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

ENROLLING
Protocol # :
20-084
Conditions
Solid Tumors
Advanced Cancer
Renal Cancer
Gastric Cancer
Gastroesophageal Junction Adenocarcinoma
NSCLC
Lung Cancer
Brain Tumor
Glioblastoma Multiforme
EGFR Gene Mutation
MET Amplification
HGF
Thyroid Cancer
Pancreatic Cancer
Colon Cancer
MET Alteration
MET Fusion
Exon 14 Skipping
Phase
I/II
Disease Sites
Neuroendocrine/Carcinoid
Gastroesophageal Junction
Gallbladder/Biliary
Lip, Oral Cavity and Pharynx
Esophagus
Stomach
Small Intestine
Colon
Rectum
Anus
Liver
Pancreas
Other Digestive Organ
Larynx
Lung
Other Respiratory and Intrathoracic Organs
Bones and Joints
Soft Tissue
Mycosis Fungoides
Other Skin
Breast
Cervix
Corpus Uteri
Ovary
Other Female Genital
Prostate
Other Male Genital
Urinary Bladder
Kidney
Other Urinary
Eye and Orbit
Brain and Nervous System
Thyroid
Unknown Sites
Ill-Defined Sites
Other Endocrine System
Kaposi's Sarcoma
Melanoma, Skin
Principal Investigator
Awad, Mark
Site Investigator
Costa, Daniel
Site Research Nurses
Aspinwall, Sheridan
Burke, Millicent
Drevers, Dawn
Janell, Samantha
Kelley, Elaine
Kelley, Kristina
Lam, Ethan
MacLeod, Taylor, H.
Souza, Joseph

Trial Description

To assess:

- efficacy of APL-101 as monotherapy for the treatment of NSCLC harboring MET Exon 14
skipping mutations, NSCLC harboring MET amplification, solid tumors harboring MET
amplification, solid tumors harboring MET fusion, primary CNS tumors harboring MET
alterations, solid tumors harboring wild-type MET with overexpression of HGF and MET

- efficacy of APL-101 as an add-on therapy to EGFR inhibitor for the treatment of NSCLC
harboring EGFR activating mutations and developed acquired resistance with MET
amplification and disease progression after documented CR or PR with 1st line EGFR
inhibitors (EGFR-I)

Eligibility Requirements

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.

20-084