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

Study Overview
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Brief Summary
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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.

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

Conditions
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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

Intervention / Treatment
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* Drug: JDQ443
* Drug: TNO155
* Biological: tislelizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 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: 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 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS, KRAS G12C, Metastatic cancer, Advanced cancer, Enzyme inhibitor, PD-1, SHP2, Targeted therapy, Non-small-cell lung cancer, colorectal cancer, Molecular mechanisms of pharmacological action