A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer
- Conditions
- Carcinoma, Non-Small-Cell LungNeoplasm Metastasis
- Interventions
- Registration Number
- NCT06119581
- Lead Sponsor
- Eli Lilly and Company
- Brief Summary
The purpose of this study is to assess if adding LY3537982 (olomorasib) in combination with standard of care anti-cancer drugs is more effective than standard of care in participants with untreated advanced NSCLC. NSCLC must have a change in a gene called KRAS G12C. Study participation, including follow-up, could last up to 3 years, depending on how you and your lung cancer are doing.
- Detailed Description
Dose Optimization, Part A, and Part B are randomized. Safety Lead-In for Part B is single arm, non-randomized.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1016
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Histologically or cytologically confirmed NSCLC with Stage IIIB-IIIC or Stage IV disease, not suitable for curative intent radical surgery or radiation therapy.
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Part B and Safety Lead-In Part B: the histology of the tumor must be predominantly non-squamous (in line with pemetrexed label).
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Must have disease with evidence of KRAS G12C mutation.
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Must have known programmed death-ligand 1 (PD-L1) expression
- Part A: Greater than or equal to (≥)50 percent (%).
- Part B: 0% to 100%.
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Must have measurable disease per RECIST v1.1.
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Must have an ECOG performance status of 0 or 1.
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Estimated life expectancy ≥12 weeks.
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Ability to swallow capsules.
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Must have adequate laboratory parameters.
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Contraceptive use should be consistent with local regulations for those participating in clinical studies.
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Women of childbearing potential must
- Have a negative pregnancy test.
- Not be breastfeeding during treatment
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Have a documented additional validated targetable oncogenic driver mutation or alteration in genes such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), BRAF (V600E), human epidermal growth factor receptor 2 (HER2), MET (exon 14), ROS1, rearranged during transfection (RET), or neurotrophic tyrosine receptor kinase (NTRK)1/2/3.
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Have had any of the following prior to randomization:
-- Prior systemic therapy (chemotherapy, immunotherapy, targeted therapy, or biological therapy) for advanced or metastatic NSCLC.
--- 1 cycle of standard-of-care treatment prior to study enrollment will be allowed for cases where immediate treatment is clinically indicated:
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Have known active central nervous system metastases and/or carcinomatous meningitis.
Exclusion Criteria for Participants receiving Pemetrexed and Platinum (Part B and Safety Lead-In Part B)
- Have predominantly squamous cell histology for NSCLC
- Only for participants with mild to moderate renal insufficiency: Unable to avoid aspirin, ibuprofen, or other nonsteroidal anti-inflammatory drugs (NSAIDs) two days before (5 days for long acting NSAIDs), day of, and two days after administration of pemetrexed
- Is unable or unwilling to take folic acid or vitamin B12 supplementation.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Dose Optimization: LY3537982 Dose Level 1 plus Pembrolizumab Pembrolizumab LY3537982 Dose level 1 administered orally in combination with pembrolizumab administered intravenously (IV) in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Dose Optimization: LY3537982 Dose Level 2 plus Pembrolizumab LY3537982 LY3537982 Dose level 2 administered orally in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Dose Optimization: LY3537982 Dose Level 2 plus Pembrolizumab Pembrolizumab LY3537982 Dose level 2 administered orally in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Safety Lead In: LY3537982 plus Pembrolizumab, Pemetrexed and Platinum Pembrolizumab LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Safety Lead In: LY3537982 plus Pembrolizumab, Pemetrexed and Platinum Cisplatin LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Safety Lead In: LY3537982 plus Pembrolizumab, Pemetrexed and Platinum Carboplatin LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Safety Lead In: LY3537982 plus Pembrolizumab, Pemetrexed and Platinum Pemetrexed LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part A: LY3537982 plus Pembrolizumab Pembrolizumab LY3537982 administered orally in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part A: Placebo plus Pembrolizumab Pembrolizumab Placebo administered orally in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part A: Placebo plus Pembrolizumab