Study of Efficacy and Safety of JDQ443 Single-agent as First-line Treatment for Patients With Locally Advanced or Metastatic KRAS G12C- Mutated Non-small Cell Lung Cancer With a PD-L1 Expression < 1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation.

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05445843

Collaborator

(none)

120

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This study aims to assess the antitumor activity and safety of JDQ443 single-agent as first-line treatment for participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbor a KRAS G12C mutation and a PD-L1 expression < 1% regardless of STK11 mutation status (cohort A), or a PD-L1 expression ≥ 1% and an STK11 co-mutation (cohort B).

Condition or Disease	Intervention/Treatment	Phase
Locally Advanced or Metastatic KRAS G12C-mutated NSCLC With a PD-L1 Expression <1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation	Drug: JDQ443	Phase 2

Detailed Description

This is a non-randomized, open-label, single arm, multicenter, phase II study evaluating the antitumor activity and safety of JDQ443 single agent as first-line treatment for participants with locally advanced or metastatic KRAS G12C-mutated NSCLC. The study will have 2 non-comparative cohorts (Cohort A and B) that will recruit participants in parallel.

The study treatment begins on Cycle 1 Day 1 (C1D1) with the first administration of JDQ443. Each cycle is 21 days.

Study completion is defined as the earliest occurrence of one of the following:

The last participant completes last study visit (and the assessments associated with this visit have been documented and followed-up appropriately by the Investigator), dies, withdraws consent or is lost to follow-up, whichever comes first.
In the event of an early study termination decision, the date of that decision.
Another clinical study becomes available that can continue to provide JDQ443 to study participants and all participants with ongoing treatment are transferred to that clinical study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

KontRASt-06: An Open-label Phase II Trial Evaluating the Activity and Safety of JDQ443 Single-agent as First-line Treatment for Patients With Locally Advanced or Metastatic KRAS G12C-mutated Non-small Cell Lung Cancer With a PD-L1 Expression < 1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation.

Anticipated Study Start Date :

Oct 31, 2022

Anticipated Primary Completion Date :

Nov 2, 2026

Anticipated Study Completion Date :

Nov 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A- PD-L1<1% Participants whose tumors harbor a KRAS G12C mutation and a PD-L1 expression <1%, regardless of STK11 mutation status.	Drug: JDQ443 JDQ443 orally administered
Experimental: Cohort B- PD-L1≥ 1% and STK11 mutation Participants whose tumors harbor a KRAS G12C mutation, a PD-L1 expression ≥ 1% and an STK11 co-mutation.	Drug: JDQ443 JDQ443 orally administered

Arm

Intervention/Treatment

Experimental: Cohort A- PD-L1<1%

Participants whose tumors harbor a KRAS G12C mutation and a PD-L1 expression <1%, regardless of STK11 mutation status.

Drug: JDQ443

JDQ443 orally administered

Experimental: Cohort B- PD-L1≥ 1% and STK11 mutation

Participants whose tumors harbor a KRAS G12C mutation, a PD-L1 expression ≥ 1% and an STK11 co-mutation.

Drug: JDQ443

JDQ443 orally administered

Outcome Measures

Primary Outcome Measures

Overall response rate (ORR) by blinded independent review committee (BIRC) in cohort A [Up to approximately 24 months]
ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) as best overall response (BOR) per response evaluation criteria in solid tumors (RECIST) version 1.1 by BIRC in cohort A

