ABSTRACT
BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour. RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Pancreatic Ductal/drug therapy , Pancreatic Neoplasms/drug therapy , Adult , Aged , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Bayes Theorem , Benzene Derivatives/administration & dosage , Benzene Derivatives/adverse effects , Benzene Derivatives/pharmacokinetics , Carcinoma, Pancreatic Ductal/metabolism , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacokinetics , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Pancreatic Neoplasms/metabolism , Propionates/administration & dosage , Propionates/adverse effects , Propionates/pharmacokinetics , Receptors, Notch/antagonists & inhibitors , Receptors, Notch/metabolism , Signal Transduction/drug effects , Sulfones/administration & dosage , Sulfones/adverse effects , Sulfones/pharmacokinetics , GemcitabineABSTRACT
BACKGROUND: We sought to determine the maximal tolerated dose of the MEK inhibitor trametinib with weekly paclitaxel, with a view to exploring the combination's activity in melanoma lacking a BRAF V600 mutation. METHODS: In this phase 1 study we used a fixed dose of paclitaxel (80 mg/m2 intravenous (IV) on days 1, 8 and 15 of each 4 week cycle) and escalated the dose of trametinib (to a maximum 2mg orally (PO) daily), following a 3+3 design. Eligible patients had advanced melanoma and could have received up to two previous lines of treatment for metastatic disease. FINDINGS: 15 patients were enrolled, all but one of whose melanoma was wild type for BRAF at codon 600. The maximal monotherapy dose of trametinib proved tolerable with weekly paclitaxel. The most frequent adverse events observed were rash and fatigue. Six (40%) partial responses were reported, including four of eight patients with NRAS mutations. Median progression free survival was 5.5 months (95% confidence interval (CI) 1.8-7.8 months) and overall survival, 14.1 months (95% CI 4.6-not reached). INTERPRETATION: Trametinib can safely be given with weekly paclitaxel at the full monotherapy dose. In this small group promising progression free and overall survival were observed in patients with melanoma lacking a V600 BRAF mutation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Melanoma/drug therapy , Paclitaxel/administration & dosage , Pyridones/administration & dosage , Pyrimidinones/administration & dosage , Skin Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Paclitaxel/adverse effects , Pyridones/adverse effects , Pyrimidinones/adverse effectsABSTRACT
BACKGROUND: Melanoma is a potentially curable cancer, but around 20% of patients will develop disease which is beyond surgical clearance. Rising incidence alongside breakthroughs in understanding the molecular biology of this disease identifying systemic therapies offering survival gains now demand a more proactive, integrated approach to melanoma management. SOURCES OF DATA: PubMed references relating to aspects of melanoma research and treatment. AREAS OF AGREEMENT: Rapidly rising incidence throughout the world. Effective surgery as well as new molecular targeted systemic biological agents and immunotherapies necessitating early diagnosis and multidisciplinary therapeutic interventions. AREAS OF CONTROVERSY: Role of screening and prevention. Benefit of interventions for locoregional melanoma, including role of sentinel lymph node biopsy. Integration and sequencing of treatments for unresectable melanoma. GROWING POINTS: Molecular determinants of melanoma influencing disease outcome and treatment decisions. AREAS TIMELY FOR DEVELOPING RESEARCH: Education and training of patient and healthcare professionals. Role of screening, surveillance and follow-up strategies. Biology of melanoma guiding treatment decisions.
