Clinical trial • Phase I/II • Oncology
1-{6-[(4M)-4-(5-CHLORO-6-METHYL-1H -INDAZOL-4-YL)-5-METHYL-3-(1-METHYL-1H -INDAZOL-5-YL)-1H -PYRAZOL-1-YL]-2-AZASPIRO[3.3]HEPTAN-2-YL}PROP-2-EN-1-ONE for KRAS G12C-mutant advanced solid tumors | Non-small cell lung cancer | Colorectal cancer
Phase I/II trial of 1-{6-[(4M)-4-(5-CHLORO-6-METHYL-1H -INDAZOL-4-YL)-5-METHYL-3-(1-METHYL-1H -INDAZOL-5-YL)-1H -PYRAZOL-1-YL]-2-AZASPIRO[3.3]HEPTAN-2-YL}…
Overview
- Trial Therapeutic Area
- Oncology
- Trial Disease
- KRAS G12C-mutant advanced solid tumors | Non-small cell lung cancer | Colorectal cancer
- Trial Stage
- Phase I/II
- Drug Modality
- Small molecule|Monoclonal antibody
Key dates
- Initial CTIS Submission Date
- 02-08-2024
- First CTIS Authorization Date
- 02-09-2024
Trial design
Randomised, open-label, no placebo or external active comparator specified. arms include jdq443 single agent, jdq443 + tno155, jdq443 + tislelizumab, and jdq443 + tno155 + tislelizumab; a jdq443 dose-randomization group is included (different jdq443 dose levels vs each other) — specific comparator drug doses/schedules not specified in available data.-controlled, adaptive Phase I/II trial across 19 sites in Germany, Netherlands, Belgium and others.
- Randomised
- Yes
- Open Label
- Yes
- Comparator
- No placebo or external active comparator specified. Arms include JDQ443 single agent, JDQ443 + TNO155, JDQ443 + tislelizumab, and JDQ443 + TNO155 + tislelizumab; a JDQ443 dose-randomization group is included (different JDQ443 dose levels vs each other) — specific comparator drug doses/schedules not specified in available data.
- Adaptive
- True, dose-escalation/adaptive design to identify maximum tolerated dose (MTD) and/or recommended dose/regimen; DLT evaluation during first cycle guides escalation decisions; includes dose expansion and a dose-randomization subgroup.
- Biomarker Stratified
- True, KRAS G12C mutation
- Single Multiple Or Escalation Dose Combined
- Yes
- Target Sample Size
- 282
Eligibility
Recruits 282 Vulnerable population selected. Study documents include adult ICFs and specific follow-up/ICF documents for pregnant participants and for pregnant partners/parent legal guardians. Consent is obtained via adult informed consent forms; no paediatric consent/assent procedures are described in the available materials..
- Vulnerable Population
- Vulnerable population selected. Study documents include adult ICFs and specific follow-up/ICF documents for pregnant participants and for pregnant partners/parent legal guardians. Consent is obtained via adult informed consent forms; no paediatric consent/assent procedures are described in the available materials.
Inclusion criteria
- {"criterion_text":"- 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.\n- 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.\n- 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.\n- 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.\n- 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.\n- 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.\n- All Patients: • ECOG performance status of 0 or 1.\n- 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
- {"criterion_text":"- Tumors harboring driver mutations that have approved targeted therapies, with the exception of KRAS G12C mutations.\n- 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.\n- 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.\n- 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).\n- Clinically significant cardiac disease or risk factors at screening\n- Insufficient bone marrow, hepatic or renal function at screening"}
Endpoints
Primary endpoints
- {"endpoint_text":"- 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","definition_or_measurement_approach":"DLTs observed during the first cycle; AEs/SAEs graded and recorded including lab values, ECGs and vital signs by treatment arm."}
