Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer.

Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.

Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer.

BACKGROUND: There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study. METHODS: The germline DNA of 131 patients was genotyped for 10 variants in TYMS, MTHFR, DPYD, UGT1A1, ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed. RESULTS: MTHFR 1298A>C and MTHFR diplotypes (for 677C>T and 1298A>C) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C-1298C) and diplotypes (CA-TA and TA-TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response. CONCLUSION: MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug.

Phase I study of biweekly oxaliplatin, gemcitabine and capecitabine in patients with advanced upper gastrointestinal malignancies.

BACKGROUND: Oxaliplatin, gemcitabine and capecitabine are all active agents against upper gastrointestinal and pancreaticobiliary cancers. PATIENTS AND METHODS: Patients with upper gastrointestinal malignancies treated with 0-2 prior chemotherapy regimens received oxaliplatin (85-100 mg/m(2)) as a 2-h i.v. infusion with gemcitabine (800-1000 mg/m(2)) at a constant rate i.v. infusion (CI) of 10 mg/m(2)/min on days 1 and 15 of a 28-day cycle. Capecitabine (600-800 mg/m(2)) was administered orally twice a day on days 1-7 and 15-21. A three per cohort dose escalation schema was used to determine the maximum tolerated dose (MTD) and the dose-limiting toxic effects (DLTs) of this combination regimen. RESULTS: Thirty patients with advanced upper gastrointestinal malignancies were enrolled. The MTD was defined as oxaliplatin 100 mg/m(2) i.v. over 2 h plus gemcitabine 800 mg/m(2) i.v. at a CI of 10 mg/m(2)/min on days 1 and 15 with capecitabine 800 mg/m(2) p.o. b.i.d. days 1-7 and 15-21 of a 29-day cycle. DLTs include grade 3 fatigue and grade 3 dyspnea. One complete and two partial responses were observed. CONCLUSIONS: This biweekly schedule of oxaliplatin, gemcitabine and capecitabine is tolerable and warrants further investigation in biliary and pancreatic malignancies.

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar.

Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20-25 mg m(-2) intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m(-2) and escalated in an accelerated titration design to 25 mg m(-2). Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m(-2). The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10-73) ml h(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m(-2) in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.

Phase I study of rubitecan and gemcitabine in patients with advanced malignancies.

BACKGROUND: Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies. PATIENTS AND METHODS: Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle. RESULTS: The MTD was defined as rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients. CONCLUSIONS: The recommended phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.

Treatment advances in non-Hodgkin's lymphoma.

Non-Hodgkin's lymphomas (NHL) encompass a heterogeneous group of lymphoid malignancies with varying natural histories and prognoses. Recent classifications for NHL have defined distinct lymphoma entities based on morphology, immunophenotype, genetic features, clonal cell lineage and clinical features. These new, more precise classifications and characterizations of NHL will be essential in developing new targeted therapies. However, for this brief review, we will continue describe NHL primarily as indolent or aggressive. Treatment options for patients with indolent, but generally incurable, lymphomas include a 'watch and wait' approach, single agent alkylators, nucleoside analogues, combination chemotherapy, immunotherapy with monoclonal antibodies, radiolabelled monoclonal antibodies, or interferon (IFN). Vaccine therapy for indolent lymphomas is currently under intense investigation. For aggressive lymphomas, combination chemotherapy remains the standard of care. Major advances in the management of aggressive lymphomas include validation of the international prognostic index and clarification of the role of high-dose therapy with bone marrow or stem cell transplant in patients with relapsed aggressive lymphomas. Multiple randomised pilot trials of high dose therapy as initial therapy for aggressive lymphomas have shown conflicting results and await confirmatory studies.