Phase I Study of Repotrectinib and Osimertinib in NSCLC Patients

NCT04772235 | Recruiting Phase 1 DMC

• 2 other identifiers: IOR-TPT-IST-0022020-005151-20
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 4

Brief Summary

This is a Phase I study of repotrectinib in combination with osimertinib in patients with advanced or metastatic EGFR mutant non small cell lung cancer (NSCLC). The study will be conducted in 2 parts, Part Ia and Part Ib, and its purpose will be to find the incidence of dose-limiting toxicities (DLTs) as defined by the primary safety and tolerability endpoint. The Phase Ia study will also determine the impact of repotrectinib on osimertinib pharmacokinetics (PK) and the maximum tolerated dose (MTD), if reached, of repotrectinib given in combination with osimertinib and the recommended Phase II dose (RP2D). Dose escalation will be conducted according to a 'Rolling-6' based study design with 3 dose levels for repotrectinib: 80 mg once a day (QD), 160 mg QD or 160 mf QD during 14 days followed by 160 mg twice a day (BID); in combination with 80 mg QD of osimertinib. A total of 6 patients will be enrolled in each dose level cohort. In addition, this Phase Ib study will test early drug activity (efficacy) of the proposed combination treatment in an expansion cohort at the RP2D.

Conditions

Nsclc

Keywords

Advanced and/or metastatic; EGFR mutant

Outcome Measures

Primary Outcomes (2)

• Adverse events (AEs)

  Number of patients experiencing AEs, both non treatment related and treatment related, classified by severity and graded according to the NCI CTCAE v5.0

  Throughout the study period. Approximately 48 months

• Incidence of Dose limiting toxicities (DLTs)

  Number of patients experiencing AEs that have been predefined as DLTs: Toxicities resulting in an excessive number of missed doses, Hematologic, renal, hepatic toxicities grade ≥ 3; during the DLT observation period (Cycle 1, 21 days). Only patients in the Part A (dose escalation) of the study.

  During the treatment cycle 1, 21 days

Secondary Outcomes (11)

• Objective response rate (ORR)

  Throughout the study period. Approximately 48 months

• Complete response rate (CR)

  Throughout the study period. Approximately 48 months

• Partial response rate (PR)

  Throughout the study period. Approximately 48 months

• Clinical Benefit Rate (CBR)

  Throughout the study period. Approximately 48 months

• Duration of Response (DoR)

  Throughout the study period. Approximately 48 months

Study Arms (1)

Advanced and/or metastatic EGFR mutant NSCLC

EXPERIMENTAL

Eligible advanced and/or metastatic EGFR mutant NSCLC patients will receive the combination of osimertinib and repotrectinib.

Drug: Repotrectinib; Drug: Osimertinib

Interventions

Repotrectinib DRUG

Repotrectinib will be taken orally once daily with or without food Part A: Dose escalation phase, with 3 dose levels for repotrectinib: (1) 80 mg QD, (2) 160 mg QD and (3) 160 mg QD for 14 days followed by 160 mg BID; in combination with 80 mg QD of osimertinib Part B: at the RP2D for all patients in combination with osimertinib.

Also known as: TPX-0005

Advanced and/or metastatic EGFR mutant NSCLC

Osimertinib DRUG

Osimertinib will be taken orally at 80 mg once daily with or without food. Part A: lead in dose in monotherapy at 80 mg QD during 14 days. In combination with repotrectinib afterwards. Depending on the safety and PK/ dose dependent interactions (DDIs) readout during the DLT assessment period, osimertinib dose may be adjusted. Part B: at the RP2D level in combination with repotrectinib

