Clinical trial NCT05263986: The Clinical Trial to Evaluate the Pharmacokinetics and Safety of MRTX849 in Patients With Advanced Solid Tumors
Official title: A Phase 1, Open-label, Single-arm Study to Evaluate the Pharmacokinetics and Safety of MRTX849 in Chinese Patients With Advanced Solid Tumors With KRAS G12C Mutation
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Advanced or Metastatic Solid Tumor
Keywords: KRAS G12C mutation
Lead sponsor: Zai Lab (Hong Kong), Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Mirati Therapeutics Inc.
First posted: 2022-03-03
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a phase 1, open-label, single-arm study in Chinese patients with unresectable, locally advanced or metastatic solid tumor with KRAS G12C mutation, for which treatment with curative intent is not available.

Patients must have a documented KRAS G12C mutation determined by tissue or liquid-based local testing.

The PK profile of MRTX849 in Chinese patients will be evaluated after administration of a single and repeat oral doses of 600 mg BID. In the PK lead-in period, blood samples will be collected pre-dose and up to 96 hours post a single oral dose of 600 mg MRTX849. Following this lead-in period, patients will start the dosing regimen of 600 mg BID orally, and blood samples will be collected pre-dose and up to 12 hours after multiple doses of MRTX849 600 mg BID on Cycle 1 Day 8 (C1D8).

Safety including AEs, ECGs, laboratory parameters and vital signs of each patient will be monitored throughout the conduct of the study.

Disease response and progression will be evaluated in accordance with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).


Eligibility criteria: Inclusion Criteria:

* 1. Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation.

  2. Unresectable or metastatic disease.

  3. Available therapy:
  1. no available treatment with curative intent,
  2. no available standard-of-care treatment or patient is ineligible or declines treatment.

     4. Presence of measurable or non-measurable disease per RECIST 1.1.

     5. Age ≥ 18 years.

     6. Life expectancy of at least 3 months.

     7. Most recent prior systemic therapy (e.g., chemotherapy, immunotherapy, or investigational agent) and radiation therapy discontinued at least 2 weeks before first dose date.

     8. Recovery from the adverse effects of prior therapy at the time of enrollment to ≤ Grade 1 (excluding alopecia).

     9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

     10. Laboratory values within the ranges below during the screening period:

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  1. Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0 x 109/L)
  2. Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L)
  3. Hemoglobin ≥ 9 g/dL, in the absence of transfusions for at least 2 weeks
  4. Total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) (if associated with liver metastases or Gilbert's disease, ≤ 3 x ULN)
  5. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN (if associated with liver metastases, ≤ 5 x ULN)
  6. Creatinine clearance (CrCl) ≥ 60 mL/min.

     11. Women of childbearing potential (WOCBP) or men whose partner is a WOCBP agree to use contraception while participating in this study, and for a period of 6 months following termination of study treatment.

     12. Completed informed consent process, including signing Ethics Committee (EC)-approved informed consent form.

     13. Willing to comply with clinical trial instructions and requirements.

     Exclusion Criteria:
* 1. Use of the treatment known to cause prolonged corrected QT interval (QTc) or with a known risk of Torsades de Pointes that cannot be switched to alternative treatment within 5 half-lives prior to MRTX849 dosing initiation

  2. Use of any drugs or substances including herbal supplements known or suspected to alter MRTX849 absorption, distribution, metabolism, or excretion:
  1. Inhibitors of CYP3A4, CYP2C8, P-glycoprotein (P-gp), or breast cancer resistance protein (BCRP) within 7 days or 5 half-lives, whichever is longer, prior to MRTX849 dosing initiation.
  2. Inducers of CYP3A4 or CYP2C8 within 14 days or 5 half-lives, whichever is longer, prior to MRTX849 dosing initiation.
  3. Proton-pump inhibitors within 7 days or 5 half-lives, whichever is longer, prior to MRTX849 dosing initiation.

     3. Active brain metastases or carcinomatous meningitis. Patients are eligible if brain metastases are adequately treated and patients are neurologically stable for at least 2 weeks prior to study entry without the use of corticosteroids or are on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent).

     4. History of significant hemoptysis or hemorrhage within 4 weeks prior to MRTX849 dosing initiation.

     5. Any of the following cardiac abnormalities:

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  1. Unstable angina pectoris or myocardial infarction within 6 months prior to

     MRTX849 dosing initiation.
  2. Symptomatic or uncontrolled atrial fibrillation within 6 months prior to

     MRTX849 dosing initiation.
  3. Congestive heart failure ≥ New York Heart Association (NYHA) Class 3 within 6 months prior to MRTX849 dosing initiation.
  4. Prolonged QTc interval \> 480 milliseconds.

     6. History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow oral medications.

     7. Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B or C infection. Note that the following are permitted:

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  1. Patients treated for hepatitis C (HCV) with no detectable viral load;
  2. Patients treated for HIV with no detectable viral load for at least 1 month prior to study entry while on a stable regimen of agents that are not strong inhibitors of CYP3A4; and
  3. Patients with hepatitis B (HBV) receiving prophylaxis against reactivation of hepatitis B (either \[HBsAg-positive with normal ALT and HBV DNA \<2,000 IU/mL or \<10,000 copies/mL\] or \[HBsAg-negative and anti-HBc-positive\]).

     8. Major surgery within 4 weeks prior to MRTX849 dosing initiation.

     9. History of stroke or transient ischemic attack within 6 months prior to MRTX849 dosing initiation.

     10. Known or suspected presence of another malignancy that could be mistaken for the malignancy under study during disease assessments.

     11. Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented within the screening period prior to MRTX849 dosing initiation.

     12. Breast-feeding or planning to breast feed during the study or within 6 months after study treatment with MRTX849.

     13. Any serious illness, uncontrolled intercurrent illness, psychiatric illness, active or uncontrolled infection, or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with the patient's participation in the study, or with the interpretation of the results.

Primary outcomes:
measure: Main PK parameters: Cmax
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: Tmax
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: AUC0-12
timeFrame: Approximately 12 hours after dose initiation
measure: Main PK parameters: AUC0-t
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: AUC0-∞
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: t1/2
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: CL/F
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: Vz/F
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: Cmax, ss
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: Tmax, ss
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: Cmin, ss
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: Cavg
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: AUCss
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: Rac for Cmax and AUCtau
timeFrame: Approximately 2 weeks after dose initiation
measure: Main PK parameters: PTR
timeFrame: Approximately 2 weeks after dose initiation
Secondary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: Approximately 12 months after dose initiation
measure: Incidence of Treatment-Emergent Serious Adverse Events
timeFrame: Approximately 12 months after dose initiation
measure: Incidence of Treatment-Related Adverse Events
timeFrame: Approximately 12 months after dose initiation
measure: Incidence of Treatment-Related Serious Adverse Events
timeFrame: Approximately 12 months after dose initiation
measure: Incidence of abnormal laboratory value
timeFrame: Approximately 12 months after dose initiation
Other outcomes:
measure: Objective response rate (ORR)
timeFrame: Approximately 12 months after dosed
measure: Duration of response (DOR)
timeFrame: Approximately 12 months after dosed
Locations:
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Chongqing
country: China
facility: Chongqing University Cancer Hospital
state: Chongqing
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Union hospital, Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Changchun
country: China
facility: The first Hospital of Jilin University
state: Jilin
city: Linyi
country: China
facility: Lin Yi Cancer Hospital
state: Shandong
city: Shanghai
country: China
facility: Shanghai Chest Hospital
state: Shanghai
Study officials:
References: