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

Lung Cancer Clinical Trial

— SPARTA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03175224
• Other study ID #: APL-101-01
• Status: Recruiting
• Phase: Phase 2
• Start date: September 27, 2017
• Est. completion date: November 30, 2026

Study information

• Verified date: October 2023
• Source: Apollomics Inc.
• Contact: Vivian Huey
• Phone: 6502094055
• Email: clinops[@]apollomicsinc.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 497
• Est. completion date: November 30, 2026
• Est. primary completion date: March 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Advanced Cancer
• Brain Tumor
• Colon Cancer
• EGFR Gene Mutation
• Gastric Cancer
• Gastroesophageal Junction Adenocarcinoma
• Glioblastoma
• Glioblastoma Multiforme
• Kidney Neoplasms
• Lung Cancer
• Lung Neoplasms
• MET Amplification
• Neoplasms
• NSCLC
• Pancreatic Cancer
• Renal Cancer
• Solid Tumors
• Thyroid Cancer

Intervention

Drug:
• APL-101 Oral Capsules
Subjects will receive APL-101 capsules BID for oral administration.

Locations

Country	Name	City	State
Australia	Border Medical Oncology	Albury
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Peninsula and Southeast Oncology	Frankston
Australia	St Vincents Hospital Melbourne	Melbourne
Australia	Sir Charles Gairdner Hospital	Nedlands
Australia	Calvary Central Districts Hospita	North Adelaide
Canada	Cross Cancer Institute	Edmonton
Canada	Lady Davis Institute for Medical Research Jewish General Hospital	Montreal	Quebec
Canada	McGill University Health Center - Research Institute	Montréal
Canada	Princess Margaret Hospital	Toronto
Canada	Cancer Care Manitoba	Winnipeg
Finland	Tampere University Hospital	Tampere
France	CHRU de Brest - Hôpital Morvan	Brest
France	CHRU de Lille	Lille
France	Centre Leon Berard	Lyon
France	Centre d'Essais Precoces en Cancerologie de Marseille	Marseille
France	Hopital Bichat - Claude Bernard - AP-HP	Paris
France	CHU Rennes - Hopital Pontchaillou	Rennes
France	Gustave Roussy	Villejuif
Hungary	Orszagos Koranyi Pulmonologiai Intezet	Budapest
Hungary	Szent Borbala Korhaz	Tatabanya
Hungary	Torokbalinti Tudogyogyintezet	Torokbalint
Italy	Azienda Ospedaliero-Universitaria delle Marche	Ancona
Italy	IRCCS Azienda Ospedaliero-Universitaria di Bologna - Policlinico di Sant'Orsola	Bologna
Italy	Azienda Ospedaliero Universitaria Policlinico G. Rodolico-San Marco - Presidio Ospedaliero G. Rodolico	Catania
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	IRCCS Ospedale San Raffaele	Milan
Italy	Istituto Europeo di Oncologia	Milano
Italy	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
Puerto Rico	PanOncology Trials, LLC	Rio Piedras
Russian Federation	Arkhangelsk Clinical Oncological Dispensary	Arkhangelsk
Russian Federation	JSC Group of companies Medsi	Otradnoye
Russian Federation	Private Medical Institution Euromedservice	Saint Petersburg
Russian Federation	Saint-Petersburg Clinical Research Center of Specialized Types of Medical Care (Oncology)	Saint Petersburg
Russian Federation	Ogarev Mordovia State University	Saransk
Russian Federation	JSC Current Medical Technologies	St. Petersburg
Russian Federation	Volgograd Regional Clinical Oncology Dispensary	Volgograd
Singapore	National Cancer Centre Singapore	Singapore
Singapore	Oncocare Cancer Centre	Singapore
Singapore	Tan Tock Seng Hospital	Singapore
Spain	Hospital Germans Trias i Pujol	Badalona
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Institut Catala d'Oncologia - L'Hospitalet	Barcelona
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Puerta de Hierro Majadahonda	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Central de Asturias	Oviedo
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Instituto Valenciano de Oncologia	Valencia
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	Chi-Mei Hospital - Liouying Branch	Tainan
Taiwan	National Taiwan University Hospital	Taipei City
Taiwan	Linkou Chang Gung Memorial Hospital (CGMHLK)	Taoyuan City
United Kingdom	Imperial College Healthcare NHS Trust	London
United Kingdom	University College London Hospital	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Royal Marsden Hospital - Surrey	Surrey Quays
United States	The Don & Sybil Harrington Cancer Center	Amarillo	Texas
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Ohio Health Research Institute	Columbus	Ohio
United States	The Ohio State University (OSU)	Columbus	Ohio
United States	Florida Cancer Specialists - South	Fort Myers	Florida
United States	St. Francis Cancer Center	Greenville	South Carolina
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Cedars-Sinai Medical Center - Samuel Oschin Comprehensive Cancer Institute	Los Angeles	California
United States	University of Southern California / Norris Comprehensive Cancer Center	Los Angeles	California
United States	University of Wisconsin	Madison	Wisconsin
United States	Miami Cancer Institute	Miami	Florida
United States	West Virginia University Cancer Institute	Morgantown	West Virginia
United States	Sarah Cannon and HCA Research Institute	Nashville	Tennessee
United States	Christiana Hospital	Newark	Delaware
United States	Kaiser Permanente - CA	Riverside	California
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	HealthPartners Cancer Research Center	Saint Louis Park	Minnesota
United States	Florida Cancer Specialists - North	Saint Petersburg	Florida
United States	UCSF - Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Providence Medical Foundation	Santa Monica	California
United States	Providence St. Joseph Health	Santa Rosa	California
United States	Maryland Oncology Hematology	Silver Spring	Maryland
United States	Florida Cancer Specialists	Tallahassee	Florida
United States	Moffitt	Tampa	Florida
United States	Kaiser Permanente - Vallejo	Vallejo	California
United States	Florida Cancer Specialists	West Palm Beach	Florida
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Apollomics Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Finland,  France,  Hungary,  Italy,  Puerto Rico,  Russian Federation,  Singapore,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective response rate (ORR = CR + PR) per IRC committee (BIRC) based on RECIST v1.1 (or relevant criteria per tumor type)	Anti-tumor activity per RECIST v1.1, RANO criteria for CNS tumors, or relevant evaluation criteria per tumor type.	From time of informed consent signature through completion of treatment (1 cycle = 28 days) or progression
Secondary	Median duration of response (DOR) per IRC.	DOR per RECIST v1.1 criteria, RANO criteria for CNS tumors, or relevant evaluation criteria per tumor type.	Approximately 2 years
Secondary	ORR per investigator assessment based on RECIST v1.1.	ORR per RECIST v1.1 or relevant evaluation criteria per tumor type.	Approximately 2 years
Secondary	Median DOR per investigator assessment.	DOR per RECIST v1.1, RANO criteria for CNS tumors, or relevant evaluation criteria per tumor type.	Approximately 2 years
Secondary	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).	Benefit rate per RECIST v1.1, RANO criteria for CNS tumors, or relevant evaluation criteria per tumor type.	Approximately 2 years
Secondary	Median time to progression (TTP).	TTP per RECIST v1.1 or relevant evaluation criteria per tumor type.	Approximately 2 years
Secondary	Progression Free Survival (PFS) and overall survival (OS) at 6, 12, 18 and 24 months	PFS and OS per RECIST v1.1 or relevant evaluation criteria per tumor type.	Approximately 3 years

External Links

•   Apollomics, Inc. website