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Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (KontRASt-03)

Primary Purpose

KRAS G12C Mutant Solid Tumors, Carcinoma, Non-Small Cell Lung, Carcinoma, Non-Small-Cell Lung

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
JDQ443
trametinib
Ribociclib
cetuximab
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for KRAS G12C Mutant Solid Tumors focused on measuring KRAS G12C, targeted therapy, NSCLC, CRC, advanced solid tumors, JDQ443, trametinib, ribociclib, cetuximab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Dose Escalation:

- Patients with advanced (metastatic or unresectable) KRAS G12C mutant solid tumors who have received standard of care therapy or are ineligible to receive such therapy.

Phase II:

  • Patients with advanced (metastatic or unresectable) KRAS G12C mutant non-small cell lung cancer who have received platinum-based chemotherapy regimen and immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy
  • Patients with advanced (metastatic or unresectable) KRAS G12C mutant colorectal cancer who have received fluropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, unless patient was ineligible to such therapy.

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 treating institution's guidelines.

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 a subset of groups in Phase II.
  • Active brain metastases, including symptomatic brain metastases or known leptomeningeal disease
  • Clinically significant cardiac disease or risk factors at screening
  • Insufficient bone marrow, hepatic or renal function at screening Other protocol-defined inclusion/exclusion criteria may apply

Sites / Locations

  • Massachusetts General Hospital .Recruiting
  • Dana Farber Cancer Institute Dept.of DFCIRecruiting
  • NYU School of Medicine Langone HealthRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting
  • Novartis Investigative SiteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

JDQ443+trametinib

JDQ443+ribociclib

JDQ443+cetuximab

Arm Description

JDQ443 in combination with trametinib

JDQ443 in combination with ribociclib

JDQ443 in combination with cetuximab

Outcomes

Primary Outcome Measures

Dose escalation: Incidence and severity of dose limiting toxicities (DLTs) of each combination treatment.
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value that is not primarily related to disease, disease progression, intercurrent illness/injury, or concomitant medications that occurs within the first 28 days of study treatment and meets a defined criteria.
Dose escalation: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment
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).
Dose escalation: Frequency of dose interruptions and reductions, by treatment
The number of patients with dose adjustments (reductions and interruptions) will be summarized by treatment group.
Dose Escalation: Dose intensity by treatment
Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of response.
PhaseII: Overall Response Rate by Blinded Independent Review Committee (BIRC) per RECIST 1.1
ORR is the proportion of patients with a best overall response (BOR) of Complete Response (CR) or Partial Response (PR).

Secondary Outcome Measures

Dose escalation and Phase II: ORR by local review per RECIST 1.1
ORR is the proportion of patients with a BOR of CR or PR.
Dose escalation and Phase II: Disease Control Rate (DCR) by local review per RECIST 1.1
DCR is the proportion of patients with a BOR of CR or PR or Stable Disease (SD). The objective of this endpoint is to summarize patients with signs of "activity" defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
Dose escalation and Phase II: Duration of Response (DoR) by local review per RECIST 1.1
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.
Dose escalation and Phase II: Progression-Free Survival (PFS) by local review 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 due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
Phase II: DCR by BIRC per RECIST 1.1
DCR is the proportion of patients with a BOR of CR or PR or SD. The objective of this endpoint is to summarize patients with signs of "activity" defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
Phase II: DoR by BIRC per RECIST 1.1
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.
Phase II: PFS by BIRC 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 due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
Phase II: Overall survival (OS)
OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive.
Dose escalation and Phase II: PK parameters - Maximum Concentration (Cmax), as applicable per arm
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass x volume-1)
Dose escalation and Phase II: PK parameters - Minimum Concentration (Cmin), as applicable per arm
Observed concentration at the end of a dosing interval (taken directly before next administration)
Dose escalation: Time to achieve Cmax - Tmax, as applicable per arm
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time)
Dose escalation and Phase II: Plasma or serum concentration vs time profiles - AUCtau, as applicable per arm
The Area under curve calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)
Dose escalation and Phase II: Plasma or serum concentration vs time profiles - AUCinf, as applicable per arm
The AUC from time zero to infinity (mass x time x volume-1)
Phase II: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment
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).
Phase II: Frequency of dose interruptions and reductions, by treatment
The number of patients with dose adjustments (reductions and interruptions) will be summarized by treatment group.
Phase II: Dose intensity by treatment
Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of response.