- {"endpoint_text":"- Dose Escalation: - Tolerability: Frequency of dose interruptions, reductions, and dose intensity, by treatment","definition_or_measurement_approach":"Frequency and incidence of dose interruptions, dose reductions and calculated dose intensity per treatment arm."}
- {"endpoint_text":"- Dose Expansion: - ORR per RECIST 1.1 (all groups except the brain metastasis group)","definition_or_measurement_approach":"Overall response rate assessed per RECIST 1.1 criteria."}
- {"endpoint_text":"- Dose Expansion: - OIRR per mRANO-BM (brain metastasis group only)","definition_or_measurement_approach":"Overall intracranial response rate assessed using modified RANO-BM (mRANO-BM) criteria."}
- {"endpoint_text":"- Dose Expansion: - Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, ECGs, and vital signs","definition_or_measurement_approach":"Incidence and severity of AEs/SAEs captured and graded; laboratory, ECG and vital signs changes monitored."}
- {"endpoint_text":"- Dose Expansion: - Tolerability: Frequency of dose interruptions, reductions, and dose intensity","definition_or_measurement_approach":"Recording frequency of dose interruptions/reductions and dose intensity by treatment."}
- {"endpoint_text":"- Dose Expansion: - Efficacy: ORR* per RECIST 1.1 (JDQ443 dose randomization group only)","definition_or_measurement_approach":"ORR measured per RECIST 1.1 in the JDQ443 dose-randomized subgroup."}
Secondary endpoints
- {"endpoint_text":"- 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)","definition_or_measurement_approach":"Efficacy endpoints assessed per RECIST 1.1 (ORR, DCR, BOR, PFS, DOR) and OS recorded."}
- {"endpoint_text":"- 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.","definition_or_measurement_approach":"PK sampling to derive concentration-time profiles and calculate AUC, Cmax, Cmin, Tmax, half-life for JDQ443, HZC320, TNO155 and tislelizumab."}
- {"endpoint_text":"- Dose Escalation: • Antidrug antibody (ADA) incidence by treatment","definition_or_measurement_approach":"Incidence of anti-drug antibodies (ADA) measured for relevant biologic treatments (tislelizumab) by treatment arm."}
- {"endpoint_text":"- Dose Expansion: - ORR, DCR, BOR, PFS, and DOR per RECIST 1.1; and OS","definition_or_measurement_approach":"Efficacy outcomes per RECIST 1.1 and overall survival recorded."}
- {"endpoint_text":"- Dose Expansion: - IDCR, BOIR, IPFS and DOIR per mRANO-BM (brain metastasis group only)","definition_or_measurement_approach":"Intracranial efficacy endpoints (IDCR, BOIR, IPFS, DOIR) assessed per mRANO-BM in brain metastasis subgroup."}
- {"endpoint_text":"- 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","definition_or_measurement_approach":"DLTs in first cycle and AE/SAE monitoring including labs, ECGs and vitals by treatment."}
- {"endpoint_text":"- Dose Expansion: - Tolerability: Frequency of dose interruptions, reductions, and dose intensity, by treatment","definition_or_measurement_approach":"Frequency of dose interruptions/reductions and dose intensity assessed by treatment."}
- {"endpoint_text":"- 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","definition_or_measurement_approach":"PK profiles and derived parameters for JDQ443, metabolite HZC320, TNO155 and tislelizumab."}
- {"endpoint_text":"- Dose Expansion: - Incidence of anti-tislelizumab antibodies by treatment","definition_or_measurement_approach":"Incidence of anti-tislelizumab antibodies measured by treatment arm."}
Recruitment
- Planned Sample Size
- 282
- Recruitment Window Months
- 66
- Consent Approach
- Informed consent obtained from adult participants via country-specific Main ICFs. Multiple language ICFs are provided (English, German, Dutch, Spanish, French, Italian as seen in document listings). Additional ICFs/info sheets exist for molecular pre-screening, pregnant participants, pregnant partners and data protection; consent is completed by the adult participant (or relevant legal guardian for specified follow-up forms). No paediatric assent processes are described.
