advanced solid tumors harboring the KRAS G12C mutation MedDRA version: 21.1 Level: LLT Classification code 10065147 Term: Malignant solid tumor System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10061451 Te
Conditions
Interventions
Product Name: opnurasib
Product Code: JDQ443
Pharmaceutical Form: Tablet
INN or Proposed INN: opnurasib
Current Sponsor code: JDQ443
Other descriptive name: JDQ443
Concentration unit: mg milligram(s)
Sponsors
Novartis Pharma AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Dose Escalation: • Patients with advanced (metastatic or unresectable) KRAS G12C mutant solid tumors who have received standard of care therapy or are intolerant or ineligible to approved therapies. Dose Expansion: • Patients with advanced (metastatic or unresectable) KRAS G12C mutant non-small cell lung cancer who have received a platinum-based chemotherapy regimen and immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy. Treatment with a prior KRAS G12C inhibitor is not allowed. • Patients with advanced (metastatic or unresectable) KRAS G12C mutant non-small cell lung cancer who have received a platinum-based chemotherapy regimen and immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy, and one treatment line of a direct KRAS G12C inhibitor given as a single agent and discontinued within 6 months of the first day of study treatment. • Patients with advanced (metastatic or unresectable) KRAS G12C mutant NSCLC who have received a platinum-based chemotherapy regimen and an immune checkpoint inhibitor therapy either in combination or in sequence, unless patient was ineligible to receive such therapy. The patient must have at least one untreated brain metastasis. Treatment with a prior KRAS G12C inhibitor is not allowed. • Patients with advanced (metastatic or unresectable) KRAS G12C mutant colorectal cancer who have received standard-of-care therapy, including a fluropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, unless patient was ineligible to such therapy. Treatment with a prior KRAS G12C inhibitor is not allowed. • Patients with advanced (metastatic or unresectable) KRAS G12C mutant solid tumors other than NSCLC or CRC who have received standard of care therapy or are intolerant or ineligible to approved therapies. Treatment with a prior KRAS G12C inhibitor is not allowed. All Patients: • ECOG performance status of 0 or 1. • Patients must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the institution’s own guidelines and requirements for such procedures. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 285 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 190
Exclusion criteria
Exclusion criteria: • Tumors harboring driver mutations that have approved targeted therapies, with the exception of KRAS G12C mutations. • Prior treatment with a KRAS G12C inhibitor is excluded for patients in the single agent dose escalation arm and a subset of groups in dose expansion. • Prior treatment with a SHP2 or SOS1 inhibitor is not allowed for NSCLC patients enrolled into the dose expansion parts of the JDQ443 single agent and JDQ443 plus TNO155 expansion arms. • Untreated brain metastases (applicable to all patients except the brain metastasis group), symptomatic brain metastases (applicable to all patients), or known leptomeningeal disease (applicable to all patients) • Clinically significant cardiac disease or risk factors at screening • Insufficient bone marrow, hepatic or renal function at screening
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Dose Escalation: • To assess the safety and tolerability of JDQ443 single agent and JDQ443 in combination with TNO155, JDQ443 in combination with tislelizumab, and JDQ443 in combination with TNO155 and tislelizumab, and to identify the maximum tolerated dose and/or recommended dose and regimen for future studies. Dose Expansion: • To evaluate the overall response rate (ORR) for JDQ443 single agent and JDQ443 in combination with TNO155, JDQ443 in combination with tislelizumab, and JDQ443 in combination with TNO155 and tislelizumab. • To evaluate the preliminary overall intracranial response rate (OIRR) of JDQ443 single agent (brain metastasis group only) •To evaluate the preliminary safety/tolerability and anti-tumor activity of JDQ443 single agent in patients with NSCLC (JDQ443 dose randomization group only);Secondary Objective: • To evaluate the anti-tumor activity of the study treatments. • To further characterize the safety and tolerability of the study treatments (dose expansion part only). • To characterize the PK of JDQ443 single agent and PK of JDQ443, TNO155, and tislelizumab in JDQ443 in combination with TNO155, JDQ433 in combination with tislelizumab and JDQ443 in combination with TNO155 and tislelizumab • To evaluate the immunogenicity of tislelizumab when dosed in combination with JDQ443 and / or TNO155. • To evaluate the intracranial preliminary anti-tumor activity of JDQ443 single agent (brain metastasis group only);Primary end point(s): Dose Escalation: - Safety: Incidence and severity of dose limiting toxicities (DLTs) during the first cycle of monotherapy or combination treatment during the dose escalation part. Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including changes in laboratory values, electrocardiograms (ECGs), and vital signs by treatment - Tolerability: Frequency of dose interruptions, reductions, and dose intensity, by treatment Dose Expansion: ORR per RECIST 1.1 (all groups except | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Dose Escalation: • ORR, DCR, Best Overall Response (BOR), Progression-fee survival (PFS) and Duration of Response (DOR) per RECIST 1.1; and Overall Survival (OS) • Plasma or serum concentration vs time profiles and derived PK parameters (i.e. AUC, Cmax, Cmin, Tmax, half-life) of JDQ443 and its metabolite HZC320, TNO155 and tislelizumab. • Antidrug antibody (ADA) incidence by treatment Dose Expansion: • ORR, DCR, BOR, PFS and DOR per RECIST 1.1; and OS • IDCR, BOIR, IPFS and DOIR per mRANO-BM (brain metastasis group only) • Safety: Incidence and severity of dose limiting toxicities (DLTs) during the first cycle of monotherapy or combination treatment. Incidence and severity of AEs and SAEs, including changes in laboratory values, ECGs, and vital signs by treatment Tolerability: Frequency of dose interruptions, reductions, and dose intensity, by treatment • Plasma or serum concentration vs time profiles and derived PK parameters (i.e. AUC, Cmax, Cmin, Tmax, half-life) of JDQ443 and its metabolite HZC320, TNO155, and tislelizumab • Incidence of anti-tislelizumab antibodies by treatment ;Timepoint(s) of evaluation of this end point: • Efficacy: pre specified time-points as per protocol • Safety/tolerability: continously during on-treatment period • PK: as defined per protocol and Statistical Analysis Plan | — |
Countries
Australia, Belgium, Canada, China, Denmark, France, Germany, Hong Kong, Italy, Japan, Korea, Republic of, Netherlands, Singapore, Spain, Taiwan, United States
Contacts
Public ContactClinical Trial Information Desk
Novartis Pharma AG
Outcome results
None listed