Study of JDQ443 in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (KontRASt-01)

A Phase Ib/II Open-label, Multi-center Dose Escalation Study of JDQ443 in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation

This is a phase Ib/II open label study. The escalation part will characterize the safety and tolerability of JDQ443 single agent and JDQ443 in combination with the other study treatments (TNO155 and tislelizumab) in advanced solid tumor patients. After the determination of the maximum tolerated dose / recommended dose for a particular treatment arm, dose expansion will assess the anti-tumor activity and further assess the safety, tolerability, and PK/PD of each regimen at the maximum tolerated dose / recommended dose or lower dose.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung; Lung Cancer; Neoplasms, Lung; Pulmonary Neoplasms; Neoplasms, Pulmonary; Pulmonary Cancer; Cancer of Lung; Cancer of the Lung; KRAS G12C Mutant Solid Tumors; Carcinoma, Colorectal
• Intervention / Treatment: Drug: JDQ443; Drug: TNO155; Biological: tislelizumab

• Study Type: Interventional
• Enrollment (Actual): 344
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H2W 1T8
      • Novartis Investigative Site
• China
  • Beijing, China, 100036
    • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Novartis Investigative Site
• Denmark
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
• France
  • Lyon, France, 69373
    • Novartis Investigative Site
  • Marseille, France, 13273
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Baden-Wurttemberg
    • Freiburg im Breisgau, Baden-Wurttemberg, Germany, 79106
      • Novartis Investigative Site
  • North Rhine-Westphalia
    • Cologne, North Rhine-Westphalia, Germany, 50937
      • Novartis Investigative Site
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • Novartis Investigative Site
• Hong Kong
  • Hong Kong, Hong Kong, 999077
    • Novartis Investigative Site
• Italy
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20133
      • Novartis Investigative Site
    • Milan, MI, Italy, 20162
      • Novartis Investigative Site
• Japan
  • Aichi-ken
    • Nagoya, Aichi-ken, Japan, 4668560
      • Novartis Investigative Site
  • Chiba
    • Kashiwa, Chiba, Japan, 2778577
      • Novartis Investigative Site
  • Osaka
    • Osaka, Osaka, Japan, 5418567
      • Novartis Investigative Site
  • Tokyo
    • Chuo Ku, Tokyo, Japan, 1040045
      • Novartis Investigative Site
    • Koto Ku, Tokyo, Japan, 1358550
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119074
    • Novartis Investigative Site
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• South Korea
  • Seoul, South Korea, 03722
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08035
    • Novartis Investigative Site
  • Madrid, Spain, 28050
    • Novartis Investigative Site
  • Málaga, Spain, 29010
    • Novartis Investigative Site
  • Valencia, Spain, 46010
    • Novartis Investigative Site
  • A Coruna
    • Santiago Compostela, A Coruna, Spain, 15706
      • Novartis Investigative Site
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine-Winship Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Hillman Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • Uni Of TX MD Anderson Cancer Cntr

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Adult patients with advanced (metastatic or unresectable) KRAS G12C mutant solid tumors who have received standard of care or are intolerant or ineligible to approved therapies
• ECOG Performance Status of 0 or 1
• At least one measurable lesion as defined by RECIST 1.1
• Prior treatment with a KRAS G12C inhibitor may be allowed for dose escalations of combinations and a subset of groups in dose expansion

Exclusion Criteria:

