Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (KontRASt-03)

KontRASt-03: A Phase Ib/II, Multicenter, Open-label Platform Study of JDQ443 With Select Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation

This is Phase Ib/II, multicenter, open-label adaptive platform study of JDQ443 with select therapies in patients with advanced solid tumors harboring the KRAS G12C mutation.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Colorectal Cancer; Non-Small Cell Lung Cancer; Nonsmall Cell Lung Cancer; Carcinoma, Non-Small Cell Lung; Colorectal Tumors; Colorectal Carcinoma; Neoplasms, Colorectal; Non-Small Cell Lung Carcinoma; KRAS G12C Mutant Solid Tumors
• Intervention / Treatment: Drug: JDQ443; Drug: trametinib; Drug: Ribociclib; Biological: cetuximab

Detailed Description

JDQ443 will be considered "backbone" treatment in this trial and combined with selected therapies, or "partner(s)". The combination of a backbone and a partner will constitute a treatment arm. After dose escalation, treatment arms that reach a maximum tolerated dose /recommended dose and are determined to be safe may, but are not required to, proceed to Phase II to further explore safety, tolerability, and anti-tumor activity.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2; Phase 1

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• France
  • Bordeaux, France, 33076
    • Novartis Investigative Site
  • Lyon, France, 69373
    • Novartis Investigative Site
• Germany
  • Baden-Wurttemberg
    • Freiburg im Breisgau, Baden-Wurttemberg, Germany, 79106
      • Novartis Investigative Site
• Italy
  • MI
    • Milan, MI, Italy, 20162
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• South Korea
  • Seoul, South Korea, 03080
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08036
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Madrid, Spain, 28050
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New York
    • New York, New York, United States, 10015
      • NYU School of Medicine

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Dose Escalation:

- Patients with advanced (metastatic or unresectable) KRAS G12C mutant solid tumors who have received standard of care therapy or are ineligible to receive such therapy.

Phase II:

• Patients with advanced (metastatic or unresectable) KRAS G12C mutant non-small cell lung cancer who have received platinum-based chemotherapy regimen and immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy
• Patients with advanced (metastatic or unresectable) KRAS G12C mutant colorectal cancer who have received fluropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, unless patient was ineligible to such therapy.

All patients:

• ECOG performance status of 0 or 1.
• Patients must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines.

Exclusion Criteria:

• Tumors harboring driver mutations that have approved targeted therapies, with the exception of KRAS G12C mutations
• Prior treatment with a KRAS G12C inhibitor is excluded for patients in a subset of groups in Phase II.
• Active brain metastases, including symptomatic brain metastases or known leptomeningeal disease
• Clinically significant cardiac disease or risk factors at screening
• Insufficient bone marrow, hepatic or renal function at screening Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: JDQ443+trametinib; JDQ443 in combination with trametinib	Drug: JDQ443; KRAS G12C inhibitor, oral; Drug: trametinib; MEK inhibitor, oral; Other Names: TMT212
Experimental: JDQ443+ribociclib; JDQ443 in combination with ribociclib	Drug: JDQ443; KRAS G12C inhibitor, oral; Drug: Ribociclib; CDK4/6 inhibitor, oral; Other Names: LEE011
Experimental: JDQ443+cetuximab; JDQ443 in combination with cetuximab	Drug: JDQ443; KRAS G12C inhibitor, oral; Biological: cetuximab; EGFR inhibitor, intravenous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose escalation: Incidence and severity of dose limiting toxicities (DLTs) of each combination treatment.	A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value that is not primarily related to disease, disease progression, intercurrent illness/injury, or concomitant medications that occurs within the first 28 days of study treatment and meets a defined criteria.	28 days
Dose escalation: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment	All information obtained on AE will be displayed by treatment group. Summary tables will include only AEs that started/worsened during the cycles of treatment (treatment-emergent AEs).	24 months
Dose escalation: Frequency of dose interruptions and reductions, by treatment	The number of patients with dose adjustments (reductions and interruptions) will be summarized by treatment group.	24 months
Dose Escalation: Dose intensity by treatment	Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of response.	24 months
PhaseII: Overall Response Rate by Blinded Independent Review Committee (BIRC) per RECIST 1.1	ORR is the proportion of patients with a best overall response (BOR) of Complete Response (CR) or Partial Response (PR).	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose escalation and Phase II: ORR by local review per RECIST 1.1	ORR is the proportion of patients with a BOR of CR or PR.	24 months
Dose escalation and Phase II: Disease Control Rate (DCR) by local review per RECIST 1.1	DCR is the proportion of patients with a BOR of CR or PR or Stable Disease (SD). The objective of this endpoint is to summarize patients with signs of "activity" defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.	24 months
Dose escalation and Phase II: Duration of Response (DoR) by local review per RECIST 1.1	Duration of response is defined as the time from the date of the first documented response (CR or PR), to the date of first documented progression, or death due any cause.	24 months
Dose escalation and Phase II: Progression-Free Survival (PFS) by local review per RECIST 1.1	PFS is defined as the time from the date of start of treatment to the date of the first documented progression, or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.	24 months
Phase II: DCR by BIRC per RECIST 1.1	DCR is the proportion of patients with a BOR of CR or PR or SD. The objective of this endpoint is to summarize patients with signs of "activity" defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.	24 months
Phase II: DoR by BIRC per RECIST 1.1	Duration of response is defined as the time from the date of the first documented response (CR or PR), to the date of first documented progression, or death due any cause.	24 months
Phase II: PFS by BIRC per RECIST 1.1	PFS is defined as the time from the date of start of treatment to the date of the first documented progression, or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.	24 months
Phase II: Overall survival (OS)	OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive.	24 months
Dose escalation and Phase II: PK parameters - Maximum Concentration (Cmax), as applicable per arm	The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass x volume-1)	5 months
Dose escalation and Phase II: PK parameters - Minimum Concentration (Cmin), as applicable per arm	Observed concentration at the end of a dosing interval (taken directly before next administration)	5 months
Dose escalation: Time to achieve Cmax - Tmax, as applicable per arm	The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time)	5 months
Dose escalation and Phase II: Plasma or serum concentration vs time profiles - AUCtau, as applicable per arm	The Area under curve calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)	5 months
Dose escalation and Phase II: Plasma or serum concentration vs time profiles - AUCinf, as applicable per arm	The AUC from time zero to infinity (mass x time x volume-1)	5 months
Phase II: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment	All information obtained on AE will be displayed by treatment group. Summary tables will include only AEs that started/worsened during the cycles of treatment (treatment-emergent AEs).	24 months
Phase II: Frequency of dose interruptions and reductions, by treatment	The number of patients with dose adjustments (reductions and interruptions) will be summarized by treatment group.	24 months
Phase II: Dose intensity by treatment	Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of response.	24 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2022
• Primary Completion (Estimated): July 29, 2026
• Study Completion (Estimated): July 30, 2026

Study Registration Dates

• First Submitted: April 27, 2022
• First Submitted That Met QC Criteria: April 27, 2022
• First Posted (Actual): May 3, 2022

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 13, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; advanced solid tumors; targeted therapy; KRAS G12C; ribociclib; trametinib; CRC; cetuximab; JDQ443
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Respiratory Tract Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Colorectal Neoplasms; Carcinoma, Non-Small-Cell Lung; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cetuximab; trametinib; ribociclib; JDQ443
• Other Study ID Numbers: CJDQ443E12101; 2021-006196-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

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