| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced solid tumors harboring the KRAS G12C mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced cancer with a specific mutation (G12C) in the KRAS gene |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 25.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10069759 |
| E.1.2 | Term | KRAS mutation |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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).
|
|
| E.2.2 | Secondary objectives of the trial |
• 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)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Dose Escalation:
• Patients with advanced (metastatic or unresectable) KRAS G12C mutant solid tumors who have received and failed 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.
|
|
| E.4 | Principal 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 group in dose expansion.
• Prior treatment with a SHP2or 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 |
|
| E.5 End points |
| E.5.1 | 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 the brain metastasis group)
OIRR per mRANO-BM (brain metastasis group only)
Safety: Incidence and severity of AEs and SAEs, including changes in
laboratory values, ECGs, and vital signs
Tolerability: Frequency of dose interruptions, reductions, and dose
intensity
Efficacy: ORR* per RECIST 1.1 (JDQ443 dose randomization group only) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety/tolerability: continously during on-treatment period, DLTs within first treatment cycle
ORR: when all patients in the corresponding expansion group have progressed, died, withdrawn consent, been lost to follow-up, started a new antineoplastic therapy or have been followed-up for at least 8 months after treatment start, whichever occurs earlier; interim analyses for the JDQ443 single agent, JDQ443 plus TNO155 NSCLC dose expansion groups, and JDQ443 dose randomization group as per protocol |
|
| E.5.2 | Secondary end point(s) |
Dose Escalation:
•ORR, DCR, Best Overall Response (BOR), Progression-free 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 |
|
| E.5.2.1 | 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
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Singapore |
| Hong Kong |
| Taiwan |
| Australia |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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