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

Phase 2

Recruiting

• Conditions: Gastroesophageal Junction Adenocarcinoma; NSCLC; Lung Cancer; Brain Tumor; Glioblastoma Multiforme; EGFR Gene Mutation; Solid Tumors; Advanced Cancer; Renal Cancer; MET Alteration
• Interventions: Drug: APL-101 Oral Capsules

• Registration Number: NCT03175224
• Lead Sponsor: Apollomics Inc.

Brief Summary

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)

Detailed Description

Phase 1 (lead-in stage of this study) enrollment has been completed.

In this Phase 2 study, efficacy, safety, and tolerability will be assessed in the following cohorts:

* Cohort A-1: NSCLC EXON 14 skip mutation, previously untreated, MET inhibitor naive (c-Met naïve, 1L)

* Cohort A-2: NSCLC EXON 14 skip mutation, previously treated with ≤ 3 prior lines in unresectable or metastatic setting, MET inhibitor naive (c-Met naïve, 2/3L)

* Cohort B: NSCLC EXON 14 skip mutation, previously treated with ≤ 3 prior lines in unresectable or metastatic setting, MET inhibitor experienced (c-Met experienced; progressed on prior c-Met inhibitor)

* Cohort C: basket of tumor types (e.g., NSCLC, upper gastrointestinal \[GI\], colorectal, hepatobiliary cancer) harboring MET amplification except for primary CNS tumors, previously treated or previously untreated but refused standard treatment, or if treatment was unavailable or unfeasible (≤ 3 prior lines in unresectable or metastatic setting), MET inhibitor naïve

* Cohort C-1: NSCLC harboring MET amplification and wild-type epidermal growth factor receptor (EGFR), previously treated; or untreated but refused standard treatment, or if treatment was unavailable or unfeasible (≤ 3 prior lines in unresectable or metastatic setting), MET inhibitor naïve

* Cohort C-2: EGFR positive NSCLC harboring MET amplification as an acquired resistance, documented response with first-line EGFR-Inhibitor (PR or CR per RECIST ≥ 12 weeks), radiological documentation of disease progression per RECIST on first-line EGFR inhibitor therapy, MET inhibitor naïve

* Cohort D: basket of tumor types except for primary CNS tumors harboring MET gene fusions (e.g., NSCLC, upper GI, colorectal, hepatobiliary cancer), previously treated; or previously untreated but refused standard treatment, or if treatment was unavailable or unfeasible (≤ 3 prior lines in unresectable or metastatic setting), MET inhibitor naïve

* Cohort E: primary CNS tumors with MET alterations (single or co-occurred MET fusion including PTPRZ1-MET \[ZM\] fusion, MET Exon 14 skipping mutation, or MET amplification), previously treated or previously untreated but refused standard treatment, or if treatment was unavailable or unfeasible (≤ 3 prior lines), MET inhibitor naïve

* Cohort F: basket of tumor types harboring wild-type MET with over-expression of HGF and MET (e.g., NSCLC, upper GI, colorectal, hepatobiliary cancer or primary CNS tumors), previously treated; or previously untreated but refused standard treatment, or if treatment was unavailable or unfeasible (≤ 3 prior lines in unresectable or metastatic setting), MET inhibitor naïve

Study Timeline

• Study First Submitted: 2017-06-01
• Study First Submitted QC: 2017-06-01
• Study First Posted: 2017-06-05
• Study Start: 2017-09-27
• Status Verified: 2023-10
• Last Update Submitted: 2024-05-08
• Last Update Posted: 2024-05-10
• Primary Completion: 2026-03-30
• Study Completion: 2026-11-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 497

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Basket of tumor types MET amplification except for primary CNS tumors	APL-101 Oral Capsules	Cohort C: APL-101 Oral Capsules
NSCLC Exon 14 Skip Treatment Naive	APL-101 Oral Capsules	Cohort A-1: APL-101 Oral Capsules
NSCLC Exon 14 Skip Previously Treated	APL-101 Oral Capsules	Cohort A-2: APL-101 Oral Capsules
NSCLC Exon 14 MET Inhibitor Experienced	APL-101 Oral Capsules	Cohort B: APL-101 Oral Capsules
NSCLC MET amplification and EGFR wild-type	APL-101 Oral Capsules	Cohort C-1: APL-101 Oral Capsules
EGFR positive NSCLC MET amplification as an acquired resistance	APL-101 Oral Capsules	Cohort C-2: APL-101 Oral Capsules + Standard of Care EGFR Inhibitor
Basket of solid tumor with MET gene fusions except for primary CNS tumors	APL-101 Oral Capsules	Cohort D: APL-101 Oral Capsules
Primary CNS tumors with MET alterations	APL-101 Oral Capsules	Cohort E: APL-101 Oral Capsules
Basket of tumor types wild-type MET with over-expression of HGF and MET	APL-101 Oral Capsules	Cohort F: APL-101 Oral Capsules

Primary Outcome Measures

Name	Time	Method
Objective response rate (ORR = CR + PR) per IRC committee (BIRC) based on RECIST v1.1 (or relevant criteria per tumor type)	From time of informed consent signature through completion of treatment (1 cycle = 28 days) or progression	Anti-tumor activity per RECIST v1.1, RANO criteria for CNS tumors, or relevant evaluation criteria per tumor type.

