APL-101 Study of Subjects With NSCLC With c-Met EXON 14 Skip Mutations and c-Met Dysregulation Advanced Solid Tumors

Major Inclusion Criteria:

1. Men and women 18 years of age or older.
2. 9 cohorts will be enrolled:

• Cohort A1 / Exon 14 NSCLC MET inhibitor naive in first line: Histologically orcytologically confirmed NSCLC with Exon 14 skipping mutations; all histologies;unresectable or metastatic disease (Stage 3b/4); treatment-naive subjects infirst line; not received any MET inhibitor and no known MET kinase inhibitorresistance mutations
• Cohort A2 / Exon 14 NSCLC - MET inhibitor naïve: Histologically or cytologicallyconfirmed NSCLC with Exon 14 skipping mutations; all histologies; unresectable ormetastatic disease (Stage 3b/4); pretreated subjects refractory to or intolerantof standard therapies with no more than three lines of prior therapy in theunresectable or metastatic setting; not received any MET inhibitor and no knownMET kinase inhibitor resistance mutations
• Cohort B / Exon 14 NSCLC MET inhibitor experienced: ENROLLMENT COMPLETED
• Cohort C / MET amplification basket tumor types excluding primary CNS tumors: Anysolid tumor type regardless of histology excluding primary CNS tumors, with METamplification; unresectable or metastatic disease, refractory to or intolerant ofstandard therapies, or refused standard therapies, or if therapy was unavailableor unfeasible, with no more than 3 prior lines of therapy in the unresectable ormetastatic setting; not received any MET inhibitor and no known MET kinaseinhibitor resistance mutations
• Cohort C1 / MET amplification and wild-type EGFR NSCLC: NSCLC regardless ofhistology, harboring MET amplification and wild-type EGFR; unresectable ormetastatic disease, previously untreated or treated with no more than 3 priorlines of therapy in the unresectable or metastatic setting; not received any METinhibitor and no known MET kinase inhibitor resistance mutations
• Cohort C2 / EGFR positive NSCLC with acquired MET amplification (APL-101 Add-onTherapy): Unresectable or metastatic NSCLC regardless of histology, harboringEGFR activating mutations with acquired MET-Amplification as resistance mechanismto the EGFR-I; developed resistance to first-line EGFR-inhibitor therapy after aninitial response (documented PR for at least 12 weeks); radiologicaldocumentation of disease progression per RECIST on first-line EGFR inhibitortherapy; currently on an EGFR-inhibitor therapy and agrees to receive APL-101 asan add-on therapy during the study; no history of interstitial lung disease (ILD)/pneumonitis, Grade ≥3 liver toxicity or QT prolongation with EGFR-Itherapy; not received any MET inhibitor and no known MET kinase inhibitorresistance mutations
• Cohort D / MET fusion basket tumor types excluding primary CNS tumors: any solidtumor type regardless of histology excluding primary CNS tumors; unresectable ormetastatic disease, refractory to or intolerant of standard therapies, or refusedstandard therapies, or if therapy was unavailable or unfeasible, with no morethan 3 prior lines of therapy in the unresectable or metastatic setting; notreceived any MET inhibitor and no known MET kinase inhibitor resistance mutations
• Cohort E / Primary CNS tumors with MET alterations: subjects with primary CNStumors who meet inclusion criteria of MET dysregulations defined as single orco-occurred MET fusion including PTPRZ1-MET (ZM) fusion, MET Exon 14 skippingmutations, or MET amplification; refractory to or intolerant of standardtherapies, or refused standard therapies, or if therapy was unavailable orunfeasible, with no more than 3 prior lines of therapy in the unresectable ormetastatic setting; not received any MET inhibitor and no known MET kinaseinhibitor resistance mutations; neurological symptoms controlled on astable/decreasing dose of steroids for at least 2 weeks before C1D1
• Cohort F / Basket tumor types harboring wild-type MET with over-expression of HGFand MET: any solid tumor type regardless of histology harboring wild-type METwith overexpression of HGF and MET; Unresectable or metastatic disease,refractory to or intolerant of standard therapies, or refused standard therapies,or if therapy was unavailable or unfeasible, with no more than 3 prior lines oftherapy in the unresectable or metastatic setting; not received any MET inhibitorand no known MET kinase inhibitor resistance mutations

