Back to resultsA Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer
Primary Purpose
BRAF V600 Colorectal Cancer
Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Dabrafenib
LTT462
Trametinib
LXH254
TNO155
Spartalizumab
Tislelizumab
Sponsored by
About this trial
This is an interventional treatment trial for BRAF V600 Colorectal Cancer focused on measuring Phase Ib, BRAF-mutated, BRAF V600E, BRAF V600D, BRAF V600K, colorectal cancer, colon cancer, rectal cancer, metastatic, BLRM with EWOC
Eligibility Criteria
Key Inclusion Criteria:
- Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy at baseline and during on study therapy. Exceptions may be considered after documented discussion with Novartis.
- All patients must have a BRAF V600 mutation confirmed by local assessment.
- Patients with unresectable advanced/metastatic BRAF V600 cancer of the colon or rectum with measurable disease as determined by RECIST v1.1
- Patients must have documented disease progression following, or are intolerant to, 1 or 2 lines of chemotherapy for advanced/metastatic disease
Key Exclusion Criteria:
- Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in-situ cervical cancer, or other tumors that will not affect life expectancy
- Impairment of gastrointestinal function or gastrointestinal disease that may signficantly alter the absorption of study drugs
- History of or current evidence/risk of retinal verin occlusion or serous retinopathy
- History of or current interstitial lung disease or non-infectious pneumonitis
- Patients with a known history of testing positive for HIV
- Clinically significant cardiac disease at screening
- Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
- Pregnant or lactating women
Other protocol-defined inclusion/exclusion may apply.
Sites / Locations
- University Of California Los Angeles Santa Monica Location
- Massachusetts General Hospital Massachusetts General Hospital
- Sarah Cannon Research Institute SC
- Uni of TX MD Anderson Cancer Cntr
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Dabrafenib + LTT462 backbone arm 1
Dabrafenib + LTT462 + trametinib triplet arm 1
Dabrafenib + LTT462 + LXH254 triplet arm 2
Dabrafenib + LTT462 + TNO155 triplet arm 3
Dabrafenib + LTT462 + spartalizumab triplet arm 4
Dabrafenib + trametinib + TNO155 triplet arm 5
Dabrafenib + LTT462 + Tislelizumab triplet arm 6
Arm Description
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer - Arm is closed for further enrollment.
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer - Arm is closed for further enrollment.
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Outcomes
Primary Outcome Measures
Incidence and nature of dose limiting toxicities (DLTs) in the first cycle
To characterize safety and tolerability of each treatment arm tested and identify recommended doses (RD) and regimens for future studies
Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs, and ECGs
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
Frequency of dose interruptions
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
Frequency of dose reductions
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
Dose intensity
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
Secondary Outcome Measures
AUClast derived from Serum/plasma concentration of individual investigational drugs within combination treatments
To characterize the PK of each investigational drug within each treatment arm
Best overall response (BOR)
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
Progression free survival (PFS)
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
Overall response rate (ORR)
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
Duration of response (DOR)
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
Disease control rate (DCR)
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
Change from baseline of the PD marker DUSP6 in tumor tissue (dose escalation only)
To evaluate PD effect in their respective combinations in tumor
AUCtau derived from Serum/plasma concentration of individual investigational drugs within combination treatments
To characterize the PK of each investigational drug within each treatment arm
Cmax derived from Serum/plasma concentration of individual investigational drugs within combination treatments
To characterize the PK of each investigational drug within each treatment arm
Tmax derived from Serum/plasma concentration of individual investigational drugs within combination treatments
To characterize the PK of each investigational drug within each treatment arm
Full Information
NCT ID
NCT04294160
First Posted
March 2, 2020
Last Updated
October 19, 2023
Sponsor
Novartis Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT04294160
Brief Title
A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer
Official Title
A Phase Ib, Multicenter, Open-label Dose Escalation and Expansion Platform Study of Select Drug Combinations in Adult Patients With Advanced or Metastatic BRAF V600 Colorectal Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 22, 2020 (Actual)
Primary Completion Date
May 17, 2024 (Anticipated)
Study Completion Date
May 17, 2024 (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
No
5. Study Description
Brief Summary
A phase Ib, open-label platform study of select drug combinations chosen in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies.
Detailed Description
This is a phase Ib, multi-center, open-label study with multiple treatment arms in adult patients with advanced or metastatic BRAF V600 (E, D, or K) in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies. The open platform design of this study is adaptive to allow removal of combination treatment arm(s) based on emerging data and facilitate introduction of new candidate combinations. The study is comprised of a dose escalation part and may be followed by a dose expansion part for any combination treatment arm.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
BRAF V600 Colorectal Cancer
Keywords
Phase Ib, BRAF-mutated, BRAF V600E, BRAF V600D, BRAF V600K, colorectal cancer, colon cancer, rectal cancer, metastatic, BLRM with EWOC
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
122 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Dabrafenib + LTT462 backbone arm 1
Arm Type
Experimental
Arm Description
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Arm Title
Dabrafenib + LTT462 + trametinib triplet arm 1
Arm Type
Experimental
Arm Description
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Arm Title
Dabrafenib + LTT462 + LXH254 triplet arm 2
Arm Type
Experimental
Arm Description
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer - Arm is closed for further enrollment.
