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 or
cytologically confirmed NSCLC with Exon 14 skipping mutations; all histologies;
unresectable or metastatic disease (Stage 3b/4); treatment-naive subjects in
first line; not received any MET inhibitor and no known MET kinase inhibitor
resistance mutations.
- - Cohort A2 / Exon 14 NSCLC - MET inhibitor naïve: Histologically or
cytologically confirmed NSCLC with Exon 14 skipping mutations; all histologies;
unresectable or metastatic disease (Stage 3b/4); pretreated subjects refractory
to or intolerant of standard therapies with no more than three lines of prior
therapy in the unresectable or metastatic setting; not received any MET
inhibitor and no known MET 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:
Any solid tumor type regardless of histology excluding primary CNS tumors, with
MET amplification; 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 of therapy in
the unresectable or metastatic setting; not received any MET inhibitor and no
known MET kinase inhibitor resistance mutations.
- - Cohort C1 / MET amplification and wild-type EGFR NSCLC: NSCLC regardless of
histology, harboring MET amplification and wild-type EGFR; unresectable or
metastatic disease, previously untreated or treated with no more than 3 prior
lines of therapy in the unresectable or metastatic setting; not received any
MET inhibitor and no known MET kinase inhibitor resistance mutations.
- - Cohort C2 / EGFR positive NSCLC with acquired MET amplification (APL-101 Add-on
Therapy): Unresectable or metastatic NSCLC regardless of histology, harboring
EGFR activating mutations with acquired MET-Amplification as resistance
mechanism to the EGFR-I; developed resistance to first-line EGFR-inhibitor
therapy after an initial response (documented PR for at least 12 weeks);
radiological documentation of disease progression per RECIST on first-line EGFR
inhibitor therapy; currently on an EGFR-inhibitor therapy and agrees to receive
APL-101 as an add-on therapy during the study; no history of interstitial lung
disease (ILD)/pneumonitis, Grade ≥3 liver toxicity or QT prolongation with
EGFR-I therapy; not received any MET inhibitor and no known MET kinase
inhibitor resistance mutations.
- - Cohort D / MET fusion basket tumor types excluding primary CNS tumors: any
solid tumor type regardless of histology excluding primary CNS tumors;
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 of therapy in the unresectable or
metastatic setting; not received any MET inhibitor and no known MET kinase
inhibitor resistance mutations.
- - Cohort E / Primary CNS tumors with MET alterations: subjects with primary CNS
tumors who meet inclusion criteria of MET dysregulations defined as single or
co-occurred MET fusion including PTPRZ1-MET (ZM) fusion, MET Exon 14 skipping
mutations, or MET amplification; 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 of therapy in the unresectable or
metastatic setting; not received any MET inhibitor and no known MET kinase
inhibitor resistance mutations; neurological symptoms controlled on a
stable/decreasing dose of steroids for at least 2 weeks before C1D1.
- - Cohort F / Basket tumor types harboring wild-type MET with over-expression of
HGF and MET: any solid tumor type regardless of histology harboring wild-type
MET with 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 of therapy in the unresectable or metastatic setting; not received
any MET inhibitor and no known MET kinase inhibitor resistance mutations.
3. Treated or untreated asymptomatic parenchymal CNS disease or leptomeningeal disease
is allowed.
4. Presence of ≥1 measurable lesion (scan done ≤28 days of C1D1) to serve as target
lesion 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 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.
8. Adequate cardiac function. 9. Women of child-bearing potential must have a negative serum or Beta-hCG at screening
or 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 and
feasible) either from the primary or a metastatic site) or liquid biopsy sample (if
tumor tissue is insufficient or lacking, and approved by the sponsor) is required
for prospective central lab confirmation for study entry (subjects with previously
confirmed molecular status by the Sponsor designated central lab or FDA approved NGS
based 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 of
the study treatment regimen.
2. Known actionable mutation/gene rearrangement of EGFR (except for NSCLC subjects in
Cohort C and C-2), ALK, ROS1, RET, NTRK, KRAS, and BRAF.
3. Use or intended use of any other investigational product, including herbal
medications, through Study Treatment Termination.
4. Active uncontrolled systemic bacterial, viral, or fungal infection or clinically
significant, active disease process, which in the opinion of the investigator makes
the 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's safety or the integrity of the study outcomes, or interfere with the
absorption or metabolism 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
congenital prolonged QT syndrome, prolonged QT interval corrected by Fridericia
formula (QTcF) at screening, or concurrent treatment with a medication that is a
known risk for prolonging 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
with antiviral therapy and human immunodeficiency virus (HIV) positive subjects who
are not clinically stable or controlled on their medication (asymptomatic subjects
with CD4+ T-cell (CD4+) counts ≥ 350 cells/μL and have not had an opportunistic
infection within the 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 confirm eligibility.
8. Known significant mental illness or other conditions such as active alcohol or other
substance abuse that, in the opinion of the investigator, predisposes the subject to
high 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 may
significantly alter drug absorption. 11. Women who are breastfeeding. 12. History of another malignancy within 3 years prior to C1D1. A subject with the
following malignancies is allowed if considered cured or unlikely to recur within 3
years:
1. Carcinoma of the skin without melanomatous features.
2. Curatively treated cervical carcinoma in situ.
3. 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.
13. Subjects who are unable or unwilling to discontinue excluded medications (drugs with
known QTc risk and known strong cytochrome P450 [CYP]3A4 inducer and/or strong
inhibitors) for at least 5 half-lives prior to first dose of study drug. Subjects
may qualify if such medication(s) can be safely replaced with alternate medications
with less risk of drug-drug interaction.
14. Subjects with active COVID-19 infection.
15. 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.