Secondary Outcome Measures

Name	Time	Method
ORR per investigator assessment based on RECIST v1.1.	Approximately 2 years	ORR per RECIST v1.1 or relevant evaluation criteria per tumor type.
Median duration of response (DOR) per IRC.	Approximately 2 years	DOR per RECIST v1.1 criteria, RANO criteria for CNS tumors, or relevant evaluation criteria per tumor type.
Median DOR per investigator assessment.	Approximately 2 years	DOR per RECIST v1.1, RANO criteria for CNS tumors, or relevant evaluation criteria per tumor type.
Antitumor activity by clinical benefit rate (CR + PR + SD ≥ 4 cycles) based on RECIST v1.1, RANO criteria for CNS tumors, or other relevant criteria per tumor type Median time to progression (TTP).	Approximately 2 years	Benefit rate per RECIST v1.1, RANO criteria for CNS tumors, or relevant evaluation criteria per tumor type.
Median time to progression (TTP).	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	Approximately 3 years	PFS and OS per RECIST v1.1 or relevant evaluation criteria per tumor type.

Trial Locations

Locations (90)

Loma Linda University Medical Center; 🇺🇸 Loma Linda, California, United States

West Virginia University Cancer Institute; 🇺🇸 Morgantown, West Virginia, United States

Ohio Health Research Institute; 🇺🇸 Columbus, Ohio, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Oncocare Cancer Centre; 🇸🇬 Singapore, Singapore

PanOncology Trials, LLC; 🇵🇷 Rio Piedras, Puerto Rico

Tan Tock Seng Hospital; 🇸🇬 Singapore, Singapore

Cedars-Sinai Medical Center - Samuel Oschin Comprehensive Cancer Institute; 🇺🇸 Los Angeles, California, United States

Providence St. Joseph Health; 🇺🇸 Santa Rosa, California, United States

Kaiser Permanente - CA; 🇺🇸 Riverside, California, United States

Kaiser Permanente - Vallejo; 🇺🇸 Vallejo, California, United States

Christiana Hospital; 🇺🇸 Newark, Delaware, United States

Maryland Oncology Hematology; 🇺🇸 Silver Spring, Maryland, United States

Florida Cancer Specialists; 🇺🇸 West Palm Beach, Florida, United States

Florida Cancer Specialists - South; 🇺🇸 Fort Myers, Florida, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

HealthPartners Cancer Research Center; 🇺🇸 Saint Louis Park, Minnesota, United States

St Vincents Hospital Melbourne; 🇦🇺 Melbourne, Australia

Calvary Central Districts Hospita; 🇦🇺 North Adelaide, Australia

Lady Davis Institute for Medical Research Jewish General Hospital; 🇨🇦 Montreal, Quebec, Canada

Cancer Care Manitoba; 🇨🇦 Winnipeg, Canada

CHRU de Brest - Hôpital Morvan; 🇫🇷 Brest, France

McGill University Health Center - Research Institute; 🇨🇦 Montréal, Canada

Princess Margaret Hospital; 🇨🇦 Toronto, Canada

IRCCS Azienda Ospedaliero-Universitaria di Bologna - Policlinico di Sant'Orsola; 🇮🇹 Bologna, Italy

