A Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib as a Single Agent or in Combination With Other Anti-Cancer Therapies in Participants With Previously Untreated Advanced or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation

Official title

A Phase Ib/II, Open-Label, Multicenter Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib as a Single Agent or in Combination With Other Anti-Cancer Therapies in Patients With Previously Untreated Advanced Or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation

Overview

The purpose of this study is to evaluate the safety, pharmacokinetics (PK), and activity of single-agent divarasib or combined with other anti-cancer therapies in participants with previously untreated, advanced or metastatic non-small cell lung cancer (NSCLC).

Interventions

• Drug Divarasib
  Participants will receive divarasib orally (PO), QD on days 1-21 of each 21-day cycle.
• Drug Pembrolizumab
  Participants will receive a 200 mg IV infusion of pembrolizumab Q3W on Day 1 of each 21-day cycle.
• Drug Carboplatin
  Participants will receive IV carboplatin Q3W for four 21-day cycles.
• Drug Cisplatin
  Participants will receive IV cisplatin Q3W for four 21-day cycles.
• Drug Pemetrexed
  Participants will receive IV pemetrexed Q3W.

Primary outcome measures

• Percentage of Participants with Adverse Events (AEs) [Time frame: Baseline until 60 days after the final dose of study treatment or until initiation of another anti-cancer therapy, whichever occurs first (up to approximately 5 years)]

Secondary outcome measures (11)

• Objective Response Rate (ORR) [Time frame: Approximately 5 years]
• Duration of Response (DOR) [Time frame: Approximately 5 years]
• Progression Free Survival (PFS) [Time frame: Approximately 5 years]
• Number of Participants Reporting Presence, Frequency, Severity, and/or Degree of Interference with Daily Function of Symptomatic Side Effects as Assessed Through the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) [Time frame: Approximately 5 years]
• Change from Baseline in Symptomatic Side Effects, as Assessed Through use of the PRO-CTCAE [Time frame: Baseline up to approximately 5 years]
• Percentage of Participants Reporting "Frequent" or "Almost Constant" Diarrhea During the First Three Cycles of Treatment According to the PRO-CTCAE Criteria [Time frame: Approximately 5 years]
• Percentage of Participants Reporting "Severe" or "Very Severe" Nausea or Vomiting During the First Three Cycles of Treatment According to the PRO-CTCAE [Time frame: Approximately 5 years]
• Frequency of Participant's Response of the Degree they are Troubled with Treatment Symptoms, as Assessed Through use of the Single-item European Organisation for Research and Treatment of Cancer (EORTC) Item List 46 (IL46) [Time frame: Approximately 5 years]
• Plasma or CSF Concentration of Divarasib at Specified Timepoints [Time frame: Approximately 5 years]
• Identification of Divarasib Recommended Dose [Time frame: Approximately 5 years]
• Central Nervous System (CNS) Response [Time frame: Approximately 5 years]

Eligibility criteria

Inclusion criteria

• Confirmation of Biomarker eligibility
• Pre-treatment tumor tissue along with an associated pathology report is required for all participants enrolled on study. Representative tumor specimens must be in formalin-fixed, paraffin embedded (FFPE) blocks (preferred) or 15 unstained, freshly cut, serial slides. Although 15 slides are required, if only 10 slides are available, the participant may be eligible for the study following consultation with the Sponsor.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
• Histologically or cytologically documented locally advanced unresectable or metastatic NSCLC that is not eligible for curative surgery and/or definitive chemoradiotherapy
• No prior systemic treatment for advanced unresectable or metastatic NSCLC
• Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additionally, for participants in cohort D, measurable brain metastases defined as at least 5 millimeters and twice the slice thickness, but less than 20 mm, that is asymptomatic and does not require local therapy at the time of enrollment.

Exclusion criteria

• Known concomitant second oncogenic driver with available targeted treatment
• Squamous cell histology NSCLC
• Symptomatic, untreated, or actively progressing CNS metastases (Cohorts A, B, and C)
• Prior treatment with a KRAS G12C inhibitor
• Known hypersensitivity to any of the components of divarasib or pembrolizumab; or known hypersensitivity to pemetrexed, carboplatin, or cisplatin (Cohort B only)
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis, active tuberculosis, significant cardiovascular disease within 3 months prior to initiation of study treatment
• History of malignancy other than NSCLC within 5 years prior to initiation of study treatment, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate more >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer
• Uncontrolled tumor related pain, pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures, uncontrolled or symptomatic hypercalcemia
• Co-morbid condition that is an absolute contraindication to treatment with corticosteroids
• Inability or unwillingness to take prophylactic treatments such as corticosteroids, anti-emetics, folic acid, or vitamin B12 supplementation.
• Participants with brain metastases for whom complete surgical resections is clinically appropriate

