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

Phase 1

Active, not recruiting

• Conditions: KRAS G12C Mutant Solid Tumors; Carcinoma, Non-Small-Cell Lung; Carcinoma, Colorectal; Cancer of Lung; Cancer of the Lung; Neoplasms, Lung; Neoplasms, Pulmonary; Lung Cancer; Pulmonary Neoplasms; Pulmonary Cancer
• Interventions: Drug: JDQ443; Drug: TNO155; Biological: tislelizumab

• Registration Number: NCT04699188
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-01-05
• Study First Submitted QC: 2021-01-05
• Study First Posted: 2021-01-07
• Study Start: 2021-02-24
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-16
• Last Update Posted: 2024-12-17
• Primary Completion: 2026-04-30
• Study Completion: 2026-04-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 344

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm D	TNO155	JDQ443 in combination with TNO155 and tislelizumab
Arm A	JDQ443	JDQ443
Arm B	JDQ443	JDQ443 in combination with TNO155
Arm B	TNO155	JDQ443 in combination with TNO155
Arm C	JDQ443	JDQ443 in combination with tislelizumab
Arm C	tislelizumab	JDQ443 in combination with tislelizumab
Arm D	JDQ443	JDQ443 in combination with TNO155 and tislelizumab
Arm D	tislelizumab	JDQ443 in combination with TNO155 and tislelizumab

Primary Outcome Measures

Name	Time	Method
Dose Escalation: Incidence and severity of dose limiting toxicities (DLTs) during the first cycle of monotherapy or combination treatment	21 days	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
Dose Escalation: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)	24 months	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).
Dose Escalation: Frequency of dose interruptions and reductions, by treatment	24 months	Tolerability of study drug will be assessed by summarizing the number of and reason for dose delays and dose reductions.
Dose expansion: frequency of dose interruptions and reductions, by treatment	24 months	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.
Dose Expansion: Overall response rate (ORR) per RECIST v1.1, by treatment	24 months	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.
Dose expansion: Overall intracranial response rate (OIRR) per mRANO-BM	24 months	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.
Dose expansion: ORR per RECIST 1.1 of JDQ443 single agent in patients with non-small cell lung cancer (JDQ443 dose randomization group only)	24 months	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
Dose Escalation: Dose intensity by treatment	24 months	Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of treatment.
Dose expansion: Incidence and severity of AEs and SAEs	24 months	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.
Dose expansion: Dose intensity by treatment	24 months	Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of treatment. Applies to JDQ443 dose randomization group only

Secondary Outcome Measures

Name	Time	Method
Dose Escalation and Expansion: Plasma or serum concentration vs time profiles (AUC) by treatment	Up to 24 months	AUC is defined as area under the plasma or serum concentration versus time curve after a dose of JDQ443, TNO155 and tislelizumab
Dose Escalation and Expansion: Antidrug antibody (ADA) incidence by treatment	Up to 24 months	To evaluate the immunogenicity of tislelizumab when dosed in combination with JDQ443 and/or TNO155 - only applicable to Arms C and D
Dose Expansion: Dose intensity by treatment	24 months
Dose Expansion: Incidence and severity of AEs and SAEs by treatment	24 months
Dose expansion: Intracranial disease control rate (IDCR) per mRANO-BM	24 months	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.
Dose expansion: Best overall intracranial response (BOIR) per mRANO-BM	24 months	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.
Dose expansion: Intracranial progression free survival (IPFS) per mRANO-BM	24 months	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.
Dose expansion: Duration of intracranial response (DOIR) per mRANO-BM	24 months	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.
Dose Escalation and Expansion: Plasma concentration (Cmax) by treatment	Up to 24 months	Cmax is defined as the maximum observed plasma or serum drug concentration after single dose administration.
Dose Escalation and Expansion: Time to achieve Cmax (Tmax) by treatment	Up to 24 months	Tmax is defined as the time to reach maximum plasma or serum drug concentration after single dose administration.
Dose Escalation and Expansion: ORR per RECIST v1.1	24 months	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)
Dose Escalation and Expansion: Best Overall Response (BOR) per RECIST v1.1	24 months	BOR is defined as the best overall confirmed response recorded from the start of the treatment until disease progression/recurrence.
Dose Escalation and Expansion: Progression-free survival (PFS) per RECIST v1.1, Overall Survival (OS)	24 months	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
Dose Escalation and Expansion: Duration of Response (DOR) per RECIST v1.1	24 months	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.
Dose Escalation and Expansion: Disease Control Rate (DCR) per RECIST v1.1	24 months	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
Dose Expansion: Frequency of dose interruptions and reductions, by treatment	24 months	Tolerability of study drug will be assessed by summarizing the number of and reason for dose delays and dose reductions.
Dose Expansion: Incidence and severity of dose limiting toxicities (DLTs) during the first cycle of monotherapy or combination treatment	21 days	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

Trial Locations

Locations (6)

Emory University School of Medicine-Winship Cancer Institute; 🇺🇸 Atlanta, Georgia, United States

Massachusetts General Hospital Cancer Center; 🇺🇸 Boston, Massachusetts, United States

Providence Cancer Center; 🇺🇸 Portland, Oregon, United States

Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

Uni Of TX MD Anderson Cancer Cntr; 🇺🇸 Houston, Texas, United States

Novartis Investigative Site; 🇨🇳 Taipei, Taiwan