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 (Krascendo 170)

• ClinicalTrials.gov Identifier: NCT05789082
• Recruitment Status: Recruiting
• First Posted: March 29, 2023
• Last Update Posted: May 16, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: February 21, 2023
• First Posted Date: March 29, 2023
• Last Update Posted Date: May 16, 2024
• Actual Study Start Date: June 20, 2023
• Estimated Primary Completion Date: September 30, 2025 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: March 28, 2023): 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 3 years) ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 7, 2023)

• Objective Response Rate (ORR) [ Time Frame: 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) [ Time Frame: 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
• Progression Free Survival (PFS) [ Time Frame: 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
• 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: Up to approximately 3 years ]
• Change from Baseline in Symptomatic Side Effects, as Assessed Through use of the PRO-CTCAE [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to approximately 3 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: Up to approximately 3 years ]
• Plasma Concentration of Divarasib at Specified Timepoints [ Time Frame: 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 [ Time Frame: Up to approximately 3 years ]
  The recommended dose will be based upon the totality of safety, activity, and PK data.

Original Secondary Outcome Measures (submitted: March 28, 2023)

• Objective Response Rate (ORR) [ Time Frame: 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) [ Time Frame: 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
• Progression Free Survival (PFS) [ Time Frame: 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
• 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: Up to approximately 3 years ]
• Change from Baseline in Symptomatic Side Effects, as Assessed Through use of the PRO-CTCAE [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to approximately 3 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: Up to approximately 3 years ]
• Plasma concentration of GDC-6036 at Specified Timepoints [ Time Frame: 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. ]
• Relationship Between Study Treatment and Percentage of Participants with AEs [ Time Frame: Up to approximately 3 years ]
• Relationship Between Study Treatment and ORR [ Time Frame: Up to approximately 3 years ]
• Relationship Between Study Treatment and DOR [ Time Frame: Up to approximately 3 years ]
• Relationship Between Study Treatment and PFS [ Time Frame: Up to approximately 3 years ]
• Relationship Between Study Treatment and Plasma Concentrations of GDC-6036 at Specified Timepoints [ Time Frame: Up to approximately 3 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: A Phase Ib/II, Open-Label, Multicenter Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-Small Cell Lung Cancer

Intervention

• Drug: Divarasib
  Participants will receive one of two doses of 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.

Study Arms

• Experimental: Cohort A - Combination Dose Finding + Dose Expansion

  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.

  Interventions:

  • Drug: Divarasib
  • Drug: Pembrolizumab
• Experimental: Cohort B - Combination Dose Finding + Dose Expansion
  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.
  Interventions:

  • Drug: Divarasib
  • Drug: Pembrolizumab
  • Drug: Carboplatin
  • Drug: Cisplatin
  • Drug: Pemetrexed

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 6, 2023): 96
• Original Estimated Enrollment (submitted: March 28, 2023): 60
• Estimated Study Completion Date: September 30, 2025
• Estimated Primary Completion Date: September 30, 2025 (Final data collection date for primary outcome measure)

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

Exclusion Criteria:

• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Reference Study ID Number: BO44426 https://forpatients.roche.com/; 888-662-6728 (U.S. and Canada); global-roche-genentech-trials@gene.com

• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Canada, China, Israel, Italy, Korea, Republic of, Netherlands, Poland, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT05789082
• Other Study ID Numbers: BO44426; 2022-003048-28 ( EudraCT Number ); 2023-507171-22-00 ( Other Identifier: EU CT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: May 2024