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 16 centers

• City of Hope National Medical Center — Duarte
• City of Hope - Seacliff — Huntington Beach
• City of Hope at Irvine Lennar — Irvine
• UCSD Moores Cancer Center — La Jolla
• City of Hope - Long Beach Elm — Long Beach
• Yale Cancer Center — New Haven
• Florida Cancer Specialists - SOUTH - SCRI - PPDS — Fort Myers
• Florida Cancer Specialists - NORTH - SCRI - PPDS — St. Petersburg
• … and 8 more centers

Spain · 6 centers

• ICO Badalona-H.U. Germans Trias i Pujol — Badalona
• Vall d?Hebron Institute of Oncology (VHIO), Barcelona — Barcelona
• Hospital General Universitario Gregorio Marañon — Madrid
• Hospital Universitario 12 de Octubre — Madrid
• Hospital Universitario Virgen del Rocio — Seville
• Hospital Clinico Universitario de Valencia — Valencia

Japan · 5 centers

• National Cancer Center Hospital East — Chiba
• Kindai University Hospital — Osaka
• National Cancer Center Hospital — Tokyo
• The Cancer Institute Hospital of JFCR — Tokyo
• Wakayama Medical University Hospital — Wakayama

South Korea · 5 centers

• Pusan National University Hospital — Busan
• Seoul National University Hospital — Seoul
• Asan Medical Center — Seoul
• Samsung Medical Center — Seoul
• Korea University Guro Hospital — Seoul

Belgium · 4 centers

• Cliniques Universitaires St-Luc — Brussels
• Jessa Zkh (Campus Virga Jesse) — Hasselt
• Clinique Ste-Elisabeth — Namur
• AZ Delta (Campus Rumbeke) — Roeselare

Italy · 4 centers

• Istituto Nazionale Tumori Fondazione G. Pascale — Naples
• Policlinico Universitario Agostino Gemelli IRCCS — Rome
• Irccs Istituto Nazionale Dei Tumori (Int) — Milan
• A.O. Universitaria S. Luigi Gonzaga — Orbassano

Taiwan · 4 centers

• Taichung Veterans General Hospital — Taichung
• National Cheng Kung University Hospital — Tainan
• National Taiwan Uni Hospital — Taipei
• Chang Gung Medical Foundation - Linkou — Taoyuan

Argentina · 3 centers

• Hospital Britanico — Buenos Aires
• Clinica Adventista Belgrano — Ciudad Autonoma Buenos Aires
• Centro Oncologico Riojano Integral (CORI) — La Rioja

Australia · 3 centers

• Concord Repatriation General Hospital — Concord
• Peter MacCallum Cancer Centre — Melbourne
• Alfred Health — Melbourne

Canada · 3 centers

• Ottawa Hospital Regional Cancer Centre — Ottawa
• Princess Margaret Cancer Center — Toronto
• Jewish General Hospital — Montreal

China · 3 centers

• Hunan Cancer Hospital — Changsha
• Harbin Medical University Cancer Hospital — Harbin
• Shanghai Pulmonary Hospital — Shanghai

Israel · 3 centers

• Rambam Medical Center — Haifa
• Rabin MC — Petah Tikva
• Tel Aviv Sourasky Medical Ctr — Tel Aviv

Poland · 3 centers

• Uniwersyteckie Centrum Kliniczne — Gda?sk
• Krakowski Szpital Specjalistyczny im sw. Jana Paw?a II — Krakow
• Warminsko-Mazurskie Centrum Chorób P?uc w Olsztynie — Olsztyn

Brazil · 2 centers

• Hospital de Cancer de Barretos — Barretos
• Instituto do Cancer do Estado de Sao Paulo - ICESP — São Paulo

Netherlands · 2 centers

• NKI The Netherlands Cancer Institute — Amsterdam
• UMC St Radboud — Nijmegen

Switzerland · 2 centers

• Universitätsspital Basel — Basel
• Inselspital Bern — Bern

United Kingdom · 2 centers

• Beatson West of Scotland Cancer Centre — Glasgow
• Barts & London School of Med — London

Sweden · 1 center

• Sahlgrenska University Hospital — Gothenburg

Identifiers

NCT: NCT05789082 · BO44426 · 2022-003048-28 · 2023-507171-22-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