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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: BRAF V600 Colorectal Cancer
• Intervention / Treatment: Drug: Dabrafenib; Drug: LTT462; Drug: Trametinib; Drug: LXH254; Drug: TNO155; Biological: Spartalizumab; Biological: Tislelizumab

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.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
• Belgium
  • Bruxelles, Belgium, 1000
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z5
      • Novartis Investigative Site
• Germany
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Israel
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University Of California Los Angeles Santa Monica Location
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Massachusetts General Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute SC
  • Texas
    • Houston, Texas, United States, 77030
      • Uni of TX MD Anderson Cancer Cntr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / 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 Names: 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 Names: DRB436, Tafinlar; Drug: LTT462; Capsule for oral use; Drug: Trametinib; Tablet for oral use; Other Names: 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 - Arm is closed for further enrollment.	Drug: Dabrafenib; Capsule for oral use; Other Names: 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 Names: 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 - Arm is closed for further enrollment.	Drug: Dabrafenib; Capsule for oral use; Other Names: DRB436, Tafinlar; Drug: LTT462; Capsule for oral use; Biological: Spartalizumab; Liquid in vial (Concentrate for solution for infusion) for intravenous use; Other Names: 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 Names: DRB436, Tafinlar; Drug: Trametinib; Tablet for oral use; Other Names: TMT212, Mekinist; Drug: TNO155; Capsule for oral use
Experimental: Dabrafenib + LTT462 + Tislelizumab triplet arm 6; 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 Names: DRB436, Tafinlar; Drug: LTT462; Capsule for oral use; Biological: Tislelizumab; Liquid in vial (Concentrate for solution for infusion) for intravenous use; Other Names: VDT482, BGBA317

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	30 months
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	34 months
Frequency of dose interruptions	To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies	30 months
Frequency of dose reductions	To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies	30 months
Dose intensity	To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies	30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	30 months
Best overall response (BOR)	To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.	34 months
Progression free survival (PFS)	To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.	34 months
Overall response rate (ORR)	To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.	34 months
Duration of response (DOR)	To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.	34 months
Disease control rate (DCR)	To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.	34 months
Change from baseline of the PD marker DUSP6 in tumor tissue (dose escalation only)	To evaluate PD effect in their respective combinations in tumor	30 months
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	30 months
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	30 months
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	30 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): July 22, 2020
• Primary Completion (Estimated): September 20, 2024
• Study Completion (Estimated): September 20, 2024

Study Registration Dates

• First Submitted: March 2, 2020
• First Submitted That Met QC Criteria: March 2, 2020
• First Posted (Actual): March 3, 2020

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 9, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Phase Ib, BRAF-mutated, BRAF V600E, BRAF V600D, BRAF V600K, colorectal cancer, colon cancer, rectal cancer, metastatic, BLRM with EWOC
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Trametinib; Dabrafenib; Spartalizumab; Tislelizumab; Naporafenib
• Other Study ID Numbers: CADPT01C12101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No