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

Phase 2Active Not RecruitingNCT05358249

Novartis Pharmaceuticals74 enrolled

Overview

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.

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

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

KRAS G12C Mutant Solid Tumors Carcinoma, Non-Small Cell Lung Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer

Interventions

JDQ443DRUG

KRAS G12C inhibitor, oral

trametinibDRUG

MEK inhibitor, oral

RibociclibDRUG

CDK4/6 inhibitor, oral

cetuximabBIOLOGICAL

EGFR inhibitor, intravenous

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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

Locations (13)

Massachusetts General Hospital

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

NYU School of Medicine

New York, New York, United States

Novartis Investigative Site

Leuven, Belgium

Novartis Investigative Site

Bordeaux, France

Novartis Investigative Site

Lyon, France

Novartis Investigative Site

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Singapore, Singapore

Novartis Investigative Site

Seoul, Korea, South Korea

...and 3 more locations

Outcomes

Primary Outcomes

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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 24 months

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 24 months

Phase II: PFS by BIRC per RECIST 1.1

Time frame: 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.

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 24 months