Geography
- Total Number Of Sites
- 19
- Total Number Of Participants
- 359
Germany
- Earliest CTIS Part Ii Submission Date
- 28-08-2024
- Latest Decision Or Authorization Date
- 02-09-2024
- Processing Time Days
- 5
- Number Of Sites
- 4
- Number Of Participants
- 5
Sites
- Site Name
- Universitaetsklinikum Carl Gustav Carus Dresden an der Technischen Universitaet Dresden AöR
- Department Name
- #1101: Universitätskrebszentrum Innere Medizin, Hämatologie und Onkologie
- Contact Person Name
- Martin Wermke
- Contact Person Email
- Martin.Wermke@uniklinikum-dresden.de
- Site Name
- Medical Center - University Of Freiburg
- Department Name
- #1104: Klinik für Innere Medizin! Hämatologie, Onkologie und Stammzelltransplantation
- Contact Person Name
- Justyna Rawluk
- Contact Person Email
- Justyna.rawluk@uniklinik-freiburg.de
- Site Name
- Universitaetsklinikum Essen AöR
- Department Name
- #1100: Westdeutsches Tumorzentrum, Innere Klinik (Tumorforschung)
- Contact Person Name
- Martin Schuler
- Contact Person Email
- Martin.schuler@uk-essen.de
- Site Name
- University Hospital Cologne AöR
- Department Name
- #1102: Klinik I für Innere Medizin-LCGC
- Contact Person Name
- Jürgen Wolf
- Contact Person Email
- Jurgen.wolf@uk-koeln.de
Netherlands
- Earliest CTIS Part Ii Submission Date
- 28-08-2024
- Latest Decision Or Authorization Date
- 02-09-2024
- Processing Time Days
- 5
- Number Of Sites
- 1
- Number Of Participants
- 45
Sites
- Site Name
- Netherlands Cancer Institute
- Department Name
- 1300:Clinical Research Unit
- Contact Person Name
- Neeltje Steeghs
- Contact Person Email
- n.steeghs@nki.nl
Belgium
- Earliest CTIS Part Ii Submission Date
- 28-08-2024
- Latest Decision Or Authorization Date
- 02-09-2024
- Processing Time Days
- 5
- Number Of Sites
- 1
- Number Of Participants
- 16
Sites
- Site Name
- UZ Leuven
- Department Name
- #7000 : Pneumology
- Contact Person Name
- Christophe Dooms
- Contact Person Email
- christophe.dooms@uzleuven.be
Spain
- Earliest CTIS Part Ii Submission Date
- 28-08-2024
- Latest Decision Or Authorization Date
- 09-09-2024
- Processing Time Days
- 12
- Number Of Sites
- 6
- Number Of Participants
- 37
Sites
- Site Name
- Complexo Hospitalario Universitario De Santiago
- Department Name
- #1404: Oncología
- Contact Person Name
- Neus / Luis Angel Steeghs
- Contact Person Email
- Luis.Angel.Leon.Mateos@sergas.es
- Site Name
- Hospital Universitario Virgen De La Victoria
- Department Name
- #1405: Oncología
- Contact Person Name
- Javier Garcia Corbacho
- Contact Person Email
- jgcorbacho@ibima.eu
- Site Name
- Hospital Universitari Vall D Hebron
- Department Name
- #1400: Oncología
- Contact Person Name
- Enriqueta Felip Font
- Contact Person Email
- efelip@vhio.net
- Site Name
- Institut Catala D'oncologia
- Department Name
- #1402: Oncología
- Contact Person Name
- Jose Carlos Ruffinelli Rodriguez
- Contact Person Email
- jruffinelli@iconcologia.net
- Site Name
- Hospital Clinico Universitario De Valencia
- Department Name
- #1403: Oncología
- Contact Person Name
- Valentina Gambardella
- Contact Person Email
- Valen.gambardella@gmail.com
- Site Name
- Hospital Universitario Hm Sanchinarro
- Department Name
- #1401: Oncología
- Contact Person Name
- Ramón Yarza Barrio
- Contact Person Email
- Ramon.Yarza@startmadrid.co
Italy
- Earliest CTIS Part Ii Submission Date
- 28-08-2024
- Latest Decision Or Authorization Date
- 23-09-2024
- Processing Time Days
- 26
- Number Of Sites
- 3
- Number Of Participants
- 151
Sites
- Site Name
- Fondazione IRCCS Istituto Nazionale Dei Tumori
- Department Name
- #1200: S.C. Oncologia Medica 1
- Contact Person Name
- Filippo De Braud
- Contact Person Email
- debraud_studiclinici@istitutotumori.mi.it
- Site Name
- ASST Grande Ospedale Metropolitano Niguarda
- Department Name
- #1201: S.C. Oncologia Medica FALCK Niguarda Cancer Center
- Contact Person Name
- Salvatore Siena
- Contact Person Email
- salvatore.siena@ospedaleniguarda.it
- Site Name
- Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
- Department Name
- #1203: U.O. Oncologia Medica
- Contact Person Name
- Salvatore Grisanti
- Contact Person Email
- grisanti.salvatore@gmail.com
France
- Earliest CTIS Part Ii Submission Date
- 28-08-2024
- Latest Decision Or Authorization Date
- 03-09-2024
- Processing Time Days
- 6
