Study of JDQ443 in advanced cancer with a specific mutation (G12C) of the KRAS gene

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Nov 2024 → ongoing

Decision date (initial)

2024-09-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-508073-87-00

EudraCT number

2020-004129-22

ClinicalTrials.gov

NCT04699188

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Therapy, Efficacy, Pharmacokinetic

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 objectives 5

1. To evaluate the anti-tumor activity of the study treatments.
2. To further characterize the safety and tolerability of the study treatments (dose expansion part only).
3. 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
4. To evaluate the immunogenicity of tislelizumab when dosed in combination with JDQ443 and / or TNO155.
5. To evaluate the intracranial preliminary anti-tumor activity of JDQ443 single agent (brain metastasis group only)

Conditions and MedDRA coding

Advance solid tumors harboring the KRAS G12C mutation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 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.
2. 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.
3. 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, 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.
4. Dose Expansion: • 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.
5. Dose Expansion: • 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.
6. Dose Expansion: • 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.
7. All Patients: • ECOG performance status of 0 or 1.
8. All Patients: • 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.

Exclusion criteria 6

1. Tumors harboring driver mutations that have approved targeted therapies, with the exception of KRAS G12C mutations.
2. 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.
3. 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.
4. 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), or known leptomeningeal disease (applicable to all patients).
5. Clinically significant cardiac disease or risk factors at screening
6. Insufficient bone marrow, hepatic or renal function at screening

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. 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
2. Dose Escalation: - Tolerability: Frequency of dose interruptions, reductions, and dose intensity, by treatment
3. Dose Expansion: - ORR per RECIST 1.1 (all groups except the brain metastasis group)
4. Dose Expansion: - OIRR per mRANO-BM (brain metastasis group only)
5. Dose Expansion: - Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, ECGs, and vital signs
6. Dose Expansion: - Tolerability: Frequency of dose interruptions, reductions, and dose intensity
7. Dose Expansion: - Efficacy: ORR* per RECIST 1.1 (JDQ443 dose randomization group only)

Secondary endpoints 9

1. 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)
2. Dose Escalation: • 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.
3. Dose Escalation: • Antidrug antibody (ADA) incidence by treatment
4. Dose Expansion: - ORR, DCR, BOR, PFS, and DOR per RECIST 1.1; and OS
5. Dose Expansion: - IDCR, BOIR, IPFS and DOIR per mRANO-BM (brain metastasis group only)
6. Dose Expansion: - 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
7. Dose Expansion: - Tolerability: Frequency of dose interruptions, reductions, and dose intensity, by treatment
8. Dose Expansion: - 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
9. Dose Expansion: - Incidence of anti-tislelizumab antibodies by treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 16

Locations

7 EU/EEA countries · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 7 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 68 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications