Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1

• ClinicalTrials.gov Identifier: NCT03785249
• Recruitment Status: Recruiting
• First Posted: December 24, 2018
• Last Update Posted: January 9, 2023
• Sponsor: Mirati Therapeutics Inc.
• Information provided by (Responsible Party): Mirati Therapeutics Inc.

Tracking Information

• First Submitted Date: December 18, 2018
• First Posted Date: December 24, 2018
• Last Update Posted Date: January 9, 2023
• Actual Study Start Date: January 15, 2019
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 29, 2020)

• Characterize the safety of MRTX849 in patients having advanced solid tumor malignancies with KRAS G12C mutation [ Time Frame: 20 months ]
  Number of participants with treatment related adverse events
• Evaluate the pharmacokinetics of MRTX849 [ Time Frame: 20 months ]
  Blood plasma concentration
• Evaluate clinical activity/efficacy of MRTX849 [ Time Frame: 20 months ]
  Objective response rate in accordance with Response Evaluation Criteria in Solid Tumors (RECIST)

Original Primary Outcome Measures (submitted: December 19, 2018)

• Characterize the safety of MRTX849 in patients having advanced solid tumor malignancies with KRAS G12C mutation [ Time Frame: 20 months ]
  Number of participants with treatment related adverse events
• Evaluate the pharmacokinetics of MRTX849 [ Time Frame: 20 months ]
  Blood plasma concentration

Current Secondary Outcome Measures (submitted: April 29, 2020)

• Establish maximum tolerated dose [ Time Frame: 12 months ]
  Number of participants with dose limiting toxicity
• Characterize safety and tolerability of MRTX849 in combination with selected therapeutic agents [ Time Frame: 12 months ]
  Number of participants with dose limiting toxicity
• Evaluate the pharmacokinetics of new MRTX849 oral formulations [ Time Frame: 6 months ]
  Blood plasma concentration
• Evaluate the pharmacokinetics of MRTX849 administered with food [ Time Frame: 6 months ]
  Blood plasma concentration

Original Secondary Outcome Measures (submitted: December 19, 2018)

• Establish maximum tolerated dose [ Time Frame: 12 months ]
  Number of participants with dose limiting toxicity
• Evaluate clinical activity of MRTX849 [ Time Frame: 20 months ]
  Objective response rate in accordance with Response Evaluation Criteria in Solid Tumors (RECIST)

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

Descriptive Information

• Brief Title: Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1
• Official Title: A Phase 1/2 Multiple Expansion Cohort Trial of MRTX849 in Patients With Advanced Solid Tumors With KRAS G12C Mutation KRYSTAL-1
• Brief Summary: This study will evaluate the safety, tolerability, drug levels, molecular effects, and clinical activity of MRTX849 (adagrasib) in patients with advanced solid tumors that have a KRAS G12C mutation.
• Detailed Description: This study will evaluate the safety, tolerability, pharmacokinetics, metabolites, pharmacodynamics, and clinical activity of MRTX849 (adagrasib) in patients with advanced solid tumors with a KRAS G12C mutation. MRTX849 (adagrasib) is an orally-available small molecule inhibitor of KRAS G12C.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Advanced Cancer
• Metastatic Cancer
• Malignant Neoplastic Disease

Intervention

• Drug: MRTX849
  MRTX849 will be administered orally once or twice daily in a continuous regimen
• Drug: Pembrolizumab
  Pembrolizumab is administered as an intravenous infusion once every 3 weeks
• Drug: Cetuximab
  Cetuximab will be administered as an intravenous infusion once per week or once every 2 weeks
• Drug: Afatinib
  Afatinib will be administered orally once a day in a continuous regimen

Study Arms

• Experimental: Phase 1 Dose Exploration
  Dose escalation of MRTX849 to determine maximum tolerated dose
  Intervention: Drug: MRTX849
• Experimental: Phase 1b Expansion
  Expansion cohort to ensure sufficient safety experience, pharmacokinetic information, and early evidence of clinical activity of MRTX849 to recommend Phase 2 regimens
  Intervention: Drug: MRTX849
• Experimental: Phase 2
  Separate cohorts of patients stratified by histological diagnosis, prior treatment history or co-mutation status (e.g., STK11) for evaluation of clinical activity of MRTX849
  Intervention: Drug: MRTX849
• Experimental: Pilot Phase 1b Combination with Pembrolizumab
  Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with pembrolizumab in patients with NSCLC
  Interventions:

