A Study of Repotrectinib in Combination With Other Anticancer Therapies for the Treatment of Subjects With KRAS-Mutant Solid Tumors

A Phase 1b/2 Study of Repotrectinib in Combination With Other Anticancer Therapies for the Treatment of Subjects With KRAS-Mutant Advanced Solid Tumors (TRIDENT-2)

A Phase 1b/2 Study of Repotrectinib in Combination with Other Anticancer Therapies for the Treatment of Subjects with KRAS-Mutant Advanced Solid Tumors (TRIDENT-2)

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumor; Metastatic Solid Tumor; KRAS Mutation-Related Tumors
• Intervention / Treatment: Drug: TPX-0005; Drug: Trametinib

Detailed Description

Phase 1 Dose Escalation: To evaluate tolerability of repotrectinib at increasing dose levels in combination with other anticancer therapies for the treatment of subjects with locally advanced or metastatic KRAS-mutant solid tumors

Phase 2 Efficacy Evaluation: Investigate the anti-tumor efficacy and safety of repotrectinib in combination with other anticancer therapies for the treatment of patients with locally advanced or metastatic KRAS-mutant solid tumors.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • California
    • California City, California, United States, 90033
      • Local Institution - 2101
    • California City, California, United States, 92663
      • Local Institution - 2109
  • Colorado
    • Denver, Colorado, United States, 80218
      • Local Institution - 2106
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Local Institution - 2108
  • Texas
    • Houston, Texas, United States, 77030
      • Local Institution - 2107
  • Virginia
    • Virginia Beach, Virginia, United States, 22031
      • Local Institution - 2102

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 (or as required by local regulation).
• Histological or cytological confirmation of unresectable or metastatic solid tumor malignancy harboring a KRAS mutation.
• No more than 3 prior standard treatments appropriate for tumor type and stage of disease.
• ECOG performance status ≤ 1.
• Existence of measurable disease (according to Response evaluation criteria in solid tumors [RECIST v1.1] criteria).
• Subjects with asymptomatic CNS metastases and/or asymptomatic leptomeningeal carcinomatosis are eligible.
• Adequate organ function.

Exclusion Criteria:

• Major surgery within four weeks of the start of treatment.
• Previous other cancer requiring treatment within the previous two years.
• Clinically significant cardiovascular disease.
• Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTc) > 470 msec obtained from three ECGs and any factors that increase the risk of QTc prolongation or arrhythmic events
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG
• Known clinically significant active infections not controlled with systemic treatment (bacterial, fungal, viral including HIV positivity).
• Gastrointestinal disease or other malabsorption syndromes that would impact drug absorption.
• Subjects being treated with or anticipating the need for treatment with strong CYP3A inhibitors or inducers.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TPX-0005 + Trametinib; TPX-0005 + Trametinib Dose Escalation and Dose Expansion Dose escalation: KRAS G12D mutant advanced solid tumors. Dose expansion: KRAS G12D locally advanced or metastatic NSCLC	Drug: TPX-0005; Oral TPX-0005 capsules; Other Names: repotrectinib; Drug: Trametinib; Oral trametinib tablets; Other Names: Mekinist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities	Number of participants with first cycle DLTs to determine Mean Tolderable Dose (MTD) and/or RP2D. A DLT is defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications that meets the criteria defined in each subprotocol. The MTD is defined as the highest dose level of repotrectinib given in combination with other anticancer therapy observed to cause a DLT in fewer than 33% of the treated subjects in the first treatment cycle (i.e., Cycle 1).	From initial dose to end of first cycle of treatment, approximately 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) Assessed the Investigator Using RECIST v1.1.	The ORR will be defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR). A confirmed response is a response that persists on a repeat imaging performed at least 4 weeks after initial documentation of response. Participants with a confirmed objective response (CR or PR) will be referred to as responders. Radiographic confirmation of objective tumor response (CR or PR) or disease progression will be based on RECIST v1.1. The ORR will be reported as the percentage of responders by RECIST v1.1 along with the corresponding two-sided 95% Clopper-Pearson exact CI. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = >=30% decrease in the sum diameters of target lesions.	From screening to end of treatment approximately 10 months
Cmax of Repotrectinib	Cmax is defined as maximum plasma concentration of the drug.	At Cycle 1 Day 1 and Cycle 1 Day 22
Tmax of Repotrecitinib	Tmax is defined is the time to maximum plasma concentration	At Cycle 1 Day 1 and Cycle 1 Day 22
AUC 0-24 of Repotrecitinib	Area under the plasma concentration time-curve. AUC from time 0 to 24 hours after dose.	At Cycle 1 Day 1 and Cycle 1 Day 22
Cmax of Trametinib	Cmax is defined as maximum plasma concentration of the drug.	At Cycle 1 Day 1 and Cycle 1 Day 22
Tmax of Trametinib	Tmax is defined is the time to maximum plasma concentration	At Cycle 1 Day 1 and Cycle 1 Day 22
AUC 0-24 of Trametinib	Area under the plasma concentration time-curve. AUC from time 0 to 24 hours after dose.	At Cycle 1 Day 1 and Cycle 1 Day 22

Collaborators and Investigators

• Sponsor: Turning Point Therapeutics, Inc.
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2021
• Primary Completion (Actual): March 1, 2023
• Study Completion (Actual): March 1, 2023

Study Registration Dates

• First Submitted: September 13, 2021
• First Submitted That Met QC Criteria: October 6, 2021
• First Posted (Actual): October 8, 2021

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Advanced Solid Tumor; Metastatic Solid Tumor; KRAS; Advanced/metastatic disease; KRAS-mutant
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib
• Other Study ID Numbers: CA127-1025 (Other Identifier: BMS Protocol ID); TPX-0005-13 (Other Identifier: Turning Point Therapeutics Protocol ID)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No