Placebo Placebo administered orally in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part B: LY3537982 plus Pembrolizumab, Pemetrexed, and Platinum Pembrolizumab LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part B: LY3537982 plus Pembrolizumab, Pemetrexed, and Platinum Cisplatin LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part B: LY3537982 plus Pembrolizumab, Pemetrexed, and Platinum Carboplatin LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part B: LY3537982 plus Pembrolizumab, Pemetrexed, and Platinum Pemetrexed LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part B: Placebo plus Pembrolizumab, Pemetrexed, and Platinum Pembrolizumab Placebo administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part B: Placebo plus Pembrolizumab, Pemetrexed, and Platinum Placebo Placebo administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part B: Placebo plus Pembrolizumab, Pemetrexed, and Platinum Cisplatin Placebo administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part B: Placebo plus Pembrolizumab, Pemetrexed, and Platinum Carboplatin Placebo administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part B: Placebo plus Pembrolizumab, Pemetrexed, and Platinum Pemetrexed Placebo administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Dose Optimization: LY3537982 Dose Level 1 plus Pembrolizumab LY3537982 LY3537982 Dose level 1 administered orally in combination with pembrolizumab administered intravenously (IV) in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Safety Lead In: LY3537982 plus Pembrolizumab, Pemetrexed and Platinum LY3537982 LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part A: LY3537982 plus Pembrolizumab LY3537982 LY3537982 administered orally in combination with pembrolizumab administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met. Part B: LY3537982 plus Pembrolizumab, Pemetrexed, and Platinum LY3537982 LY3537982 administered orally in combination with pembrolizumab, pemetrexed, and platinum (cisplatin or carboplatin) administered IV in 21-day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
- Primary Outcome Measures
Name Time Method Dose Optimization and Safety Lead-In Part B: Number of Participants with a Treatment Emergent Adverse Event(s) (TEAE) Randomization to first documented progression of disease or death from any cause. (Estimated as approximately 1 year) Dose Optimization and Safety Lead-In Part B: Number of Participants with a TEAE
Part A and Part B: Progression-Free Survival (PFS) Randomization to first documented progression of disease or death from any cause. (Estimated as approximately 1 year) PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded independent central review (BICR)
- Secondary Outcome Measures
Name Time Method Part A and Part B: Overall Survival (OS) Randomization to date of death from any cause. (Estimated as up to 3 years) Part A and Part B: OS
Part A and Part B: PFS Randomization to first documented progression of disease or death from any cause. (Estimated as approximately 1 year) PFS per RECIST v1.1 by investigator
Part A and Part B: Overall Response Rate (ORR): Percentage of Participants who Achieve a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) Randomization to disease progression or death. (Estimated as approximately 1 year) ORR per RECIST v1.1 by BICR and Investigator
Part A and Part B: Duration of Response (DOR) Date of first evidence of CR or PR to date of disease progression or death from any cause. (Estimated as approximately 1 year) DOR per RECIST v1.1 by BICR and Investigator
Part A and Part B: Disease Control Rate (DCR): Percentage of Participants who Achieve a BOR of CR, PR, or Stable Disease (SD) Randomization to disease progression or death from any cause. (Estimated as approximately 1 year) DCR per RECIST v1.1 by BICR and Investigator
Part A and Part B: Time to Response (TTR) Time from randomization until the date that measurement criteria for CR or PR (whichever is first recorded) are first met (Estimated as approximately 1 year) TTR per RECIST v1.1 by BICR and Investigator
Part A and Part B: Intracranial Overall Response Rate (ORR) Randomization to intracranial disease progression or death. (Estimated as approximately 1 year) Intracranial ORR per Modified RECIST (mRECIST) by BICR
Part A and Part B: Intracranial Duration of Response (DoR) Date of first evidence of CR or PR to date of intracranial disease progression or death from any cause. (Estimated as approximately 1 year) Intracranial DoR per mRECIST by BICR
Part A and Part B: PFS2 Randomization to disease progression on next line of treatment or death from any cause (Estimated as approximately 1 year Part A and Part B: PFS2 by Investigator
Part A and Part B: Changes in NSCLC-related symptoms as measured by NSCLC-SAQ Randomization through end of treatment (Estimated as approximately 1 year)] NSCLC-related symptoms are assessed by the NSCLC-SAQ total score, which is computed as the sum of the 5 domains (7 questions) and ranges from 0 to 20. The total score will be calculated if all 7 questions are completed. Higher scores indicate more severe symptomatology.
