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
The primary Phase 1 purpose of this study is to assess overall safety and 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 and c-Met Dysregulation Advanced Solid Tumors
Phase I Primary Objective
To assess overall safety and tolerability, determine the dose limiting toxicities (DLTs), and identify the recommended Phase 2 dose (RP2D).
Phase II Primary Objective:
To assess efficacy by overall response rate (ORR) and duration of response (DOR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. or relevant evaluation criteria per tumor type.
Phase I/II Secondary Objectives:
To assess incidence of serious adverse events (SAEs) and adverse events (AEs) by
relationship and severity grade.
To determine the pharmacokinetic (PK) parameters of orally administered APL-101.
To assess efficacy by clinical benefit rate (CBR: CR + P R + S D ≥ 4 cycles), time to progression (TTP), progression free survival (PFS), per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (or relevant evaluation criteria per tumor type) and overall survival (OS).
Phase I/II Exploratory Objectives:
To evaluate potential pharmacodynamic (PD) biomarkers of APL-101 and its correlation to the PK profile.
To evaluate relationship of relevant biomarkers, including c-Met protein expression, amplification, and/or mutations to clinical response.
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, see full details in protocol
Local/archival result of a positive c-Met dysregulation is required. (except in Cohort A-1 in the US). In Phase 2, Cohorts A-2 and D require provision of tumor tissue samples (archival
or fresh tumor biopsy). For Cohorts B and C, provision of tumor tissue (archival or fresh tumor biopsy) or blood (plasma) sample for entry is acceptable.
In phase 2, treated or untreated asymptomatic arenchymal CNS disease or leptomeningeal disease is allowed.
Measurable disease according to RECIST v1.1. (or relevant criteria per tumor type).
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Accepted organ function as evidenced by laboratory values specified per protocol.
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 targeted/hormonal 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.
Adequate cardiac function or normal cardiac function with left ventricular ejection function (LVEF) greater than of equal to 50% at screening.
Women of child-bearing potential (WOCBP) must have a negative serum or β-human chorionic gonadotropin (β-hCG) at screening or evidence of surgical sterility or evidence of postmenopausal status. Post-menopausal status is defined as any of the following: natural menopause with menses > 1 year ago, radiation or chemotherapy induced oophorectomy with menses > 1 year ago and follicle stimulating hormone (FSH) level in the menopausal range.
All subjects with reproductive potential must agree, and site must document as such, the use of effective contraceptive measures (e.g., oral contraceptives, intrauterine device, or double barrier
method of condom and spermicide) during the study and 7 months (WOCBP) or 4 months (men) following the last dose of study drug.
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, or symptomatic or unstable arrhythmia requiring medical therapy, or history of congenital prolonged QT syndrome or whose corrected QT interval by Fridericia formula (QTcF) at screening is prolonged (> 450 msec based on the average of 3 measurements) or concurrent treatment with any medication that prolongs 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
Patients with complications from prior radiation therapy will not be eligible until AEs return to baseline or ≤ Grade 1.
History of another malignancy within 3 years prior to Cycle 1 Day 1. A subject with the following malignancies is allowed if, in the opinion of the investigator, they do not pose a significant risk to life expectancy: a. Carcinoma of the skin without melanomatous features. b. Curatively treated cervical carcinoma in situ. c. Bladder tumors considered superficial such as noninvasive (T1a) and carcinoma in situ (T1s), thyroid papillary cancer with prior treatment, prostate cancer which has been surgically or medically treated and not likely to recur within 3 years.
Patients who are unable or unwilling to discontinue excluded medications for at least 5 half-lives prior to first dose of study drug.
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