A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer
Study Details
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
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.
Study Design
Arms and Interventions
| 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:
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:
Drug: LTT462
Capsule for oral use
Drug: Trametinib
Tablet for oral use
Other Names:
|
| 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:
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:
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:
Drug: LTT462
Capsule for oral use
Biological: Spartalizumab
Liquid in vial (Concentrate for solution for infusion) for intravenous use
Other Names:
|
| 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:
Drug: Trametinib
Tablet for oral use
Other Names:
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:
Drug: LTT462
Capsule for oral use
Biological: Tislelizumab
Liquid in vial (Concentrate for solution for infusion) for intravenous use
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence and nature of dose limiting toxicities (DLTs) in the first cycle [30 months]
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 [34 months]
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
- Frequency of dose interruptions [30 months]
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
- Frequency of dose reductions [30 months]
To characterize safety and tolerability of each treatment arm tested and identify recommended doses and regimens for future studies
- Dose intensity [30 months]
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 [30 months]
To characterize the PK of each investigational drug within each treatment arm
- Best overall response (BOR) [34 months]
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
- Progression free survival (PFS) [34 months]
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
- Overall response rate (ORR) [34 months]
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
- Duration of response (DOR) [34 months]
To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1.
- Disease control rate (DCR) [34 months]
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) [30 months]
To evaluate PD effect in their respective combinations in tumor
- AUCtau derived from Serum/plasma concentration of individual investigational drugs within combination treatments [30 months]
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 [30 months]
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 [30 months]
To characterize the PK of each investigational drug within each treatment arm
Eligibility Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UCLA Medical Center Santa Monica Location | Los Angeles | California | United States | 90095 |
| 2 | Massachusetts General Hospital Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
| 3 | Sarah Cannon Research Institute SC | Nashville | Tennessee | United States | 37203 |
| 4 | University of Texas MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
| 5 | Novartis Investigative Site | Westmead | New South Wales | Australia | 2145 |
| 6 | Novartis Investigative Site | Bruxelles | Belgium | 1000 | |
| 7 | Novartis Investigative Site | Leuven | Belgium | 3000 | |
| 8 | Novartis Investigative Site | Toronto | Ontario | Canada | M5G 1Z5 |
| 9 | Novartis Investigative Site | Dresden | Germany | 01307 | |
| 10 | Novartis Investigative Site | Essen | Germany | 45147 | |
| 11 | Novartis Investigative Site | Ulm | Germany | 89081 | |
| 12 | Novartis Investigative Site | Tel Aviv | Israel | 6423906 | |
| 13 | Novartis Investigative Site | Amsterdam | Netherlands | 1066 CX | |
| 14 | Novartis Investigative Site | Singapore | Singapore | 119228 | |
| 15 | Novartis Investigative Site | Barcelona | Catalunya | Spain | 08035 |
| 16 | Novartis Investigative Site | Valencia | Comunidad Valenciana | Spain | 46010 |
| 17 | Novartis Investigative Site | Madrid | Spain | 28009 | |
| 18 | Novartis Investigative Site | Manchester | United Kingdom | M20 4BX |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CADPT01C12101