Secondary Outcome Measures

ORR by BIRC in cohort B [Up to approximately 24 months]
ORR is defined as the percentage of participants with a CR or PR as BOR per RECIST 1.1 by BIRC in cohort B
Duration of response (DOR) by BIRC in both cohorts [From first documented response to disease progression or death, up to approximately 24 months]
DOR is defined as the time from the first occurrence of a PR or a CR per RECIST 1.1 by BIRC to the occurrence of disease progression or death due to any cause. DOR will be calculated separately for each of the two cohorts.
Progression Free Survival (PFS) by BIRC in both cohorts [From first study treatment to first documented progression or death, up to approximately 24 months]
PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression per RECIST 1.1 by BIRC or date of death due to any cause. PFS will be calculated separately for each of the two cohorts.
Overall survival (OS) in both cohorts [From enrollment to death, up to approximately 36 months]
OS is defined as the time from the date of enrollment to the date of death due to any cause. OS will be calculated separately for each of the two cohorts.
Disease control rate (DCR) by BIRC in both cohorts [Up to approximately 24 months]
DCR is defined as the percentage of participants with a BOR of confirmed CR, PR and stable disease (SD) per RECIST 1.1 by BIRC. DCR will be calculated separately for each of the two cohorts.
Time to response (TTR) by BIRC in both cohorts [From enrollment to first documented response, up to approximately 24 months]
TTR is defined as the time from the date of enrollment to the date of first documented response of either CR or PR per RECIST 1.1 by BIRC. TTR will be calculated separately for each of the two cohorts.
ORR by local radiology assessment in both cohorts [Up to approximately 24 months]
ORR is defined as the percentage of participants with a CR or PR as BOR per RECIST 1.1 by local review assessment. ORR will be calculated separately for each of the two cohorts.
DOR by local review assessment in both cohorts [From first documented response to disease progression or death, up to approximately 24 months]
DOR is defined as the time from the first occurrence of a PR or a CR per RECIST 1.1 by local review assessment to the occurrence of disease progression or death due to any cause. DOR will be calculated separately for each of the two cohorts.
DCR by local review assessment in both cohorts [Up to approximately 24 months]
DCR is defined as the percentage of participants with a BOR of confirmed CR, PR and SD per RECIST 1.1 by local review assessment. DCR will be calculated separately for each of the two cohorts.
TTR by local review assessment in both cohorts [From enrollment to first documented response, up to approximately 24 months]
TTR is defined as the time from the date of enrollment to the date of first documented response of either CR or PR per RECIST 1.1 by local review assessment. TTR will be calculated separately for each of the two cohorts.
PFS by local review assessment in both cohorts [From first study treatment to first documented progression or death, up to approximately 24 months]
PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression per RECIST 1.1 by local review assessment or date of death due to any cause. PFS will be calculated separately for each of the two cohorts.
ORR by BIRC and local radiology assessment for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) [Up to approximately 24 months]
ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) as best overall response (BOR) per RECIST 1.1 by local review assessment and by BIRC. ORR will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts
DOR by BIRC and local radiology assessment for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) [From first documented response to disease progression or death, up to approximately 24 months]
DOR is defined as the time from the first occurrence of a PR or a CR per RECIST 1.1 by local review assessment and by BIRC to the occurrence of disease progression or death due to any cause. DOR will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts.
DCR by BIRC and local radiology assessment for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) [Up to approximately 24 months]
DCR is defined as the percentage of participants with a BOR of confirmed CR, PR and stable disease (SD) per RECIST 1.1 by local review assessment and by BIRC. DCR will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts
TTR by BIRC and local radiology assessment for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) [From enrollment to first documented response, up to approximately 24 months]
TTR is defined as the time from the date of enrollment to the date of first documented response of either CR or PR per RECIST 1.1 by local review assessment and by BIRC. TTR will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts
PFS by BIRC and local radiology assessment for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) [From first study treatment to first documented progression or death, up to 24 months]
PFS is defined as the time from the date of first dose of study treatment to the date of the first documented disease progression per RECIST 1.1 by local review assessment and BIRC or date of death due to any cause. PFS will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts
OS for participants whose tumors harbor an STK11 mutation regardless of PD-L1 expression status (pooled from both cohorts) [From enrollment to death, up to approximately 36 months]
OS is defined as the time from the date of enrollment to the date of death due to any cause. OS will be calculated for all participants whose tumors harbor an STK11 mutation by pooling participants from both cohorts
Maximum concentration (Cmax) of JDQ443 in plasma [Up to approximately 24 months]
Blood samples will be collected for pharmacokinetics characterization.
Time to reach maximum concentration at steady-state (Tmax,ss) of JDQ443 in plasma [Up to approximately 24 months]
Blood samples will be collected for pharmacokinetics characterization.
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of JDQ443 in plasma [Up to approximately 24 months]
Blood samples will be collected for pharmacokinetics characterization.
Area Under the Curve From Time Zero to the last measurable concentration sampling time at steady-state (AUClastss) of JDQ443 in plasma [Up to approximately 24 months]
Blood samples will be collected for pharmacokinetics characterization.
Observed concentration at the end of a dosing interval at steady-state (Cmin,ss) of JDQ443 in plasma [Up to approximately 24 months]
Blood samples will be collected for pharmacokinetics characterization.
Total body clearance (CL/F) of JDQ443 from the plasma [Up to approximately 24 months]
Blood samples will be collected for pharmacokinetics characterization.
Time to definitive deterioration (TTD) in NSCLC-SAQ total score [From baseline up to approximately 24 months]
The Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) is a 7-item, patient-reported outcome measure which assess patient-reported symptoms associated with advanced NSCLC: cough, pain, dyspnea, fatigue, and appetite.
TTD in the physical functioning scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 [From baseline up to approximately 24 months]
The EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional and social functioning), 3 symptom scales (fatigue, pain and nausea/vomiting), a GHS/QoL scale, and six single items (constipation, diarrhea, insomnia, shortness of breath, appetite loss and financial difficulties).
Chain from baseline in NSCLC-SAQ [From baseline up to approximately 24 months]
The NSCLC-SAQ is a 7-item, patient-reported outcome measure which assess patient-reported symptoms associated with advanced NSCLC: cough, pain, dyspnea, fatigue, and appetite.
Change from baseline in EORTC QLQ-C30 [From baseline up to approximately 24 months]
The EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional and social functioning), 3 symptom scales (fatigue, pain and nausea/vomiting), a GHS/QoL scale, and six single items (constipation, diarrhea, insomnia, shortness of breath, appetite loss and financial difficulties).
Change from baseline in FACT GP5 [From baseline up to approximately 24 months]
Functional Assessment of Cancer Therapy-General version (FACT-GP5) is a single question which assesses how bothersome the side effects of treatment are for participants with cancer.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion criteria

