TY - GEN
T1 - A Phase 1 first-in-human trial to evaluate the safety and tolerability of CCT3833, an oral panRAF inhibitor, in patients with advanced solid tumours, including metastatic melanoma.
AU - Dean, Emma
AU - Banerji, U
AU - Girotti, Romina
AU - Niculescu-Duvaz, I
AU - Lopes, F
AU - Davies, L
AU - Niculescu-Duvaz, D
AU - Dhomen, N
AU - Ellis, S
AU - Ali, Z
AU - O'Carrigan, B
AU - Carter, L
AU - Chisolm, L
AU - Dive, Caroline
AU - Lane, HA
AU - Lorigan, Paul
AU - Gore, ME
AU - Larkin, J
AU - Marais, Richard
AU - Springer, C
PY - 2016
Y1 - 2016
N2 - Background: Over 70,000 patients are diagnosed with malignant melanoma in the USA every year with a high proportion occurring in young people. Although treatments targeting the mitogen activated protein kinase signal transduction pathway including BRAF inhibitors have improved survival for patients with BRAF mutated melanoma, their utility is limited by intrinsic and acquired resistance of diverse mechanisms. Patients with a RAS mutated melanoma also represent a current unmet need. CCT3833 is a potent inhibitor of mutant BRAF, CRAF and SRC kinases. Preclinical data using CCT3833 in a range of mutant RAF or RAS cell lines in vitro and human tumour xenograft models in vivo demonstrated activity, including melanoma patient-derived xenografts with intrinsic or acquired resistance to selective BRAF inhibitors. These data support clinical development of CCT3833 in humans. Methods: This ongoing open-label, multi-centre Phase I trial of CCT3833 is in two parts; an initial dose escalation stage (Part A) in a rolling six design, followed by a dose expansion (Part B). The primary objectives are to evaluate the safety and tolerability profile of CCT3833 and establish the Recommended Phase 2 Dose (RP2D). CCT3833 is administered orally once daily on a continuous basis over a 28-day cycle. In Part A, a single dose is administered for safety and pharmacokinetic (PK) purposes prior to commencing continuous dosing. Secondary objectives include characterisation of the PK profile and correlation with tolerability / efficacy of CCT3833 in humans and assessment of response (radiological or clinical), supported by PD analyses. Eligible subjects include patients with advanced solid malignancies with performance status 0 to 1, fit for entry into a Phase 1 clinical trial. Part B will enrol patients with BRAF- or RAS- mutated metastatic melanoma into 3 cohorts i) treatment naïve V600E BRAF mutant melanoma ii) V600E BRAF mutant melanoma with progression on BRAF inhibitor therapy or iii) RAS mutant melanoma. Three cohorts of the dose escalation have been completed without DLT. Enrolment to cohort 4 began in January 2016. Clinical trial information: NCT02437227. Clinical trial information: NCT02437227
AB - Background: Over 70,000 patients are diagnosed with malignant melanoma in the USA every year with a high proportion occurring in young people. Although treatments targeting the mitogen activated protein kinase signal transduction pathway including BRAF inhibitors have improved survival for patients with BRAF mutated melanoma, their utility is limited by intrinsic and acquired resistance of diverse mechanisms. Patients with a RAS mutated melanoma also represent a current unmet need. CCT3833 is a potent inhibitor of mutant BRAF, CRAF and SRC kinases. Preclinical data using CCT3833 in a range of mutant RAF or RAS cell lines in vitro and human tumour xenograft models in vivo demonstrated activity, including melanoma patient-derived xenografts with intrinsic or acquired resistance to selective BRAF inhibitors. These data support clinical development of CCT3833 in humans. Methods: This ongoing open-label, multi-centre Phase I trial of CCT3833 is in two parts; an initial dose escalation stage (Part A) in a rolling six design, followed by a dose expansion (Part B). The primary objectives are to evaluate the safety and tolerability profile of CCT3833 and establish the Recommended Phase 2 Dose (RP2D). CCT3833 is administered orally once daily on a continuous basis over a 28-day cycle. In Part A, a single dose is administered for safety and pharmacokinetic (PK) purposes prior to commencing continuous dosing. Secondary objectives include characterisation of the PK profile and correlation with tolerability / efficacy of CCT3833 in humans and assessment of response (radiological or clinical), supported by PD analyses. Eligible subjects include patients with advanced solid malignancies with performance status 0 to 1, fit for entry into a Phase 1 clinical trial. Part B will enrol patients with BRAF- or RAS- mutated metastatic melanoma into 3 cohorts i) treatment naïve V600E BRAF mutant melanoma ii) V600E BRAF mutant melanoma with progression on BRAF inhibitor therapy or iii) RAS mutant melanoma. Three cohorts of the dose escalation have been completed without DLT. Enrolment to cohort 4 began in January 2016. Clinical trial information: NCT02437227. Clinical trial information: NCT02437227
M3 - Conference contribution
VL - 34
BT - Journal of Clinical Oncology
ER -