Full Information

First Posted
April 27, 2022
Last Updated
September 18, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT05358249
Brief Title
Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation
Acronym
KontRASt-03
Official Title
KontRASt-03: A Phase Ib/II, Multicenter, Open-label Platform Study of JDQ443 With Select Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 24, 2022 (Actual)
Primary Completion Date
May 5, 2027 (Anticipated)
Study Completion Date
June 16, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is Phase Ib/II, multicenter, open-label adaptive platform study of JDQ443 with select therapies in patients with advanced solid tumors harboring the KRAS G12C mutation.
Detailed Description
JDQ443 will be considered "backbone" treatment in this trial and combined with selected therapies, or "partner(s)". The combination of a backbone and a partner will constitute a treatment arm. After dose escalation, treatment arms that reach a maximum tolerated dose /recommended dose and are determined to be safe may, but are not required to, proceed to Phase II to further explore safety, tolerability, and anti-tumor activity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
KRAS G12C Mutant Solid Tumors, Carcinoma, Non-Small Cell Lung, Carcinoma, Non-Small-Cell Lung, Non-Small Cell Lung Cancer, Non-Small Cell Lung Carcinoma, Nonsmall Cell Lung Cancer, Colorectal Cancer, Colorectal Carcinoma, Colorectal Neoplasms, Colorectal Tumors, Neoplasms, Colorectal
Keywords
KRAS G12C, targeted therapy, NSCLC, CRC, advanced solid tumors, JDQ443, trametinib, ribociclib, cetuximab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
346 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
JDQ443+trametinib
Arm Type
Experimental
Arm Description
JDQ443 in combination with trametinib
Arm Title
JDQ443+ribociclib
Arm Type
Experimental
Arm Description
JDQ443 in combination with ribociclib
Arm Title
JDQ443+cetuximab
Arm Type
Experimental
Arm Description
JDQ443 in combination with cetuximab
Intervention Type
Drug
Intervention Name(s)
JDQ443
Intervention Description
KRAS G12C inhibitor, oral
Intervention Type
Drug
Intervention Name(s)
trametinib
Other Intervention Name(s)
TMT212
Intervention Description
MEK inhibitor, oral
Intervention Type
Drug
Intervention Name(s)
Ribociclib
Other Intervention Name(s)
LEE011
Intervention Description
CDK4/6 inhibitor, oral
Intervention Type
Biological
Intervention Name(s)
cetuximab
Intervention Description
EGFR inhibitor, intravenous
Primary Outcome Measure Information:
Title
Dose escalation: Incidence and severity of dose limiting toxicities (DLTs) of each combination treatment.
Description
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value that is not primarily related to disease, disease progression, intercurrent illness/injury, or concomitant medications that occurs within the first 28 days of study treatment and meets a defined criteria.
Time Frame
28 days
Title
Dose escalation: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment
Description
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).
Time Frame
24 months
Title
Dose escalation: Frequency of dose interruptions and reductions, by treatment
Description
The number of patients with dose adjustments (reductions and interruptions) will be summarized by treatment group.
Time Frame
24 months
Title
Dose Escalation: Dose intensity by treatment
Description
Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of response.
Time Frame
24 months
Title
PhaseII: Overall Response Rate by Blinded Independent Review Committee (BIRC) per RECIST 1.1
Description
ORR is the proportion of patients with a best overall response (BOR) of Complete Response (CR) or Partial Response (PR).
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Dose escalation and Phase II: ORR by local review per RECIST 1.1
Description
ORR is the proportion of patients with a BOR of CR or PR.
Time Frame
24 months
Title
Dose escalation and Phase II: Disease Control Rate (DCR) by local review per RECIST 1.1
Description
DCR is the proportion of patients with a BOR of CR or PR or Stable Disease (SD). The objective of this endpoint is to summarize patients with signs of "activity" defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
Time Frame
24 months
Title
Dose escalation and Phase II: Duration of Response (DoR) by local review per RECIST 1.1
Description
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.
Time Frame
24 months
Title
Dose escalation and Phase II: Progression-Free Survival (PFS) by local review per RECIST 1.1
Description
PFS is defined as the time from the date of start of treatment to the date of the first documented progression, or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
Time Frame
24 months
Title
Phase II: DCR by BIRC per RECIST 1.1
Description
DCR is the proportion of patients with a BOR of CR or PR or SD. The objective of this endpoint is to summarize patients with signs of "activity" defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
