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A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT04294160
Recruitment Status : Recruiting
First Posted : March 3, 2020
Last Update Posted : November 16, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
BRAF V600 Colorectal Cancer Drug: Dabrafenib Drug: LTT462 Drug: Trametinib Drug: LXH254 Drug: TNO155 Biological: Spartalizumab Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 395 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 22, 2020
Estimated Primary Completion Date : August 17, 2023
Estimated Study Completion Date : August 17, 2023

Arm Intervention/treatment
Experimental: Dabrafenib + LTT462 backbone arm 1
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Drug: Dabrafenib
Capsule for oral use
Other Name: DRB436, Tafinlar

Drug: LTT462
Capsule for oral use

Experimental: Dabrafenib + LTT462 + trametinib triplet arm 1
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Drug: Dabrafenib
Capsule for oral use
Other Name: DRB436, Tafinlar

Drug: LTT462
Capsule for oral use

Drug: Trametinib
Tablet for oral use
Other Name: TMT212, Mekinist

Experimental: Dabrafenib + LTT462 + LXH254 triplet arm 2
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Drug: Dabrafenib
Capsule for oral use
Other Name: DRB436, Tafinlar

Drug: LTT462
Capsule for oral use

Drug: LXH254
Tablet for oral use

Experimental: Dabrafenib + LTT462 + TNO155 triplet arm 3
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Drug: Dabrafenib
Capsule for oral use
Other Name: DRB436, Tafinlar

Drug: LTT462
Capsule for oral use

Drug: TNO155
Capsule for oral use

Experimental: Dabrafenib + LTT462 + spartalizumab triplet arm 4
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Drug: Dabrafenib
Capsule for oral use
Other Name: DRB436, Tafinlar

Drug: LTT462
Capsule for oral use

Biological: Spartalizumab
Liquid in vial (Concentrate for solution for infusion) for intravenous use
Other Name: PDR001

Experimental: Dabrafenib + trametinib + TNO155 triplet arm 5
dose escalation to determine maximum tolerated dose (MTD)/ Recommended dose (RD) in adult patients with advanced or metastatic BRAF V600 colorectal cancer
Drug: Dabrafenib
Capsule for oral use
Other Name: DRB436, Tafinlar

Drug: Trametinib
Tablet for oral use
Other Name: TMT212, Mekinist

Drug: TNO155
Capsule for oral use




Primary Outcome Measures :
  1. Incidence and nature of dose limiting toxicities (DLTs) in the first cycle [ Time Frame: 30 months ]
    To characterize safety and tolerability of each treatment arm tested and identify recommended doses (RD) and regimens for future studies

  2. Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs, and ECGs [ Time Frame: 34 months ]
    To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies

  3. Frequency of dose interruptions [ Time Frame: 30 months ]
    To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies

  4. Frequency of dose reductions [ Time Frame: 30 months ]
    To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies

  5. Dose intensity [ Time Frame: 30 months ]
    To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies


Secondary Outcome Measures :
  1. AUClast derived from Serum/plasma concentration of individual investigational drugs within combination treatments [ Time Frame: 30 months ]
    To characterize the PK of each investigational drug within each treatment arm

  2. Best overall response (BOR) [ Time Frame: 34 months ]
    To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.

  3. Progression free survival (PFS) [ Time Frame: 34 months ]
    To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.

  4. Overall response rate (ORR) [ Time Frame: 34 months ]
    To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.

  5. Duration of response (DOR) [ Time Frame: 34 months ]
    To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.

  6. Disease control rate (DCR) [ Time Frame: 34 months ]
    To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.

  7. Change from baseline of the PD marker DUSP6 in tumor tissue (dose escalation only) [ Time Frame: 30 months ]
    To evaluate PD effect in their respective combinations in tumor

  8. AUCtau derived from Serum/plasma concentration of individual investigational drugs within combination treatments [ Time Frame: 30 months ]
    To characterize the PK of each investigational drug within each treatment arm

  9. Cmax derived from Serum/plasma concentration of individual investigational drugs within combination treatments [ Time Frame: 30 months ]
    To characterize the PK of each investigational drug within each treatment arm

  10. Tmax derived from Serum/plasma concentration of individual investigational drugs within combination treatments [ Time Frame: 30 months ]
    To characterize the PK of each investigational drug within each treatment arm



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04294160


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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United States, California
University of California at Los Angeles Santa Monica Location Recruiting
Los Angeles, California, United States, 90095
Contact: Sandy Hernandez    310-582-4069    SCHernandez@mednet.ucla.edu   
Principal Investigator: Zev A. Wainberg         
United States, Massachusetts
Massachusetts General Hospital Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Karen Barnett       kpbarnett@mgh.harvard.edu   
Principal Investigator: Ryan Corcoran         
United States, Tennessee
Sarah Cannon Research Institute SC Recruiting
Nashville, Tennessee, United States, 37203
Contact: Haley Saunders       Haley.Saunders@SarahCannon.com   
Principal Investigator: Meredith Ann McKean         
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Mari Gray    713-792-2921    migray@mdanderson.org   
Principal Investigator: Scott Kopetz         
Australia, New South Wales
Novartis Investigative Site Recruiting
Westmead, New South Wales, Australia, 2145
Belgium
Novartis Investigative Site Recruiting
Bruxelles, Belgium, 1000
Novartis Investigative Site Recruiting
Leuven, Belgium, 3000
Canada, Ontario
Novartis Investigative Site Recruiting
Toronto, Ontario, Canada, M5G 1Z5
Germany
Novartis Investigative Site Recruiting
Dresden, Germany, 01307
Novartis Investigative Site Recruiting
Essen, Germany, 45147
Novartis Investigative Site Recruiting
Ulm, Germany, 89081
Israel
Novartis Investigative Site Recruiting
Tel Aviv, Israel, 6423906
Netherlands
Novartis Investigative Site Recruiting
Amsterdam, Netherlands, 1066 CX
Singapore
Novartis Investigative Site Recruiting
Singapore, Singapore, 119228
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Valencia, Comunidad Valenciana, Spain, 46010
Novartis Investigative Site Recruiting
Madrid, Spain, 28009
United Kingdom
Novartis Investigative Site Recruiting
Manchester, United Kingdom, M20 4BX
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04294160    
Other Study ID Numbers: CADPT01C12101
First Posted: March 3, 2020    Key Record Dates
Last Update Posted: November 16, 2021
Last Verified: November 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Phase Ib, BRAF-mutated, BRAF V600E, BRAF V600D, BRAF V600K, colorectal cancer, colon cancer, rectal cancer, metastatic, BLRM with EWOC
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Trametinib
Dabrafenib
Spartalizumab
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immune Checkpoint Inhibitors