The Clinical Trial to Evaluate the Pharmacokinetics and Safety of MRTX849 in Patients With Advanced Solid Tumors

NCT05263986 | Unknown Phase 1

• 1 other identifier: ZL-2312-005
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 8

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).

Conditions

Advanced or Metastatic Solid Tumor

Keywords

KRAS G12C mutation

Outcome Measures

Primary Outcomes (15)

• Main PK parameters: Cmax

  Maximum plasma concentration (Cmax) after single dose

  Approximately 2 weeks after dose initiation

• Main PK parameters: Tmax

  Maximum plasma concentration (Tmax) after single dose

  Approximately 2 weeks after dose initiation

• Main PK parameters: AUC0-12

  Area under the concentration-time curve from time 0 to 12 hours (AUC0-12) after single dose

  Approximately 12 hours after dose initiation

• Main PK parameters: AUC0-t

  Area under the concentration-time curve from time 0 to the last measurable concentration (AUC0-t) after single dose

  Approximately 2 weeks after dose initiation

• Main PK parameters: AUC0-∞

  Area under the concentration-time curve from time 0 to infinity (AUC0-∞) after single dose

  Approximately 2 weeks after dose initiation

• Main PK parameters: t1/2

  Terminal half-life (t1/2) after single dose

  Approximately 2 weeks after dose initiation

• Main PK parameters: CL/F

  Apparent clearance (CL/F) after single dose

  Approximately 2 weeks after dose initiation

• Main PK parameters: Vz/F

  Apparent volume of distribution associated with the terminal phase (Vz/F) after single dose

  Approximately 2 weeks after dose initiation

• Main PK parameters: Cmax, ss

  Maximum plasma concentration at steady state (Cmax, ss)

  Approximately 2 weeks after dose initiation

• Main PK parameters: Tmax, ss

  Time to observed maximum plasma concentration at steady state (Tmax, ss)

  Approximately 2 weeks after dose initiation

• Main PK parameters: Cmin, ss

  Trough concentration (Cmin, ss)

  Approximately 2 weeks after dose initiation

• Main PK parameters: Cavg

  Average concentration during a dosing interval (Cavg)

  Approximately 2 weeks after dose initiation

• Main PK parameters: AUCss

  Area under the concentration-time curve at steady state (AUCss)

  Approximately 2 weeks after dose initiation

• Main PK parameters: Rac for Cmax and AUCtau

  Accumulation ratio (Rac for Cmax and AUCtau)

  Approximately 2 weeks after dose initiation

• Main PK parameters: PTR

  Peak-to-trough ratio (PTR)

  Approximately 2 weeks after dose initiation

Secondary Outcomes (5)

• Incidence of Treatment-Emergent Adverse Events

  Approximately 12 months after dose initiation

• Incidence of Treatment-Emergent Serious Adverse Events

  Approximately 12 months after dose initiation

• Incidence of Treatment-Related Adverse Events

  Approximately 12 months after dose initiation

• Incidence of Treatment-Related Serious Adverse Events

  Approximately 12 months after dose initiation

• Incidence of abnormal laboratory value

  Approximately 12 months after dose initiation

Other Outcomes (2)

• Objective response rate (ORR)

  Approximately 12 months after dosed

• Duration of response (DOR)

  Approximately 12 months after dosed

Study Arms (1)

Assigned Interventions

EXPERIMENTAL

In the 5-day PK lead-in period, patients will receive a single oral dose of 600 mg MRTX849 on Day 1 and there will be no drug administration in the subsequent 4 days. Following the PK lead-in period, patients will receive MRTX849 600 mg BID (an interval of approximate 12 hours between 2 doses) orally in 3-week cycles until disease progression, unacceptable AEs, patient refusal, or death. Dosing schedules may be adjusted depending on safety results.

Drug: MRTX849

Interventions

MRTX849 DRUG

Approximately 18-24 patients to ensure at least 12 PK evaluable patients. Subjects will be administered a single oral dose of 600 mg MRTX849 in PK lead in D1, and will start the dosing regimen of 600 mg BID orally from C1D1.

Assigned Interventions

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation.
• \. Unresectable or metastatic disease.
• \. Available therapy:
• no available treatment with curative intent,
• no available standard-of-care treatment or patient is ineligible or declines treatment.
• \. Presence of measurable or non-measurable disease per RECIST 1.1.
• \. Age ≥ 18 years.
• \. Life expectancy of at least 3 months.
• \. Most recent prior systemic therapy (e.g., chemotherapy, immunotherapy, or investigational agent) and radiation therapy discontinued at least 2 weeks before first dose date.
• \. Recovery from the adverse effects of prior therapy at the time of enrollment to ≤ Grade 1 (excluding alopecia).
• \. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• \. Laboratory values within the ranges below during the screening period:
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• Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0 x 109/L)
• Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L)

You may not qualify if:

• \. 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
• \. Use of any drugs or substances including herbal supplements known or suspected to alter MRTX849 absorption, distribution, metabolism, or excretion:
• 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.
• Inducers of CYP3A4 or CYP2C8 within 14 days or 5 half-lives, whichever is longer, prior to MRTX849 dosing initiation.
• Proton-pump inhibitors within 7 days or 5 half-lives, whichever is longer, prior to MRTX849 dosing initiation.
• \. 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).
• \. History of significant hemoptysis or hemorrhage within 4 weeks prior to MRTX849 dosing initiation.
• \. Any of the following cardiac abnormalities:
• <!-- -->
• Unstable angina pectoris or myocardial infarction within 6 months prior to
• MRTX849 dosing initiation.
• Symptomatic or uncontrolled atrial fibrillation within 6 months prior to
• MRTX849 dosing initiation.
• Congestive heart failure ≥ New York Heart Association (NYHA) Class 3 within 6 months prior to MRTX849 dosing initiation.
• Prolonged QTc interval \> 480 milliseconds.

Sponsors & Collaborators

• Zai Lab (Shanghai) Co., Ltd.: lead
• Mirati Therapeutics Inc.: collaborator

Study Sites (8)

Beijing Cancer Hospital

Beijing, Beijing Municipality, China

Location

Chongqing University Cancer Hospital

Chongqing, Chongqing Municipality, China

Location

Henan Cancer Hospital

Zhengzhou, Henan, China

Location

Union hospital, Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, China

Location

Hunan Cancer Hospital

Changsha, Hunan, China

Location

The first Hospital of Jilin University

Changchun, Jilin, China

Location

Lin Yi Cancer Hospital

Linyi, Shandong, China

Location

Shanghai Chest Hospital

Shanghai, Shanghai Municipality, China

Location

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

adagrasib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 13, 2022
• First Posted: March 3, 2022
• Study Start: May 30, 2022
• Primary Completion: October 31, 2023
• Study Completion: October 31, 2023
• Last Updated: February 27, 2023

Record last verified: 2023-02

Locations

CN (8)