Time Frame
24 months
Title
Phase II: DoR by BIRC per RECIST 1.1
Description
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.
Time Frame
24 months
Title
Phase II: PFS by BIRC per RECIST 1.1
Description
PFS is defined as the time from the date of start of treatment to the date of the first documented progression, or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.
Time Frame
24 months
Title
Phase II: Overall survival (OS)
Description
OS is defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last known date patient alive.
Time Frame
24 months
Title
Dose escalation and Phase II: PK parameters - Maximum Concentration (Cmax), as applicable per arm
Description
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass x volume-1)
Time Frame
5 months
Title
Dose escalation and Phase II: PK parameters - Minimum Concentration (Cmin), as applicable per arm
Description
Observed concentration at the end of a dosing interval (taken directly before next administration)
Time Frame
5 months
Title
Dose escalation: Time to achieve Cmax - Tmax, as applicable per arm
Description
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time)
Time Frame
5 months
Title
Dose escalation and Phase II: Plasma or serum concentration vs time profiles - AUCtau, as applicable per arm
Description
The Area under curve calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)
Time Frame
5 months
Title
Dose escalation and Phase II: Plasma or serum concentration vs time profiles - AUCinf, as applicable per arm
Description
The AUC from time zero to infinity (mass x time x volume-1)
Time Frame
5 months
Title
Phase II: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) by treatment
Description
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).
Time Frame
24 months
Title
Phase II: Frequency of dose interruptions and reductions, by treatment
Description
The number of patients with dose adjustments (reductions and interruptions) will be summarized by treatment group.
Time Frame
24 months
Title
Phase II: Dose intensity by treatment
Description
Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of response.
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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 ineligible to receive such therapy. Phase II: Patients with advanced (metastatic or unresectable) KRAS G12C mutant non-small cell lung cancer who have received platinum-based chemotherapy regimen and immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy Patients with advanced (metastatic or unresectable) KRAS G12C mutant colorectal cancer who have received fluropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, unless patient was ineligible to such therapy. 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 treating institution's guidelines. 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 a subset of groups in Phase II. Active brain metastases, including symptomatic brain metastases or known leptomeningeal disease Clinically significant cardiac disease or risk factors at screening Insufficient bone marrow, hepatic or renal function at screening Other protocol-defined inclusion/exclusion criteria may apply
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
1-888-669-6682
Email
novartis.email@novartis.com
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
+41613241111
Facility Information:
Facility Name
Massachusetts General Hospital .
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eleanor Seyfried
Email
eseyfried@mgh.harvard.edu
First Name & Middle Initial & Last Name & Degree
Rebecca Heist
Facility Name
Dana Farber Cancer Institute Dept.of DFCI
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Taylor Marinko
Email
taylor_marinko@dfci.harvard.edu
First Name & Middle Initial & Last Name & Degree
Jia Luo
Facility Name
NYU School of Medicine Langone Health
City
New York
State/Province
New York
ZIP/Postal Code
10015
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sasha Richardson
Phone
212-731-5662
Email
sasha.richardson@nyulangone.org
First Name & Middle Initial & Last Name & Degree
Janice Mehnert
Facility Name
Novartis Investigative Site
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Bordeaux
ZIP/Postal Code
33076
Country
France
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Lyon
ZIP/Postal Code
69373
Country
France
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20162
Country
Italy
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Singapore
ZIP/Postal Code
168583
Country
Singapore
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08036
Country
Spain
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Individual Site Status
Recruiting
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28050
Country
Spain
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

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

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