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori; 🇮🇹 Meldola, Italy

CHU Rennes - Hopital Pontchaillou; 🇫🇷 Rennes, France

JSC Current Medical Technologies; 🇷🇺 St. Petersburg, Russian Federation

Chi-Mei Hospital - Liouying Branch; 🇨🇳 Tainan, Taiwan

Linkou Chang Gung Memorial Hospital (CGMHLK); 🇨🇳 Taoyuan City, Taiwan

Royal Marsden Hospital - Surrey; 🇬🇧 Surrey Quays, United Kingdom

Hospital Clinic Barcelona; 🇪🇸 Barcelona, Spain

Hospital del Mar; 🇪🇸 Barcelona, Spain

Arkhangelsk Clinical Oncological Dispensary; 🇷🇺 Arkhangelsk, Russian Federation

JSC Group of companies Medsi; 🇷🇺 Otradnoye, Russian Federation

Institut Catala d'Oncologia - L'Hospitalet; 🇪🇸 Barcelona, Spain

Hospital Germans Trias i Pujol; 🇪🇸 Badalona, Spain

National Taiwan University Hospital; 🇨🇳 Taipei City, Taiwan

Hospital Universitario Central de Asturias; 🇪🇸 Oviedo, Spain

Imperial College Healthcare NHS Trust; 🇬🇧 London, United Kingdom

Miami Cancer Institute; 🇺🇸 Miami, Florida, United States

Sarah Cannon and HCA Research Institute; 🇺🇸 Nashville, Tennessee, United States

Azienda Ospedaliero-Universitaria delle Marche; 🇮🇹 Ancona, Italy

Azienda Ospedaliero Universitaria Policlinico G. Rodolico-San Marco - Presidio Ospedaliero G. Rodolico; 🇮🇹 Catania, Italy

Istituto Europeo di Oncologia; 🇮🇹 Milano, Italy

IRCCS Ospedale San Raffaele; 🇮🇹 Milan, Italy

University College London Hospital; 🇬🇧 London, United Kingdom

Centre Leon Berard; 🇫🇷 Lyon, France

Ogarev Mordovia State University; 🇷🇺 Saransk, Russian Federation

Volgograd Regional Clinical Oncology Dispensary; 🇷🇺 Volgograd, Russian Federation

Moffitt; 🇺🇸 Tampa, Florida, United States

Wake Forest University Health Sciences; 🇺🇸 Winston-Salem, North Carolina, United States

UCSF - Helen Diller Family Comprehensive Cancer Center; 🇺🇸 San Francisco, California, United States

Providence Medical Foundation; 🇺🇸 Santa Monica, California, United States

Florida Cancer Specialists - North; 🇺🇸 Saint Petersburg, Florida, United States

The Ohio State University (OSU); 🇺🇸 Columbus, Ohio, United States

St. Francis Cancer Center; 🇺🇸 Greenville, South Carolina, United States

Peninsula and Southeast Oncology; 🇦🇺 Frankston, Australia

Sir Charles Gairdner Hospital; 🇦🇺 Nedlands, Australia

Tampere University Hospital; 🇫🇮 Tampere, Finland

Centre d'Essais Precoces en Cancerologie de Marseille; 🇫🇷 Marseille, France

Hopital Bichat - Claude Bernard - AP-HP; 🇫🇷 Paris, France

Torokbalinti Tudogyogyintezet; 🇭🇺 Torokbalint, Hungary

Szent Borbala Korhaz; 🇭🇺 Tatabanya, Hungary

Istituto Oncologico Veneto-I.R.C.C.S. - Ospedale Busonera; 🇮🇹 Padova, Italy

AOU Citta della Salute e della Scienza di Torino - Ospedale le Molinette; 🇮🇹 Torino, Italy

Hospital Universitario Puerta de Hierro Majadahonda; 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Hospital Universitario Ramon y Cajal; 🇪🇸 Madrid, Spain

Taichung Veterans General Hospital; 🇨🇳 Taichung, Taiwan

The Christie NHS Foundation Trust; 🇬🇧 Manchester, United Kingdom

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

Hospital General Universitario Gregorio Maranon; 🇪🇸 Madrid, Spain

University of Southern California / Norris Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

Gustave Roussy; 🇫🇷 Villejuif, France

Penn State Milton S. Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

Border Medical Oncology; 🇦🇺 Albury, Australia

The Don & Sybil Harrington Cancer Center; 🇺🇸 Amarillo, Texas, United States

Flinders Medical Centre; 🇦🇺 Bedford Park, South Australia, Australia

University of Wisconsin; 🇺🇸 Madison, Wisconsin, United States

Saint-Petersburg Clinical Research Center of Specialized Types of Medical Care (Oncology); 🇷🇺 Saint Petersburg, Russian Federation

Cross Cancer Institute; 🇨🇦 Edmonton, Canada

CHRU de Lille; 🇫🇷 Lille, France

Private Medical Institution Euromedservice; 🇷🇺 Saint Petersburg, Russian Federation

Hospital Universitario Virgen del Rocio; 🇪🇸 Sevilla, Spain

Instituto Valenciano de Oncologia; 🇪🇸 Valencia, Spain

Orszagos Koranyi Pulmonologiai Intezet; 🇭🇺 Budapest, Hungary

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

National Cancer Centre Singapore; 🇸🇬 Singapore, Singapore

University of North Carolina; 🇺🇸 Chapel Hill, North Carolina, United States