A Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib 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
- Conditions
- Non-Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT05789082
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
The purpose of this study is to evaluate the safety, pharmacokinetics (PK), and activity of divarasib combined with other anti-cancer therapies in participants with previously untreated, advanced or metastatic non-small cell lung cancer (NSCLC).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 240
- 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
- Known concomitant second oncogenic driver with available targeted treatment
- Squamous cell histology NSCLC
- Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort B - Combination Dose Finding + Dose Expansion Pembrolizumab Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed. Cohort B - Combination Dose Finding + Dose Expansion Divarasib Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed. Cohort A - Combination Dose Finding + Dose Expansion Pembrolizumab Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) once a day (QD) combined with pembrolizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W). During the expansion stage, some participants are planned to be randomized to one divarasib combination dose level; other participants are planned to be randomized to another divarasib combination dose level. Divarasib will be given in combination with pembrolizumab. Cohort B - Combination Dose Finding + Dose Expansion Carboplatin Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed. Cohort B - Combination Dose Finding + Dose Expansion Cisplatin Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed. Cohort B - Combination Dose Finding + Dose Expansion Pemetrexed Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed. Cohort A - Combination Dose Finding + Dose Expansion Divarasib Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) once a day (QD) combined with pembrolizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W). During the expansion stage, some participants are planned to be randomized to one divarasib combination dose level; other participants are planned to be randomized to another divarasib combination dose level. Divarasib will be given in combination with pembrolizumab.
- Primary Outcome Measures
Name Time Method Percentage of Participants with Adverse Events (AEs) 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 3 years)
- Secondary Outcome Measures
Name Time Method Objective Response Rate (ORR) Up to approximately 3 years The percentage of participants who experience a complete response or partial response, as determined by the investigator, according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Duration of Response (DOR) Up to approximately 3 years The time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
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) Up to approximately 3 years Progression Free Survival (PFS) Up to approximately 3 years The time from randomization, or date of first treatment for participants enrolled prior to the expansion stage, to the first occurrence of disease progression or death from any cause during the study (whichever occurs first), as determined by the investigator according to RECIST v1.1
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) Up to approximately 3 years Change from Baseline in Symptomatic Side Effects, as Assessed Through use of the PRO-CTCAE Baseline up to approximately 3 years Percentage of Participants Reporting "Frequent" or "Almost Constant" Diarrhea During the First Three Cycles of Treatment According to the PRO-CTCAE Criteria Up to approximately 3 years Percentage of Participants Reporting "Severe" or "Very Severe" Nausea or Vomiting During the First Three Cycles of Treatment According to the PRO-CTCAE Up to approximately 3 years Plasma Concentration of Divarasib at Specified Timepoints At Days 1, 8 and 15 of Cycles 1 and 2; Days 1 and 15 of Cycles 3 and 4; Day 1 of every other Cycle after Cycle 5, until treatment discontinuation (up to approximately 3 years). Each cycle is 21 days. Identification of Divarasib Recommended Dose Up to approximately 3 years The recommended dose will be based upon the totality of safety, activity, and PK data.
Trial Locations
- Locations (60)
Oncology & Hematology Associates of Southwest Virginia, Inc
🇺🇸Blacksburg, Virginia, United States
Virginia Oncology Associates
🇺🇸Norfolk, Virginia, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
City of Hope - Seacliff
🇺🇸Huntington Beach, California, United States
City of Hope at Irvine Lennar
🇺🇸Irvine, California, United States
UCSD Moores Cancer Center
🇺🇸La Jolla, California, United States
Yale Cancer Center
🇺🇸New Haven, Connecticut, United States
NYU Langone Hospital - Long Island
🇺🇸Mineola, New York, United States
NYU Cancer Center
🇺🇸New York, New York, United States
Mount SInai Medical Center
🇺🇸New York, New York, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Hospital Britanico
🇦🇷Buenos Aires, Argentina
Clinica Adventista Belgrano
🇦🇷Ciudad Autonoma Buenos Aires, Argentina
Centro Oncologico Riojano Integral (CORI)
🇦🇷La Rioja, Argentina
Concord Repatriation General Hospital
🇦🇺Concord, New South Wales, Australia
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Alfred Health
🇦🇺Melbourne, Victoria, Australia
Cliniques Universitaires St-Luc
🇧🇪Bruxelles, Belgium
Jessa Zkh (Campus Virga Jesse)
🇧🇪Hasselt, Belgium
Clinique Ste-Elisabeth
🇧🇪Namur, Belgium
AZ Delta (Campus Rumbeke)
🇧🇪Roeselare, Belgium
Hospital de Cancer de Barretos
🇧🇷Barretos, São Paulo, Brazil
Instituto do Cancer do Estado de Sao Paulo - ICESP
🇧🇷Sao Paulo, São Paulo, Brazil
Princess Margaret Cancer Center
🇨🇦Toronto, Ontario, Canada
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Hunan Cancer Hospital
🇨🇳Changsha CITY, China
Harbin Medical University Cancer Hospital
🇨🇳Harbin, China
Shanghai Pulmonary Hospital
🇨🇳Shanghai, China
Rambam Medical Center
🇮🇱Haifa, Israel
Rabin MC
🇮🇱Petach Tikva, Israel
Tel Aviv Sourasky Medical Ctr
🇮🇱Tel Aviv, Israel
Istituto Nazionale Tumori Fondazione G. Pascale
🇮🇹Napoli, Campania, Italy
Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹Roma, Lazio, Italy
Irccs Istituto Nazionale Dei Tumori (Int)
🇮🇹Milano, Lombardia, Italy
A.O. Universitaria S. Luigi Gonzaga
🇮🇹Orbassano, Piemonte, Italy
Pusan National University Hospital
🇰🇷Busan, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Korea University Guro Hospital
🇰🇷Seoul, Korea, Republic of
NKI The Netherlands Cancer Institute
🇳🇱Amsterdam, Netherlands
UMC St Radboud
🇳🇱Nijmegen, Netherlands
Uniwersyteckie Centrum Kliniczne
🇵🇱Gda?sk, Poland
Krakowski Szpital Specjalistyczny im sw. Jana Paw?a II
🇵🇱Kraków, Poland
Warminsko-Mazurskie Centrum Chorób P?uc w Olsztynie
🇵🇱Olsztyn, Poland
ICO Badalona-H.U. Germans Trias i Pujol
🇪🇸Badalona, Barcelona, Spain
Vall d?Hebron Institute of Oncology (VHIO), Barcelona
🇪🇸Barcelona, Spain
Hospital General Universitario Gregorio Marañon
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario Virgen del Rocio
🇪🇸Sevilla, Spain
Hospital Clinico Universitario de Valencia
🇪🇸Valencia, Spain
Sahlgrenska University Hospital
🇸🇪Göteborg, Sweden
Universitätsspital Basel
🇨ðŸ‡Basel, Switzerland
Inselspital Bern
🇨ðŸ‡Bern, Switzerland
Taichung Veterans General Hospital
🇨🇳Taichung, Taiwan
National Cheng Kung University Hospital
🇨🇳Tainan, Taiwan
National Taiwan Uni Hospital
🇨🇳Taipei, Taiwan
Chang Gung Medical Foundation - Linkou
🇨🇳Taoyuan, Taiwan
Beatson West of Scotland Cancer Centre
🇬🇧Glasgow, United Kingdom
Barts & London School of Med
🇬🇧London, United Kingdom