Also known as: Tagrisso

Advanced and/or metastatic EGFR mutant NSCLC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients of age ≥18.
• Histological or cytological confirmation of locally advanced or metastatic, non-squamous cell lung carcinoma (NSCLC) in patients who are not candidates for local curative treatment through radical surgery and/or radiotherapy.
• Stage IV, according to Tumor-nodes-metastasis (TNM) Version 8, including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease for which there is no curative treatment (including patients who progress after chemoradiotherapy in Stage III disease).
• Patients must have been locally diagnosed with EGFR activating mutation (including exon 18, exon 19, exon 21 and mutation T790M) based on FDA approved test (or a local equivalent laboratory developed) test (LDT)). Confirmatory central review will be performed for all patients, in case of discrepancy on EGFR status, central review will prevail.
• Eastern cooperative oncology group (ECOG) performance status 0-1.
• Existence of measurable or evaluable disease (according to RECIST 1.1 criteria).
• Patients with asymptomatic central nervous system (CNS) metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the following criteria:
• Patients requiring steroids at a stable or decreasing dose (≤ 12 mg/day dexamethasone or equivalent) for at least 14 days are eligible. Patients on stable doses of levetiracetam (same dose for 14 days) are eligible to be enrolled.
• A minimum of 14 days must have elapsed from the completion of whole brain radiation treatment (WBRT) before the start of treatment with repotrectinib, and all side effects (with the exception of alopecia) from WBRT are resolved to CTCAE grade ≤ 1.
• Having available tumor tissue samples, via a biopsy or surgical resection of the primary tumor or metastatic tumor tissue, within 60 days prior to the start of treatment.
• Life expectancy ≥12 weeks, as determined by a physician.
• Adequate hematological function, defined as: absolute neutrophil count (ANC) \>1.5 x 109/L, platelet count \>100.0 x 109/L, and hemoglobin \>9.0 g/dL (transfusion allowed at baseline).
• Adequate liver function, defined as: total bilirubin \<1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \<2.5 x ULN.
• Adequate renal function, defined as: calculated (Cockcroft-Gault formula) or measured creatinine clearance \>50 mL/min and proteinuria \<2+ (dipstick).
• Ability to take part in all study procedures, per investigators.

You may not qualify if:

• Prior exposure to repotrectinib.
• Diagnosis with any other lung cancer subtype apart from adenocarcinoma including patients with mixed NSCLC with predominantly squamous cell cancer, or with any small-cell lung cancer component, or a tertiary mutation.
• Presence or history of any other primary malignancy other than NSCLC within 5 years prior to enrollment into the study.
• Patients with a history of adequately treated basal or squamous cell carcinoma of the skin or any adequately treated in situ carcinoma may be included in the study.
• Presence of only one measurable or evaluable tumor lesion that has already been resected or irradiated prior to enrollment in the study.
• Known presence of EGFR exon 20 insertion mutation based on most recent applicable molecular testing.
• Clinically significant cardiovascular disease (either active or within 6 months prior to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2.
• Any of the following cardiac criteria:
• Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) \> 470 msec obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \> 250 msec)
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval
• Known active infections requiring ongoing treatment (bacterial, fungal, viral including HIV positivity).
• Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
• Peripheral neuropathy ≥ grade 2.
• History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis. Patients with a history of prior radiation pneumonitis are not excluded.

Sponsors & Collaborators

• Instituto Oncológico Dr Rosell: lead
• Turning Point Therapeutics, Inc.: collaborator

Study Sites (4)

Hospital Regional Universitario de Málaga

Málaga, Andalusia, 29010, Spain

RECRUITING

Hospital Son Espases

Palma, Balearic Islands, 07120, Spain

RECRUITING

Quiron Dexeus

Barcelona, Catalonia, 08018, Spain

RECRUITING

Hospital Universitario Gregorio Marañón

Madrid, 28007, Spain

RECRUITING

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

repotrectinib; osimertinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Andrés Aguilar Hernández, M.D.

  Institute of oncology Dr. Rosell

  STUDY CHAIR

Central Study Contacts

A responsible person designated by the sponsor

CONTACT

0034934344412; investigacion@mfar.net

Responsible person designated by the sponsor, Ph.D.

CONTACT

0034934344412; investigacion@mfar.net

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a single arm, open-label, non-randomized Phase I study with a first dose escalation phase in 3 cohorts to find the RP2D and MTD followed by an expansion phase at the RP2D.

Study Record Dates

• First Submitted: February 17, 2021
• First Posted: February 26, 2021
• Study Start: February 11, 2022
• Primary Completion: April 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: April 3, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

ES (4)