  • Drug: MRTX849
  • Drug: Pembrolizumab
• Experimental: Pilot Phase 1b Combination with Cetuximab
  Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with CRC
  Interventions:

  • Drug: MRTX849
  • Drug: Cetuximab
• Experimental: Pilot Phase 1b Combination with Afatinib
  Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with afatinib in patients with NSCLC
  Interventions:

  • Drug: MRTX849
  • Drug: Afatinib
• Experimental: Phase 2 Combination with Cetuximab
  Phase 2 evaluation of the clinical activity of MRTX849 in combination with cetuximab in patients with CRC
  Interventions:

  • Drug: MRTX849
  • Drug: Cetuximab
• Experimental: Pilot Phase 1b Combination with Cetuximab in NSCLC
  Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with NSCLC
  Interventions:

  • Drug: MRTX849
  • Drug: Cetuximab
• Experimental: Pilot Phase 1b Combination with Cetuximab in PDAC
  Phase 1 evaluation of the safety, tolerability, PK and clinical activity of MRTX849 in combination with cetuximab in patients with pancreatic adenocarcinoma (PDAC)
  Interventions:

  • Drug: MRTX849
  • Drug: Cetuximab

Publications *

• Janne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, Johnson ML, Sabari JK, Leventakos K, Yau E, Bazhenova L, Negrao MV, Pennell NA, Zhang J, Anderes K, Der-Torossian H, Kheoh T, Velastegui K, Yan X, Christensen JG, Chao RC, Spira AI. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N Engl J Med. 2022 Jul 14;387(2):120-131. doi: 10.1056/NEJMoa2204619. Epub 2022 Jun 3.
• Sabari JK, Velcheti V, Shimizu K, Strickland MR, Heist RS, Singh M, Nayyar N, Giobbie-Hurder A, Digumarthy SR, Gainor JF, Rajan AP, Nieblas-Bedolla E, Burns AC, Hallin J, Olson P, Christensen JG, Kurz SC, Brastianos PK, Wakimoto H. Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2022 Aug 2;28(15):3318-3328. doi: 10.1158/1078-0432.CCR-22-0383.
• Ou SI, Janne PA, Leal TA, Rybkin II, Sabari JK, Barve MA, Bazhenova L, Johnson ML, Velastegui KL, Cilliers C, Christensen JG, Yan X, Chao RC, Papadopoulos KP. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). J Clin Oncol. 2022 Aug 10;40(23):2530-2538. doi: 10.1200/JCO.21.02752. Epub 2022 Feb 15.
• Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, Johnson ML, Heist RS, Patil T, Riely GJ, Jacobson JO, Yang X, Persky NS, Root DE, Lowder KE, Feng H, Zhang SS, Haigis KM, Hung YP, Sholl LM, Wolpin BM, Wiese J, Christiansen J, Lee J, Schrock AB, Lim LP, Garg K, Li M, Engstrom LD, Waters L, Lawson JD, Olson P, Lito P, Ou SI, Christensen JG, Janne PA, Aguirre AJ. Acquired Resistance to KRASG12C Inhibition in Cancer. N Engl J Med. 2021 Jun 24;384(25):2382-2393. doi: 10.1056/NEJMoa2105281.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 6, 2023): 822
• Original Estimated Enrollment (submitted: December 19, 2018): 200
• Estimated Study Completion Date: September 2024
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation
• Unresectable or metastatic disease
• Standard treatment is not available or patient declines; first-line treatment for NSCLC for certain cohorts
• Adequate organ function

Exclusion Criteria:

• History of intestinal disease or major gastric surgery or inability to swallow oral medications
• Other active cancer

Sex/Gender

• Sexes Eligible for Study: All

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

Contacts

Contact: Mirati Therapeutics Study Locator Services; 1-844-893-5530; miratistudylocator@emergingmed.com

• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT03785249
• Other Study ID Numbers: 849-001
• Has Data Monitoring Committee: Yes

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: No

• Current Responsible Party: Mirati Therapeutics Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Mirati Therapeutics Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Hirak Der-Torossian; Mirati Therapeutics

• PRS Account: Mirati Therapeutics Inc.
• Verification Date: January 2023