3. Treated or untreated asymptomatic parenchymal CNS disease or leptomeningeal disease isallowed.
4. Presence of ≥1 measurable lesion (scan done ≤28 days of C1D1) to serve as targetlesion according to relevant criteria
5. ECOG performance status of 0-1. For subjects with primary CNS tumors, KPS score ≥70.
6. Acceptable organ function
7. For all prior anticancer treatment, a duration of 30 days or 5 half-lives of theagents used, whichever is shorter, must have elapsed, and any encountered toxicitymust have resolved to levels meeting all the other eligibility criteria prior to thefirst dose of study treatment. Palliative radiotherapy to non-target lesions should becompleted within 2 weeks prior to APL-101 administration.
8. Adequate cardiac function
9. Women of child-bearing potential must have a negative serum or Beta-hCG at screeningor evidence of surgical sterility or evidence of post-menopausal status
10. No planned major surgery within 4 weeks of first dose of APL-101
11. Expected survival (life expectancy) ≥ 3 months from C1D1
12. Provision of sample; e.g. archival or a fresh tumor biopsy sample (if safe andfeasible) either from the primary or a metastatic site) or liquid biopsy sample (iftumor tissue is insufficient or lacking, and approved by the sponsor) is required forprospective central lab confirmation for study entry (subjects with previouslyconfirmed molecular status by the Sponsor designated central lab or FDA approved NGSbased MET testing may be exempted, subjected to Sponsor approval.

Major Exclusion Criteria:

1. Hypersensitivity to APL-101, excipients of the drug product, or other components ofthe study treatment regimen.
2. Known actionable mutation/gene rearrangement of EGFR (except for NSCLC subjects inCohort C and C-2), ALK, ROS1, RET, NTRK, KRAS, and BRAF.
3. Use or intended use of any other investigational product, including herbalmedications, through Study Treatment Termination.
4. Active uncontrolled systemic bacterial, viral, or fungal infection or clinicallysignificant, active disease process, which in the opinion of the investigator makesthe risk: benefit unfavorable for the participation of the trial.
5. Life-threatening illness, significant organ system dysfunction or comorbid conditions,or other reasons that, in the investigator's opinion, could compromise the subject'ssafety or the integrity of the study outcomes, or interfere with the absorption ormetabolism of APL-101.
6. Unstable angina or myocardial infarction within 1 year prior to first dose of APL-101,symptomatic or unstable arrhythmia requiring medical therapy, history of congenitalprolonged QT syndrome, prolonged QT interval corrected by Fridericia formula (QTcF) atscreening, or concurrent treatment with a medication that is a known risk forprolonging the QT interval. Chronic controlled atrial fibrillation is not excluded.
7. Historical seropositive results consistent with active infection for hepatitis C virus (HCV) or hepatitis B virus (HBV) with high viral loads not actively managed withantiviral therapy and human immunodeficiency virus (HIV) positive subjects who are notclinically stable or controlled on their medication (asymptomatic subjects with CD4+T-cell (CD4+) counts ≥ 350 cells/μL and have not had an opportunistic infection withinthe past 12 months prior to first dose of APL-101 would be eligible for study entry.If history is unclear, relevant test(s) at Screening will be required to confirmeligibility.
8. Known significant mental illness or other conditions such as active alcohol or othersubstance abuse that, in the opinion of the investigator, predisposes the subject tohigh risk of noncompliance with the protocol treatment or assessments.
9. Unable to swallow orally administered medication whole.
10. Impairment of gastrointestinal function or gastrointestinal disease that maysignificantly alter drug absorption
11. Women who are breastfeeding
12. History of another malignancy within 3 years prior to C1D1. A subject with thefollowing malignancies is allowed if considered cured or unlikely to recur within 3years:
13. Carcinoma of the skin without melanomatous features.
14. Curatively treated cervical carcinoma in situ.
15. Bladder tumors considered superficial such as noninvasive (T1a) and carcinoma insitu (T1s), thyroid papillary cancer with prior treatment, prostate cancer whichhas been surgically or medically treated and not likely to recur within 3 years.
16. Subjects who are unable or unwilling to discontinue excluded medications (drugs withknown QTc risk and known strong cytochrome P450 [CYP]3A4 inducer and/or stronginhibitors) for at least 5 half-lives prior to first dose of study drug. Subjects mayqualify if such medication(s) can be safely replaced with alternate medications withless risk of drug-drug interaction.
17. Subjects with active COVID-19 infection.
18. Symptomatic and/or neurologically unstable CNS metastases, or who require an increasein steroid dose to control CNS disease. Subjects who have been receiving a stablesteroid dose for at least 2 weeks prior to C1D1 may be allowed.