Part A and Part B: Time to Worsening of NSCLC-related Symptoms as Measured by NSCLC Symptom Assessment Questionnaire (NSCLC-SAQ) Randomization through end of treatment (Estimated as approximately 1 year) NSCLC symptoms will be assessed using the 7-item NSCLC-SAQ. The NSCLC-SAQ measures overall symptom severity of NSCLC, including cough, pain, dyspnea, fatigue, and poor appetite. Response options range from 0) "Not at all" to 4) "Always" or from 0) "Never" to 4) "Always." The total score ranges from 0-20. Higher scores represent worse symptoms.
Part A and Part B: Changes in physical function, as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) Physical Functioning subscale and IL19 Randomization through end of treatment (Estimated as approximately 1 year) Physical function is assessed by EORTC-QLQ-C30 Physical Functioning scale or IL19. The physical function score is calculated by generating the raw score: (Q1+Q2+Q3+Q4+Q5)/5; and then generating the transformed score: (1-((raw score-1)/3)) x 100. The score ranges from 0 to 100. Higher scores indicate better physical function.
Part A and Part B: Time to Deterioration in Physical Function, as Measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) Physical Functioning Subscale and IL19 Randomization through end of treatment (Estimated as approximately 1 year) The EORTC QLQ-C30 is a 30-question patient-reported instrument used to assess multidimensional health-related quality of life (HRQoL) in cancer patients. Physical functioning is measured by the EORTC-QLQ-30 Physical Function Scale (five items). Response options range from 1) "Not at all" to 4) "Very much." The sum score is linearly transformed to the range 0 - 100. Higher scores represent better physical function.
Part A and Part B: Proportion of Time with High Side-Effect Burden, as Measured by Functional Assessment of Cancer Therapy - General Item 5 (FACT-GP5) Randomization through end of treatment (Estimated as approximately 1 year) FACT-GP5 is a single-item, patient-reported instrument for assessing overall treatment side-effect burden. Response options range from 0) "Not at all" to 4) "Very much." Higher scores represent higher symptom burden.
Part A and Part B: Change from Baseline in Overall Health-related Quality of Life, as Measured by the EORTC QLQ-C30 Global Health Status/Quality of Life Subscale Randomization through end of treatment (Estimated as approximately 1 year) The EORTC QLQ-C30 is a 30-question patient-reported instrument used to assess multidimensional HRQoL in cancer patients. Overall HRQoL is measured by the EORTC QLQ-30 Global Health Status/Quality of Life Subscale (two items). Response options range from 1) "very poor" to 7) "excellent." Scores are linearly transformed to the range 0 - 100. Higher scores represent better overall HRQoL.
Trial Locations
- Locations (425)
Clearview Cancer Institute
🇺🇸Huntsville, Alabama, United States
Banner MD Anderson Cancer Center
🇺🇸Gilbert, Arizona, United States
Banner University Medical Center Phoenix
🇺🇸Phoenix, Arizona, United States
The University of Arizona Cancer Center - North Campus
🇺🇸Tucson, Arizona, United States
Highlands Oncology Group
🇺🇸Springdale, Arkansas, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
Mercy Cancer Center
🇺🇸Merced, California, United States
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
🇺🇸Torrance, California, United States
BASS Cancer Center
🇺🇸Walnut Creek, California, United States
USO - Rocky Mountain Cancer Centers
🇺🇸Lone Tree, Colorado, United States
Scroll for more (415 remaining)Clearview Cancer Institute🇺🇸Huntsville, Alabama, United StatesMarshall SchreederPrincipal Investigator