Histologically confirmed locally advanced (stage IIIb/IIIc not eligible for definitive chemoradiation or surgical resection with curative intent) or metastatic (stage IV) NSCLC without previous systemic treatment for metastatic disease. Prior (neo)adjuvant treatment with chemotherapy and/or immunotherapy, or prior radiotherapy administered sequentially or concomitantly with chemotherapy and/or immunotherapy for localized or locally advanced disease are accepted if the time between therapy completion and enrollment is > 12 months.
Presence of a KRAS G12C mutation (all participants) and:
Cohort A: PD-L1 expression < 1%, regardless of STK11 mutation status
Cohort B: PD-L1 expression ≥ 1% and an STK11 co-mutation
At least one measurable lesion per RECIST 1.1.
ECOG performance status ≤ 1.
Participants capable of swallowing study medication.

Key Exclusion criteria

Participants whose tumors harbor an EGFR-sensitizing mutation and/or ALK rearrangement by local laboratory testing. Participants with other known druggable alterations will be excluded, if required by local guidelines
Previous use of a KRAS G12C inhibitor or previous systemic treatment for metastatic NSCLC.
A medical condition that results in increased photosensitivity (i.e. solar urticaria, lupus erythematosus, etc).
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
Participants who are taking a prohibited medication (strong CYP3A inducers) that cannot be discontinued at least seven days prior to the first dose of study treatment and for the duration of the study

Other inclusion/exclusion criteria may apply