Etude : SPARTA / APL-101-01



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Acronyme / Nom
Situation thérapeutique
Traitement
Cadre réglementaire
MÀJ
Présentation de l'étude
Acronyme / Nom : SPARTA / APL-101-01

Situation thérapeutique : Métastatique ou localement avancé

Traitement : Thérapie ciblée

Cadre réglementaire : RIPH1

Dernière MÀJ : 30/11/2021
Titre
Spécialité(s)
CIM10 - Localisation(s)
Informations principales
Titre : 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

Spécialité : Organes respiratoires et intrathoraciques
Localisation : C34 - Tumeur maligne des bronches et du poumon

Spécialité : Toutes tumeurs solides
Localisation : C - Toutes localisations
Schéma
Phase
Stade
Ligne(s)
Informations complémentaires
Schéma : STUDY DESIGN:
This is a Phase 1/2, multi-center, global, open-label, 2-part study with a Dose Escalation Segment and Dose and Disease Expansion Cohorts study of APL-101, a c-MET inhibitor, to determine the recommended Phase 2 dose (RP2D) and dose limiting toxicities for APL-101, and to obtain preliminary efficacy and target engagement data, in subjects with NSCLC and advanced malignancies with c-Met dysregulation.

c-MET dysregulation will be determined from historical results by molecular pre-screening evaluations to determine eligibility of enrollment for both the Dose Escalation Segment (Phase 1) and Dose and Disease Expansion Cohorts (Phase 2).

Dose escalation will occur until a protocol defined dose limited toxicity (DLT) occurs and a tentative maximum tolerated dose (MTD) is determined.

Once dose is determined, five cohort groups will be further evaluated:
- Cohort A-1: NSCLC EXON 14 skip mutation (c-Met naïve, 1L)
- Cohort A-2: NSCLC EXON 14 skip mutation (c-Met naïve, 2/3L),
- Cohort B: NSCLC EXON 14 skip mutation (c-Met experienced; progressed on prior c-Met inhibitor),
- Cohort C: basket of tumor types (with c-Met high-level amplifications),
- Cohort D: basket of tumor types (with c-Met fusions)

PRIMARY OBJECTIVE:
Phase 1 Primary Objective
•To assess overall safety and tolerability, determine the dose limiting toxicities (DLTs), and identify the recommended Phase 2 dose (RP2D).
Phase 2 Primary Objective
•To assess efficacy by overall response rate (ORR) and duration of response (DOR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. or relevant evaluation criteria per tumor type.

SECONDARY OBJECTIVES
Phase 1/2 Secondary Objectives
•To assess incidence of serious adverse events (SAEs) and adverse events (AEs) by relationship and severity grade.
•To determine the pharmacokinetic (PK) parameters of orally administered APL-101.
•To assess efficacy by clinical benefit rate (CBR: CR + PR + SD ≥ 4 cycles), time to progression (TTP), progression free survival (PFS), per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (or relevant evaluation criteria per tumor type) and overall survival (OS).

Phase : I/II

Stade : Localement avancé à Métastatique

1, 2, 3, 4
Informations libres de droit
Critères d'inclusion
Critères de non-inclusion
Informations libres de droit
Critères d'inclusion et de non-inclusion
Critères d'inclusion : 1.Men/women ≥ 18 years of age or older able to understand and sign ICF before study.
3. For Ph 1, histologically and/or cytological confirmed unresectable or metastatic solid malignancy, refractory to standard therapies with no more than 3 prior lines of therapy.
4.For Ph 2, five cohorts will be enrolled:

4a. Cohort A-1: EXON 14 NSCL Cancer – c-Met inhibitor naïve (1L)
a.Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations; All histologies (pulmonary sarcomatoid carcinoma and squamous)
b.Unresectable or metastatic disease (Stage 3b/4)
d.Treatment naïve subjects in first-line
e.Not received any c-Met inhibitor

Cohort A-2: EXON 14 NSCL Cancer – c-Met inhibitor naïve (≥ 2L)
a.Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations
b.All histologies, including pulmonary sarcomatoid carcinoma and squamous
c.Unresectable or metastatic disease (Stage 3b/4)
d.Pretreated subjects refractory to or intolerable to standard therapies with no more than 3 lines of prior therapy in the metastatic setting
e.Not received any c-Met inhibitor

4b. Cohort B: EXON 14 NSCL Cancer – c-Met inhibitor experienced
a.Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations
b.All histologies, including pulmonary sarcomatoid carcinoma and squamous
c.Unresectable or metastatic disease (Stage 3b/4)
d.Refractory to standard therapies with no more than 3 prior lines of therapy in the metastatic setting
e.Radiographic progression on any c-Met inhibitor at any point in the past

4c. Cohort C: Basket Tumor Types (c-Met high-level amplifications)
a.Any tumor type regardless of histology, including osimertinib relapsed/refractory NSCLC, excluding NSCLC EXON 14 skip mutation, that meets inclusion criteria c-Met high-level amplification
b.Unresectable or metastatic disease, refractory to standard therapies with no more than 3 prior lines of therapy in the metastatic setting
c.Not received any c-Met inhibitor

4d. Cohort D: Basket Tumor Types (c-Met fusions)
a.Any other tumor type histology that meets inclusion criteria c-Met fusions
b.Unresectable or metastatic disease, refractory to standard therapies with no more than 3 prior lines of therapy in the metastatic setting
c.Not received any c-Met inhibitor

5.Abnormal c-Met dysregulation, by tissue and/or plasma, defined as the following from archival/local results or molecular pre-screening evaluations.

