Title
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

Description
This is a Phase 1/2, multi-center, global, open-label, 2-part study with a Dose Escalation Segment and Dose and Disease Expansion Cohorts study of APL-101, a c-MET inhibitor, to determine the recommended Phase 2 dose (RP2D) and dose limiting toxicities for APL-101, and to obtain preliminary efficacy and target engagement data, in subjects with NSCLC and advanced malignancies with c-Met dysregulation.
c-MET dysregulation will be determined from historical results by molecular pre-screening evaluations to determine eligibility of enrollment for both the Dose Escalation Segment (Phase 1) and Dose and Disease Expansion Cohorts (Phase 2).
Dose escalation will occur until a protocol defined dose limited toxicity (DLT) occurs and a tentative maximum tolerated dose (MTD) is determined.
Once dose is determined, five cohort groups will be further evaluated:

Cohort A-1: NSCLC EXON 14 skip mutation (c-Met naïve, 1L)

Cohort A-2: NSCLC EXON 14 skip mutation (c-Met naïve, 2/3L),

Cohort B: NSCLC EXON 14 skip mutation (c-Met experienced; progressed on prior c-Met inhibitor),

Cohort C: basket of tumor types (with c-Met high-level amplifications),

Cohort D: basket of tumor types (with c-Met fusions)

Objective
Primary Outcome Measures

Estimate the maximum tolerated dose (MTD) and the incidence of DLTs in Phase 1 [ Time Frame: From the time of informed consent signature through Cycle 1 (28 days) completion ]


Adverse events, serious adverse events, and dose limiting toxicities


Objective response rate (ORR = CR + PR) per blinded independent review committee (BIRC) based on RECIST v1.1 (or relevant criteria per tumor type) [ Time Frame: From time of informed consent signature through completion of treatment (1 cycle = 28 days) ]


Anti-tumor activity per RECIST v1.1 or relevant evaluation criteria per tumor type.

Median duration of response (DOR) per BIRC. [ Time Frame: Approximately 2 years ]


DOR per RECIST v1.1 or relevant evaluation criteria per tumor type.


ORR per investigator assessment based on RECIST v1.1. [ Time Frame: Approximately 2 years ]


ORR per RECIST v1.1 or relevant evaluation criteria per tumor type.


Median DOR per investigator assessment. [ Time Frame: Approximately 2 years ]


DOR per RECIST v1.1 or relevant evaluation criteria per tumor type.


Antitumor activity by clinical benefit rate (CR + PR + SD ≥ 4 cycles) based on RECIST v1.1 Median time to progression (TTP). [ Time Frame: Approximately 2 years ]


Benefit rate per RECIST v1.1 or relevant evaluation criteria per tumor type.


Median time to progression (TTP). [ Time Frame: Approximately 2 years ]


TTP per RECIST v1.1 or relevant evaluation criteria per tumor type.


Progression Free Survival (PFS) and overall survival (OS) at 6, 12, 18 and 24 months [ Time Frame: Approximately 3 years ]


PFS and OS per RECIST v1.1 or relevant evaluation criteria per tumor type.

Treatment Experimental: Single-Arm
APL-101 Oral Capsules
Drug: APL-101 Oral Capsules
Phase 1 Subjects will be assigned to a dose level of APL-101 in the order of study entry. Treatment includes 28-day cycles at four planned dose levels (100mg, 200mg, 300mg and 400mg). Each treatment cycle is administered by daily oral capsules taken every 12 hours.
Phase 2 Subjects will be given 400mg daily dose (200mg BID) of APL-101 capsules.
Other Names:

PLB-1001

CBI-3103

Bozitinib

CBT-101

Vebreltinib

Key Eligibility Major Inclusion Criteria:

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.

For Phase 2, five 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 (NSCLC EXON 14 skip mutation excluded), Cohort D: basket of tumor type with c-Met fusions.

Local/archival result (tissue and/or plasma) of a positive c-Met dysregulation is required (except in Cohort A-1 in the US).

Measurable disease according to RECIST v1.1. (or relevant criteria per tumor type).

Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

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

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).

Women who are breastfeeding.

Applicable Disease Sites
Anal; Bladder; Brain/Central Nervous System; Breast; Cervix; Colon and Rectum; Endocrine cancers; Esophagus; Gastrointestinal cancers, other; Genitourinary cancers, other; Head and Neck; Ill-Defined Sites; Kidney; Liver; Lung; Melanoma/Skin cancer; Ovary; Pancreas; Prostate; Sarcoma; Stomach; Thyroid; Unknown Sites; Uterus

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital