Clinical trial NCT03175224: APL-101 Study of Subjects With NSCLC With c-Met EXON 14 Skip Mutations and c-Met Dysregulation Advanced Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
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
Keywords: Advanced Solid Tumor
Relapsed Solid Tumor
Recurrent Solid Tumor
cMet exon 14 skipping
cMet fusion
GBM
HGF
EGFR positive
Lead sponsor: Apollomics Inc.
Sponsor class: INDUSTRY
First posted: 2017-06-05
Enrollment: 497
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: Objective response rate (ORR = CR + PR) per IRC committee (BIRC) based on RECIST v1.1 (or relevant criteria per tumor type)
timeFrame: From time of informed consent signature through completion of treatment (1 cycle = 28 days) or progression
Secondary outcomes:
measure: Median duration of response (DOR) per IRC.
timeFrame: Approximately 2 years
measure: ORR per investigator assessment based on RECIST v1.1.
timeFrame: Approximately 2 years
measure: Median DOR per investigator assessment.
timeFrame: Approximately 2 years
measure: 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).
timeFrame: Approximately 2 years
measure: Median time to progression (TTP).
timeFrame: Approximately 2 years
measure: Progression Free Survival (PFS) and overall survival (OS) at 6, 12, 18 and 24 months
timeFrame: Approximately 3 years
Other outcomes:
Locations:
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California / Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center - Samuel Oschin Comprehensive Cancer Institute
state: California
city: Riverside
country: United States
facility: Kaiser Permanente - CA
state: California
city: San Francisco
country: United States
facility: UCSF - Helen Diller Family Comprehensive Cancer Center
state: California
city: Santa Monica
country: United States
facility: Providence Medical Foundation
state: California
city: Santa Rosa
country: United States
facility: Providence St. Joseph Health
state: California
city: Vallejo
country: United States
facility: Kaiser Permanente - Vallejo
state: California
city: Newark
country: United States
facility: Christiana Hospital
state: Delaware
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - South
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists - North
state: Florida
city: Tallahassee
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Tampa
country: United States
facility: Moffitt
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Silver Spring
country: United States
facility: Maryland Oncology Hematology
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis Park
country: United States
facility: HealthPartners Cancer Research Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University (OSU)
state: Ohio
city: Columbus
country: United States
facility: Ohio Health Research Institute
state: Ohio
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Greenville
country: United States
facility: St. Francis Cancer Center
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Amarillo
country: United States
facility: The Don & Sybil Harrington Cancer Center
state: Texas
city: Morgantown
country: United States
facility: West Virginia University Cancer Institute
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Albury
country: Australia
facility: Border Medical Oncology
city: Frankston
country: Australia
facility: Peninsula and Southeast Oncology
city: Melbourne
country: Australia
facility: St Vincents Hospital Melbourne
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
city: North Adelaide
country: Australia
facility: Calvary Central Districts Hospita
city: Montreal
country: Canada
facility: Lady Davis Institute for Medical Research Jewish General Hospital
state: Quebec
city: Edmonton
country: Canada
facility: Cross Cancer Institute
city: Montréal
country: Canada
facility: McGill University Health Center - Research Institute
city: Toronto
country: Canada
facility: Princess Margaret Hospital
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Brest
country: France
facility: CHRU de Brest - Hôpital Morvan
city: Lille
country: France
facility: CHRU de Lille
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Centre d'Essais Precoces en Cancerologie de Marseille
city: Paris
country: France
facility: Hopital Bichat - Claude Bernard - AP-HP
city: Rennes
country: France
facility: CHU Rennes - Hopital Pontchaillou
city: Villejuif
country: France
facility: Gustave Roussy
city: Budapest
country: Hungary
facility: Orszagos Koranyi Pulmonologiai Intezet
city: Tatabanya
country: Hungary
facility: Szent Borbala Korhaz
city: Torokbalint
country: Hungary
facility: Torokbalinti Tudogyogyintezet
city: Ancona
country: Italy
facility: Azienda Ospedaliero-Universitaria delle Marche
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna - Policlinico di Sant'Orsola
city: Catania
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico G. Rodolico-San Marco - Presidio Ospedaliero G. Rodolico
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Milan
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Padova
country: Italy
facility: Istituto Oncologico Veneto-I.R.C.C.S. - Ospedale Busonera
city: Torino
country: Italy
facility: AOU Citta della Salute e della Scienza di Torino - Ospedale le Molinette
city: Rio Piedras
country: Puerto Rico
facility: PanOncology Trials, LLC
city: Arkhangelsk
country: Russian Federation
facility: Arkhangelsk Clinical Oncological Dispensary
city: Otradnoye
country: Russian Federation
facility: JSC Group of companies Medsi
city: Saint Petersburg
country: Russian Federation
facility: Private Medical Institution Euromedservice
city: Saint Petersburg
country: Russian Federation
facility: Saint-Petersburg Clinical Research Center of Specialized Types of Medical Care (Oncology)
city: Saransk
country: Russian Federation
facility: Ogarev Mordovia State University
city: St. Petersburg
country: Russian Federation
facility: JSC Current Medical Technologies
city: Volgograd
country: Russian Federation
facility: Volgograd Regional Clinical Oncology Dispensary
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore
city: Singapore
country: Singapore
facility: Oncocare Cancer Centre
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia - L'Hospitalet
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncologia
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: Chi-Mei Hospital - Liouying Branch
city: Taipei City
country: Taiwan
facility: National Taiwan University Hospital
city: Taoyuan City
country: Taiwan
facility: Linkou Chang Gung Memorial Hospital (CGMHLK)
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: London
country: United Kingdom
facility: University College London Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Surrey Quays
country: United Kingdom
facility: Royal Marsden Hospital - Surrey
Study officials:
affiliation: Apollomics Inc.
name: Peony Yu
role: STUDY_CHAIR
References: