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

Lung Cancer Clinical Trial

— KontRASt-01  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04699188
• Other study ID #: CJDQ443A12101
• Secondary ID: 2020-004129-22
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: February 24, 2021
• Est. completion date: January 8, 2027

Study information

• Verified date: June 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 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 475
• Est. completion date: January 8, 2027
• Est. primary completion date: January 8, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• JDQ443
KRAS G12C inhibitor
• TNO155
SHP2 inhibitor

Biological:
• tislelizumab
Anti PD1 antibody

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Melbourne	Victoria
Belgium	Novartis Investigative Site	Leuven
Canada	Novartis Investigative Site	Montreal	Quebec
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Fuzhou	Fujian
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Nanchang	Jiangxi
Denmark	Novartis Investigative Site	Copenhagen
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Villejuif
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Koeln
Hong Kong	Novartis Investigative Site	Hong Kong
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Japan	Novartis Investigative Site	Chuo ku	Tokyo
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Koto ku	Tokyo
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Osaka-city	Osaka
Japan	Novartis Investigative Site	Yokohama-city	Kanagawa
Korea, Republic of	Novartis Investigative Site	Seoul
Netherlands	Novartis Investigative Site	Amsterdam
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Santiago De Compostela	Galicia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Taiwan	Novartis Investigative Site	Tainan
Taiwan	Novartis Investigative Site	Taipei
United States	Emory University School of Medicine/Winship Cancer Institute Winship Cancer Center	Atlanta	Georgia
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Uni of TX MD Anderson Cancer Cntr Dept of MD Anderson CancerCent	Houston	Texas
United States	Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Providence Cancer Center	Portland	Oregon
United States	WA Uni School Of Med .	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  China,  Denmark,  France,  Germany,  Hong Kong,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Singapore,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Dose Expansion: Dose intensity by treatment		24 months
Secondary	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
Secondary	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
Secondary	Dose Expansion: Incidence and severity of AEs and SAEs by treatment		24 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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