• Tumors harboring driver mutations that have approved targeted therapies, with the exception of KRAS G12C mutations
• Symptomatic brain metastases or known leptomeningeal disease. Patients with asymptomatic treated or untreated brain metastases may be eligible
• Clinically significant cardiac disease or risk factors at screening
• A medical condition that results in increased photosensitivity 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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; JDQ443	Drug: JDQ443; KRAS G12C inhibitor
Experimental: Arm B; JDQ443 in combination with TNO155	Drug: JDQ443; KRAS G12C inhibitor; Drug: TNO155; SHP2 inhibitor
Experimental: Arm C; JDQ443 in combination with tislelizumab	Drug: JDQ443; KRAS G12C inhibitor; Biological: tislelizumab; Anti PD1 antibody
Experimental: Arm D; JDQ443 in combination with TNO155 and tislelizumab	Drug: JDQ443; KRAS G12C inhibitor; Drug: TNO155; SHP2 inhibitor; Biological: tislelizumab; Anti PD1 antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Escalation: Incidence and severity of dose limiting toxicities (DLTs) during the first cycle of monotherapy or combination treatment	A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment	21 days
Dose Escalation: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)	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	Tolerability of study drug will be assessed by summarizing the number of and reason for dose delays and dose reductions.	24 months
Dose Expansion: Overall response rate (ORR) per RECIST v1.1, by treatment	Overall response rate is defined as the proportion of patients with a BOR of CR or PR according to RECIST 1.1, and will be summarized along with the corresponding 95% exact binomial confidence interval (CI). Applies to all groups except the brain metastasis group.	24 months
Dose expansion: Overall intracranial response rate (OIRR) per mRANO-BM	OIRR per mRANO-BM is defined as the proportion of participants with a best overall intracranial response (BOIR) of CR or PR according to mRANO-BM criteria, and will be summarized along with the corresponding 90% and 95% exact CI. Applies to brain metastasis group only.	24 months
Dose Escalation: Dose intensity by treatment	Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of treatment.	24 months
Dose expansion: Incidence and severity of AEs and SAEs	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). Applies to JDQ443 dose randomization group only.	24 months
Dose expansion: frequency of dose interruptions and reductions, by treatment	Tolerability of study drug will be assessed by summarizing the number of and reason for dose delays and dose reductions. Applies to JDQ443 dose randomization group only.	24 months
Dose expansion: Dose intensity by treatment	Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of treatment. Applies to JDQ443 dose randomization group only	24 months
Dose expansion: ORR per RECIST 1.1 of JDQ443 single agent in patients with non-small cell lung cancer (JDQ443 dose randomization group only)	Overall response rate is defined as the proportion of patients with BOR of CR or PR according to RECIST 1.1, and will be summarized along with the corresponding 95% exact binomial confidence interval (CI). Applies to JDQ443 dose randomization group only	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Escalation and Expansion: ORR per RECIST v1.1	Overall response rate is defined as the proportion of patients with a BOR of CR or PR according to RECIST 1.1, and will be summarized along with the corresponding 95% exact binomial confidence interval (CI)	24 months
Dose Escalation and Expansion: Best Overall Response (BOR) per RECIST v1.1	BOR is defined as the best overall confirmed response recorded from the start of the treatment until disease progression/recurrence.	24 months
Dose Escalation and Expansion: Progression-free survival (PFS) per RECIST v1.1, Overall Survival (OS)	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. If patient has not had an event, PFS will be censored at the date of last adequate tumor assessment. PFS will be summarized using the Kaplan-Meier method, along with 95% CI	24 months
Dose Escalation and Expansion: Duration of Response (DOR) per RECIST v1.1	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. Estimates will use Kaplan-Meier method, and median DOR and corresponding 95% CI will be presented.	24 months
Dose Escalation and Expansion: Disease Control Rate (DCR) per RECIST v1.1	The disease control rate is calculated as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease. It will be summarized along with the corresponding 95% exact CI	24 months
Dose Escalation and Expansion: Plasma or serum concentration vs time profiles (AUC) by treatment	AUC is defined as area under the plasma or serum concentration versus time curve after a dose of JDQ443, TNO155 and tislelizumab	Up to 24 months