- Number Of Sites
- 3
- Number Of Participants
- 28
Sites
- Site Name
- Institut Paoli Calmettes
- Department Name
- #:9003 Medical Oncology
- Contact Person Name
- Cecile Vicier
- Contact Person Email
- VICIERC@ipc.unicancer.fr
- Site Name
- Centre Leon Berard
- Department Name
- #:9000 Medical Oncology
- Contact Person Name
- Philippe Cassier
- Contact Person Email
- philippe.cassier@lyon.unicancer.fr
- Site Name
- Institut Gustave Roussy
- Department Name
- #:9001 Medical Oncology
- Contact Person Name
- Fabrice Barlesi
- Contact Person Email
- fabrice.barlesi@gustaveroussy.fr
Denmark
- Earliest CTIS Part Ii Submission Date
- 28-08-2024
- Latest Decision Or Authorization Date
- 10-09-2024
- Processing Time Days
- 13
- Number Of Sites
- 1
- Number Of Participants
- 77
Sites
- Site Name
- Rigshospitalet
- Department Name
- #8000: Phase 1 unit
- Contact Person Name
- Kristoffer Rohrberg
- Contact Person Email
- kristoffer.staal.rohrberg@regionh.dk
Sponsor
Primary sponsor
- Full Name
- Novartis Pharma AG
- Organisation Type
- Pharmaceutical company
- Country Of Registered Address
- Switzerland
Contract research organisations
- Name
- Parexel International (IRL) Limited
- Responsibilities
- code:12 (as listed in sponsorDuties)
- Name
- Icon Clinical Research Limited
- Responsibilities
- code:1 (as listed in sponsorDuties)
- Name
- IQVIA Limited
- Responsibilities
- code:3 (as listed in sponsorDuties)
- Name
- Syneos Health Inc.
- Responsibilities
- code:1 (as listed in sponsorDuties)
- Name
- Icon Laboratory Services Inc.
- Responsibilities
- code:4 (as listed in sponsorDuties)
Third parties
- {"country":"United States","full_name":"Foundation Medicine Inc.","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Xenobiotic Laboratories Inc.","duties_or_roles":"code:4","organisation_type":"Laboratory/Research/Testing facility"}
- {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"code:15 - central imaging (calyx)","organisation_type":"Pharmaceutical company"}
- {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"code:12","organisation_type":"Pharmaceutical company"}
- {"country":"Belgium","full_name":"CellCarta","duties_or_roles":"code:4","organisation_type":"Laboratory/Research/Testing facility"}
- {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"code:1","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"code:15 - ECG analysis/review","organisation_type":"Pharmaceutical company"}
- {"country":"China","full_name":"Wuxi Apptec Co. Ltd.","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
- {"country":"Italy","full_name":"Opis S.r.l.","duties_or_roles":"code:15 - TMF archive","organisation_type":"Pharmaceutical company"}
- {"country":"United Kingdom","full_name":"Q Squared Solutions Limited","duties_or_roles":"code:4","organisation_type":"Non-Pharmaceutical company"}
- {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"code:3","organisation_type":"Pharmaceutical company"}
- {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Diagnostic Services Limited","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"code:1","organisation_type":"Pharmaceutical company"}
- {"country":"France","full_name":"SGS France","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Icon Laboratory Services Inc.","duties_or_roles":"code:4","organisation_type":"Laboratory/Research/Testing facility"}
- {"country":"India","full_name":"Veeda Clinical Research Limited","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
Investigational products
- Investigational Product Name
- JDQ443
- Active Substance
- 1-{6-[(4M)-4-(5-CHLORO-6-METHYL-1H -INDAZOL-4-YL)-5-METHYL-3-(1-METHYL-1H -INDAZOL-5-YL)-1H -PYRAZOL-1-YL]-2-AZASPIRO[3.3]HEPTAN-2-YL}PROP-2-EN-1-ONE
- Modality
- Small molecule
- Routes Of Administration
- ORAL USE
- Route
- ORAL
- Authorisation Status
- Authorised
- Investigational Product Name
- TNO155
- Active Substance
- BATOPROTAFIB
- Modality
- Small molecule
- Routes Of Administration
- ORAL USE
- Route
- ORAL
- Authorisation Status
- Authorised
- Investigational Product Name
- VDT482/ BGB-A317
- Active Substance
- TISLELIZUMAB
- Modality
- Monoclonal antibody
- Routes Of Administration
- INTRAVENOUS USE
- Route
- INTRAVENOUS
- Authorisation Status
- Authorised
- Combination Treatment
- Yes
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