Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation

Colorectal Cancer Clinical Trial

— KontRASt-03  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05358249
• Other study ID #: CJDQ443E12101
• Secondary ID: 2021-006196-42
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 24, 2022
• Est. completion date: June 16, 2027

Study information

• Verified date: February 2024
• Source: Novartis
• Contact: Novartis Pharmaceuticals
• Phone: 1-888-669-6682
• Email: novartis.email[@]novartis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 346
• Est. completion date: June 16, 2027
• Est. primary completion date: May 5, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Non-Small Cell Lung
• Carcinoma, Non-Small-Cell Lung
• Colorectal Cancer
• Colorectal Carcinoma
• Colorectal Neoplasms
• Colorectal Tumors
• KRAS G12C Mutant Solid Tumors
• Lung Neoplasms
• Neoplasms
• Neoplasms, Colorectal
• Non-Small Cell Lung Cancer
• Non-Small Cell Lung Carcinoma
• Nonsmall Cell Lung Cancer

Intervention

Drug:
• JDQ443
KRAS G12C inhibitor, oral
• trametinib
MEK inhibitor, oral
• Ribociclib
CDK4/6 inhibitor, oral

Biological:
• cetuximab
EGFR inhibitor, intravenous

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Leuven
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Lyon
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Ulm
Italy	Novartis Investigative Site	Milano	MI
Korea, Republic of	Novartis Investigative Site	Seoul
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
United States	Dana Farber Cancer Institute Dept.of DFCI	Boston	Massachusetts
United States	Massachusetts General Hospital .	Boston	Massachusetts
United States	NYU School of Medicine Langone Health	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  France,  Germany,  Italy,  Korea, Republic of,  Singapore,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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