BRAF V600 Colorectal Cancer
Conditions
Keywords
Phase Ib, BRAF-mutated, BRAF V600E, BRAF V600D, BRAF V600K, colorectal cancer, colon cancer, rectal cancer, metastatic, BLRM with EWOC
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.
Interventions
DRUGDabrafenib
Capsule for oral use
DRUGLTT462
Capsule for oral use
DRUGTrametinib
Tablet for oral use
DRUGLXH254
Tablet for oral use
DRUGTNO155
Capsule for oral use
BIOLOGICALSpartalizumab
Liquid in vial (Concentrate for solution for infusion) for intravenous use
BIOLOGICALTislelizumab
Liquid in vial (Concentrate for solution for infusion) for intravenous use
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) | 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 |
| Duration of response (DOR) | 34 months | To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1. |
| 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 |
| 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 |
| Disease control rate (DCR) | 34 months | To evaluate preliminary anti-tumor activity of each treatment arm per RECIST v1.1. |
| 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. |
Countries
Australia, Belgium, Canada, Germany, Israel, Netherlands, Singapore, Spain, United Kingdom, United States
Outcome results
None listed