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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04699188

Collaborator

(none)

375

Enrollment

Locations

Arms

41.9

Anticipated Duration (Months)

11.7

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
KRAS G12C Mutant Solid Tumors Carcinoma, Non-Small-Cell Lung Carcinoma, Colorectal Cancer of Lung Cancer of the Lung Lung Cancer Neoplasms, Lung Neoplasms, Pulmonary Pulmonary Cancer Pulmonary Neoplasms	Drug: JDQ443 Drug: TNO155 Biological: tislelizumab	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

375 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Feb 24, 2021

Anticipated Primary Completion Date :

Aug 21, 2024

Anticipated Study Completion Date :

Aug 21, 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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 Escalation: Dose intensity by treatment [24 months]
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).

Secondary Outcome Measures

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 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: 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: 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: 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
Dose Expansion: Incidence and severity of AEs and SAEs by treatment [24 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Exclusion Criteria:

Tumors harboring driver mutations that have approved targeted therapies, with the exception of KRAS G12C mutations
Active brain metastases
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University School of Medicine/Winship Cancer Institute Winship Cancer Center	Atlanta	Georgia	United States	30322
2	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
3	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
4	Providence Cancer Center	Portland	Oregon	United States	97213
5	University of Texas MD Anderson Cancer Center Dept of MD Anderson CancerCent	Houston	Texas	United States	77030
6	Novartis Investigative Site	Melbourne	Victoria	Australia	3000
7	Novartis Investigative Site	Leuven		Belgium	3000
8	Novartis Investigative Site	Montreal	Quebec	Canada	H2W 1T8
9	Novartis Investigative Site	Guangzhou	Guangdong	China	51000
10	Novartis Investigative Site	Beijing		China	100036
11	Novartis Investigative Site	Copenhagen		Denmark	DK-2100
12	Novartis Investigative Site	Lyon Cedex		France	69373
13	Novartis Investigative Site	Villejuif Cedex		France	94800
14	Novartis Investigative Site	Dresden		Germany	01307
15	Novartis Investigative Site	Essen		Germany	45147
16	Novartis Investigative Site	Freiburg		Germany	79106
17	Novartis Investigative Site	Koeln		Germany	50937
18	Novartis Investigative Site	Hong Kong		Hong Kong
19	Novartis Investigative Site	Milano	MI	Italy	20133
20	Novartis Investigative Site	Milano	MI	Italy	20162
21	Novartis Investigative Site	Nagoya	Aichi	Japan	466 8560
22	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	241-8515
23	Novartis Investigative Site	Chuo ku	Tokyo	Japan	104 0045
24	Novartis Investigative Site	Koto ku	Tokyo	Japan	135 8550
25	Novartis Investigative Site	Osaka		Japan	545-8586
26	Novartis Investigative Site	Seoul		Korea, Republic of	03722
27	Novartis Investigative Site	Amsterdam		Netherlands	1066 CX
28	Novartis Investigative Site	Singapore		Singapore	119074
29	Novartis Investigative Site	Singapore		Singapore	169610
30	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
31	Novartis Investigative Site	Madrid		Spain	28050
32	Novartis Investigative Site	Taipei		Taiwan	10002