Fridericia formula (QTcF) at screening (> 450 msec based on the average of 3 measurements), or concurrent treatment with a medication that is a known risk for prolonging the QT interval.
- Unable to swallow orally administered medication whole.
- Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g., Crohn's, ulcerative colitis, active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
Symptomatic and/or neurologically unstable CNS metastases, or who require an increase in steroid dose to control CNS disease. Subjects who have been receiving a stable steroid dose for at least 2 weeks prior to C1D1 may be allowed.
- Women who are breastfeeding.

Protocol #: 20-084

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