Dose Escalation and Expansion: Plasma concentration (Cmax) by treatment	Cmax is defined as the maximum observed plasma or serum drug concentration after single dose administration.	Up to 24 months
Dose Escalation and Expansion: Time to achieve Cmax (Tmax) by treatment	Tmax is defined as the time to reach maximum plasma or serum drug concentration after single dose administration.	Up to 24 months
Dose Escalation and Expansion: Antidrug antibody (ADA) incidence by treatment	To evaluate the immunogenicity of tislelizumab when dosed in combination with JDQ443 and/or TNO155 - only applicable to Arms C and D	Up to 24 months
Dose Expansion: Dose intensity by treatment		24 months
Dose Expansion: Frequency of dose interruptions and reductions, by treatment	Tolerability of study drug will be assessed by summarizing the number of and reason for dose delays and dose reductions.	24 months
Dose Expansion: Incidence and severity of dose limiting toxicities (DLTs) during the first cycle of monotherapy or combination treatment	A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment	21 days
Dose Expansion: Incidence and severity of AEs and SAEs by treatment		24 months
Dose expansion: Intracranial disease control rate (IDCR) per mRANO-BM	IDCR is the proportion of participants with a confirmed BOIR of CR or PR or SD (or non-CR/non-PD) per mRANO-BM criteria. It will be summarized along with the corresponding 90% and 95% CI. Applies to the brain metastasis group only.	24 months
Dose expansion: Best overall intracranial response (BOIR) per mRANO-BM	BOIR is defined as the best overall confirmed response recorded from the start of the treatment until disease progression/recurrence per mRANO-BM, or until patient comes off study, whichever comes first. BOIR will be summarized along with the corresponding 95% exact CI. Applies to the brain metastasis group only.	24 months
Dose expansion: Intracranial progression free survival (IPFS) per mRANO-BM	IPFS is defined as the time from the date of start of treatment to the date of the first documented progression per mRANO-BM, or death due to any cause. If a patient has not had an event, IPFS will be censored at the date of last adequate tumor assessment. IPFS will be summarized using the Kaplan-Meier method. Median IPFS and IPFS probability at pre specified time-points will be presented along with 95% CI. Applies to the brain metastasis group only.	24 months
Dose expansion: Duration of intracranial response (DOIR) per mRANO-BM	DOIR is defined as the time from the date of first documented intracranial response of either CR or PR to the date of the first documented intracranial progression as per mRANO-BM criteria as assessed by central review or date of death due to underlying cause of cancer. DOIR will be summarized using the KM method if data permit. Median DOIR, with corresponding 95% CI. KM estimates for DOIR proportions at specific time points, along with 95% CI will also be provided. Applies to the brain metastasis group only.	24 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Lorthiois E, Gerspacher M, Beyer KS, Vaupel A, Leblanc C, Stringer R, Weiss A, Wilcken R, Guthy DA, Lingel A, Bomio-Confaglia C, Machauer R, Rigollier P, Ottl J, Arz D, Bernet P, Desjonqueres G, Dussauge S, Kazic-Legueux M, Lozac'h MA, Mura C, Sorge M, Todorov M, Warin N, Zink F, Voshol H, Zecri FJ, Sedrani RC, Ostermann N, Brachmann SM, Cotesta S. JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12C for the Treatment of Solid Tumors. J Med Chem. 2022 Dec 22;65(24):16173-16203. doi: 10.1021/acs.jmedchem.2c01438. Epub 2022 Nov 18.

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2021
• Primary Completion (Estimated): January 25, 2027
• Study Completion (Estimated): January 25, 2027

Study Registration Dates

• First Submitted: January 5, 2021
• First Submitted That Met QC Criteria: January 5, 2021
• First Posted (Actual): January 7, 2021

Study Record Updates

• Last Update Posted (Actual): March 18, 2026
• Last Update Submitted That Met QC Criteria: March 17, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: colorectal cancer; Advanced cancer; Targeted therapy; PD-1; SHP2; KRAS G12C; Metastatic cancer; KRAS; Enzyme inhibitor; Non-small-cell lung cancer; Molecular mechanisms of pharmacological action
• Additional Relevant MeSH Terms: Pathologic Processes; 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; Neoplastic Processes; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pathological Conditions, Signs and Symptoms; Lung Neoplasms; Colorectal Neoplasms; Neoplasm Metastasis; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Antineoplastic Agents; tislelizumab; JDQ443
• Other Study ID Numbers: CJDQ443A12101; 2020-004129-22 (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