Arm Title
Dabrafenib + LTT462 + TNO155 triplet arm 3
Arm Type
Experimental
Arm Description
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Arm Title
Dabrafenib + LTT462 + spartalizumab triplet arm 4
Arm Type
Experimental
Arm Description
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer - Arm is closed for further enrollment.
Arm Title
Dabrafenib + trametinib + TNO155 triplet arm 5
Arm Type
Experimental
Arm Description
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Arm Title
Dabrafenib + LTT462 + Tislelizumab triplet arm 6
Arm Type
Experimental
Arm Description
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Intervention Type
Drug
Intervention Name(s)
Dabrafenib
Other Intervention Name(s)
DRB436, Tafinlar
Intervention Description
Capsule for oral use
Intervention Type
Drug
Intervention Name(s)
LTT462
Intervention Description
Capsule for oral use
Intervention Type
Drug
Intervention Name(s)
Trametinib
Other Intervention Name(s)
TMT212, Mekinist
Intervention Description
Tablet for oral use
Intervention Type
Drug
Intervention Name(s)
LXH254
Intervention Description
Tablet for oral use
Intervention Type
Drug
Intervention Name(s)
TNO155
Intervention Description
Capsule for oral use
Intervention Type
Biological
Intervention Name(s)
Spartalizumab
Other Intervention Name(s)
PDR001
Intervention Description
Liquid in vial (Concentrate for solution for infusion) for intravenous use
Intervention Type
Biological
Intervention Name(s)
Tislelizumab
Other Intervention Name(s)
VDT482, BGBA317
Intervention Description
Liquid in vial (Concentrate for solution for infusion) for intravenous use
Primary Outcome Measure Information:
Title
Incidence and nature of dose limiting toxicities (DLTs) in the first cycle
Description
To characterize safety and tolerability of each treatment arm tested and identify recommended doses (RD) and regimens for future studies
Time Frame
30 months
Title
Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs, and ECGs
Description
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
Time Frame
34 months
Title
Frequency of dose interruptions
Description
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
Time Frame
30 months
Title
Frequency of dose reductions
Description
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
Time Frame
30 months
Title
Dose intensity
Description
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
Time Frame
30 months
Secondary Outcome Measure Information:
Title
AUClast derived from Serum/plasma concentration of individual investigational drugs within combination treatments
Description
To characterize the PK of each investigational drug within each treatment arm
Time Frame
30 months
Title
Best overall response (BOR)
Description
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
Time Frame
34 months
Title
Progression free survival (PFS)
Description
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
Time Frame
34 months
Title
Overall response rate (ORR)
Description
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
Time Frame
34 months
Title
Duration of response (DOR)
Description
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
Time Frame
34 months
Title
Disease control rate (DCR)
Description
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
Time Frame
34 months
Title
Change from baseline of the PD marker DUSP6 in tumor tissue (dose escalation only)
Description
To evaluate PD effect in their respective combinations in tumor
Time Frame
30 months
Title
AUCtau derived from Serum/plasma concentration of individual investigational drugs within combination treatments
Description
To characterize the PK of each investigational drug within each treatment arm
Time Frame
30 months
Title
Cmax derived from Serum/plasma concentration of individual investigational drugs within combination treatments
Description
To characterize the PK of each investigational drug within each treatment arm
Time Frame
30 months
Title
Tmax derived from Serum/plasma concentration of individual investigational drugs within combination treatments
Description
To characterize the PK of each investigational drug within each treatment arm
Time Frame
30 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy at baseline and during on study therapy. Exceptions may be considered after documented discussion with Novartis.
All patients must have a BRAF V600 mutation confirmed by local assessment.
Patients with unresectable advanced/metastatic BRAF V600 cancer of the colon or rectum with measurable disease as determined by RECIST v1.1
Patients must have documented disease progression following, or are intolerant to, 1 or 2 lines of chemotherapy for advanced/metastatic disease
Key Exclusion Criteria:
Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in-situ cervical cancer, or other tumors that will not affect life expectancy
Impairment of gastrointestinal function or gastrointestinal disease that may signficantly alter the absorption of study drugs
History of or current evidence/risk of retinal verin occlusion or serous retinopathy
History of or current interstitial lung disease or non-infectious pneumonitis
Patients with a known history of testing positive for HIV
Clinically significant cardiac disease at screening
Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
Pregnant or lactating women
Other protocol-defined inclusion/exclusion may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
University Of California Los Angeles Santa Monica Location
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Massachusetts General Hospital Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Sarah Cannon Research Institute SC
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Uni of TX MD Anderson Cancer Cntr
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Novartis Investigative Site
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Novartis Investigative Site
City
Bruxelles
ZIP/Postal Code
1000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1Z5
Country
Canada
Facility Name
Novartis Investigative Site
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Novartis Investigative Site
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Novartis Investigative Site
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Novartis Investigative Site
City
Tel Aviv
ZIP/Postal Code
6423906
Country
Israel
Facility Name
Novartis Investigative Site
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Singapore
ZIP/Postal Code
119228
Country
Singapore
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
Facility Name
Novartis Investigative Site
City
Valencia
State/Province
Comunidad Valenciana
ZIP/Postal Code
46010
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28009
Country
Spain
Facility Name
Novartis Investigative Site
City
Manchester
ZIP/Postal Code
M20 4BX
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer
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