Feasibility of Long-term Proteasome Inhibition in Multiple Myeloma by in-class Transition From Bortezomib to Ixazomib.

BACKGROUND: The ongoing US MM-6 study is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral IRd (ixazomib-lenalidomide-dexamethasone) with the aim of increasing proteasome inhibitor (PI)-based treatment adherence and duration while maintaining patients' health-related quality of life (HRQoL) and improving outcomes. PATIENTS AND METHODS: US community sites are enrolling non-transplant-eligible patients with newly diagnosed multiple myeloma (MM) with no evidence of progressive disease after 3 cycles of bortezomib-based therapy to receive IRd (up to 39 cycles or until progression or toxicity). The patients use mobile or wearable digital devices to collect actigraphy (activity and sleep) data and electronically complete HRQoL, treatment satisfaction and medication adherence questionnaires. The primary endpoint is progression-free survival. The key secondary endpoints include response rates and therapy duration. RESULTS: At the data cutoff, 84 patients had been treated (median age 73 years; 44% aged ≥ 75 years; 49% men; 15% Black or African American; and 10% Hispanic or Latino). Of the 84 patients, 62% were continuing therapy. The mean duration of total PI therapy was 10.1 months and for the IRd regimen was 7.3 months. With an 8-month median follow-up, the 12-month progression-free survival rate was 86% (95% confidence interval, 73%-93%) from both the start of bortezomib-based treatment and the start of IRd. The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after iCT. The IRd safety profile was consistent with previous clinical trial data, and HRQoL and treatment satisfaction were maintained. CONCLUSION: The patients included in the US MM-6 study are representative of the real-world US MM population. The use of iCT might permit prolonged PI-based therapy with promising efficacy, without impacting patients' HRQoL or treatment satisfaction.

A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy.

Increased activation of the PI3K/Akt/mTOR pathway is a common factor in putative mechanisms of trastuzumab resistance, resulting in dysregulation of cell migration, growth, proliferation, and survival. Data from preclinical and phase 1/2 clinical studies suggest that adding everolimus (an oral mTOR inhibitor) to trastuzumab plus chemotherapy may enhance the efficacy of, and restore sensitivity to, trastuzumab-based therapy. In this phase 2 multicenter study, adult patients with HER2-positive advanced breast cancer resistant to trastuzumab and pretreated with a taxane received everolimus 10 mg/day in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients were enrolled; one remained on study treatment at the time of data cutoff. The median number of prior chemotherapy lines for advanced disease was 3.5 (range 1-11). The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99-7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85-24.11 months). Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4). Nonhematologic grade 3/4 AEs included stomatitis (20.0 %), diarrhea (5.5 %), vomiting (5.5 %), fatigue (5.5 %), and pneumonia (5.5 %), all grade 3. These findings suggest that the combination of everolimus plus trastuzumab and paclitaxel is feasible, with promising activity in patients with highly resistant HER2-positive advanced breast cancer. This combination is currently under investigation in the BOLERO-1 phase 3 trial.

Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting.

OBJECTIVE: To compare the efficacy and tolerability of dronabinol, ondansetron, or the combination for delayed chemotherapy-induced nausea and vomiting (CINV) in a 5-day, double-blind, placebo-controlled study. RESEARCH DESIGN AND METHODS: Patients receiving moderately to highly emetogenic chemotherapy received dexamethasone (20 mg PO), ondansetron (16 mg IV) and either placebo or dronabinol (2.5 mg) prechemotherapy on day 1. Patients randomized to active treatment (dronabinol and/or ondansetron) also received dronabinol (2.5 mg) after chemotherapy on day 1. On day 2, fixed doses of placebo, dronabinol (10 mg), ondansetron (16 mg), or combination therapy were administered. On days 3-5, patients received placebo, flexible doses of dronabinol (10-20 mg), ondansetron (8-16 mg), or dronabinol and ondansetron (10-20 mg dronabinol, 8-16 mg ondansetron). MAIN OUTCOME MEASURES: Total response (TR = nausea intensity <5 mm on visual analog scale, no vomiting/retching, no rescue antiemetic), nausea (occurrence and intensity) and vomiting/retching episodes. RESULTS: Sixty-four patients were randomized; 61 analyzed for efficacy. TR was similar with dronabinol (54%), ondansetron (58%), and combination therapy (47%) versus placebo (20%). Nausea absence was significantly greater in active treatment groups (dronabinol, 71%; ondansetron, 64%; combination therapy, 53%) versus placebo (15%; p < 0.05 vs. placebo for all). Nausea intensity and vomiting/retching were lowest in patients treated with dronabinol. Active treatments were well tolerated. The low number of patients due to slow enrollment limits the interpretation of these data. CONCLUSIONS: Dronabinol or ondansetron was similarly effective for the treatment of CINV. Combination therapy with dronabinol and ondansetron was not more effective than either agent alone. Active treatments were well tolerated.