Phase 1 (100, 200, and 300 mg Cohorts)
a.c-Met overexpression by IHC 2+ ≥ 50% of tumor cells
b.or c-Met amplification (c-Met/Cep-7 ratio ≥ 2.2 or GCN ≥ 6 gene copy)
c.or c-Met EXON 14 skip mutation per NGS or RT-PCR
d.or c-Met fusions including the following, but not limited to: BAIAP2L1-MET; C8orf34-MET; CAPZA2-MET; DCTN1-MET; EPS15-MET; LRRFIP1-MET; MET-MET; OXR1-MET; PPFIBP1-MET; PTPRZ1-MET; TFG-MET; TPR-MET; TRIM4-MET; ZKSCAN1-MET; KIF5B-MET and any other known c-Met activating mutations

Phase 1 (400 mg Cohort) and Phase 2 RP2D
a.c-Met high-level amplification (c-Met/Cep-7 ratio of ≥ 2.2 or GCN of ≥ 6 copy). A minimum of five subjects of the high-level amplification (c-Met/Cep-7 ratio of ≥ 5 or GCN ≥ 10 gene copy) for the Stage 1 of the Simon 2 stage design is required)
b.or c-Met EXON 14 skip mutation per NGS
c.or c-Met fusions including the following, but not limited to: BAIAP2L1-MET; C8orf34-MET; CAPZA2-MET; DCTN1-MET; EPS15-MET; LRRFIP1-MET; MET-MET; OXR1-MET; PPFIBP1-MET; PTPRZ1-MET; TFG-MET; TPR-MET; TRIM4-MET; ZKSCAN1-MET; KIF5B-MET
d. or other c-Met mutations in Dose Escalation (400 mg Cohort)

6. Local/archival result of a positive c-Met dysregulation is required. In Ph 2, Cohorts A and D require provision of tumor tissue samples. For Cohorts B and C, provision of tumor tissue or plasma sample for entry is acceptable.
7. Across Ph 2 five cohorts, treated or untreated asymptomatic parenchymal CNS disease or leptomeningeal disease is allowed.
8. Measurable disease according to RECIST v1.1. (or relevant criteria per tumor type).
9. ECOG performance status of 0–1.
10. Acceptable organ function, as evidenced by the following laboratory data during Screening period:
a.AST and alanine aminotransferase (ALT) ≤ 2.5 x ULN
b.Total serum bilirubin ≤ 1.5 x ULN
c.For subjects with liver metastases: Total bilirubin ≤ 3.0 x ULN, AST/ ALT ≤ 5 x ULN
d.Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 x 109/L)
e.Platelet count ≥ 100,000 cells/mm3 (100 x 109/L)
f.Serum creatinine levels ≤ 1.5 ULN or CrCl ≥ 60 mL/min
g.Hemoglobin ≥ 9 g/dL
11.For all prior anticancer treatment, including radiotherapy,chemotherapy or targeted agents or hormonal therapy, 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.
12.Adequate cardiac function or normal cardiac function with LVEF ≥ 50% at screening.

Critères de non-inclusion : 1.Hypersensitivity to APL-101, excipients of the drug product, or other components of the study treatment regimen.
2.Known mutation/gene rearrangement of EGFR (except for Cohort C), ALK, ROS1, RET, NTRK, KRAS and BRAF.
3.Use or intended use of any other investigational product, including herbal medication 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. Screening for chronic conditions is not required.
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, or symptomatic or unstable arrhythmia requiring medical therapy, or history of congenital prolonged QT syndrome or whose corrected QT interval by Fridericia formula (QTcF) at screening is prolonged (> 450 msec based on the average of 3 measurements) or concurrent treatment with any medication that prolongs QT interval.
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 (HIV) positive patients who are not clinically stable or controlled on their medication (i.e. asymptomatic patients 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. Patients on contraindicated medications should be evaluated and replaced with alternate medications with less risk of drug-drug interaction). If history is unclear, a test at Screening will be required.
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 (e.g., Crohn’s, ulcerative colitis, active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
11.Women who are breastfeeding.
12.Subjects with complications from prior radiation therapy will not be eligible until AEs return to baseline or ≤ Grade 1.
13.Pregnant or breastfeeding woman.
NCT
Promoteur
Coordonnateur
Informations relatives au promoteur
NCT :
NCT03175224
Promoteur :
Apollomics Inc.
Type de sponsor : Industriel
Foster City, CA 94404 USA - Foster City, CA 94404 USA
00000 HORS FRANCE

Coordonnateur :
Centre investigateur
Investigateur
TEC / ARC / IDE
État
MÀJ
Informations relatives aux investigateurs
Centre investigateur :
Centre Hospitalier Universitaire de Lille - 2 Avenue Oscar Lambret - 59000 LILLE

Investigateur :
Professeur Alexis Cortot

TEC / ARC / IDE :
Eric Wasielewski
eric.wasielewski@
chru-lille.fr
03.20.44.56.12

Statut de l'essai : OUVERT

MAJ : 02/04/2021