A phase 1 study of lenalidomide and ibrutinib in combination with rituximab in relapsed and refractory CLL.

Attempts to improve upon the activity of ibrutinib in chronic lymphocytic leukemia (CLL) include the addition of targeted therapies. The combination of lenalidomide and rituximab demonstrated an overall response rate (ORR) of 66% with a complete response (CR) of 12% in the relapsed/refractory setting. Based on these data, we conducted a phase 1 study of rituximab (R), lenalidomide (L), and ibrutinib (I) in relapsed/refractory CLL. Patients received R 375 mg/m2 cycles 1 to 6 day 1, L on cycles 1 to 12 days 1 to 21, and I until disease progression. Dose escalation used a standard 3+3 design from a dose level (DL) of L 5 mg (DL1) and increasing to 15 mg (DL3) for a total of 3 dose levels. Twelve patients were enrolled; there were 2 dose-limiting toxicities of grade 4 neutropenia at DL3; thus, DL2 was the recommended phase 2 dose. A high incidence of sustained grade 4 neutropenia occurred at all dose levels, prompting study withdrawal in 5 patients, despite growth factor support. The ORR was 67%; ORR at the RP2D was 100% (1 CR). The 12-month progression-free survival at the RP2D was 83%. Preliminary efficacy data with the triplet did not appear superior to prior reports of the rituximab-lenalidomide doublet or single-agent ibrutinib. Given these findings and the sustained neutropenia, this regimen was not pursued. The study was registered at www.clinicaltrials.gov as #NCT02200848.

Ofatumumab and bendamustine in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma.

Despite initial responses > 90% with fludarabine and rituximab-based regimens, patients with chronic lymphocytic leukemia (CLL) invariably relapse and require further treatment. Ofatumumab and bendamustine have each shown efficacy in relapsed/refractory CLL with overall response rates (ORRs) of 58% and 76%, respectively. Given excellent data with bendamustine and rituximab in relapsed/refractory CLL/small lymphocytic lymphoma (SLL), this phase II study evaluated the combination of ofatumumab and bendamustine in previously treated patients. Patients received ofatumumab 300 mg intravenously (IV) day - 7, followed by ofatumumab 1000 mg IV day 1 and bendamustine 70 mg/m(2) days 1 and 2 of each 28-day cycle. Patients received 4-6 cycles depending on number of prior therapies, as long as well-tolerated or until progression. Of 10 patients enrolled, the ORR was 40% and complete response rate was 20%. The median progression-free and overall survivals were 8.1 months and 16.2 months. Three patients developed Richter transformation. The study was closed early due to unexpected adverse events including infusion-related reactions, infection and neurotoxicity.

A phase I trial of bexarotene in combination with docetaxel in patients with advanced solid tumors.

BACKGROUND: The purpose of this study was to identify dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of docetaxel with a fixed-dose of bexarotene. PATIENTS AND METHODS: This was a phase I, single-center and open-label trial of dose-escalating docetaxel with a fixed-dose oral bexarotene. Successive cohorts of 3 patients (pts), with confirmed solid tumors refractory to standard therapy or for whom no standard therapy existed, received fixed-dose oral bexarotene (400 mg/m(2) daily) with escalating doses of docetaxel weekly (25, 30, or 35 mg/m(2)) for 3 weeks on a 4-week cycle. Cohorts were expanded to 6 pts if a DLT was noted. The MTD was determined based on the occurrence of DLT in at least 2 of 6 pts during the first cycle. RESULTS: Nineteen pts were enrolled. Seven pts were treated at 25 mg/m(2), 6 at 30 mg/m(2), and 6 at 35 mg/m(2) of docetaxel. The MTD for docetaxel was 30 mg/m(2) with 400 mg/m(2) of daily bexarotene. Hypothyroidism, hypertriglyceridemia, and fatigue were common toxicities. Three pts developed pulmonary toxicity (possible radiation recall pneumonitis [n = 2] and pulmonary hypertension because of tumor emboli [n = 1]). Two pts withdrew consent because of Grade 3 fatigue. Ten of 19 pts were noted to have stable disease and received more than 2 cycles of therapy. Of the 10 pts with stable disease, 5 had non-small-cell lung cancer (NSCLC), and of those 5 pts, 1 had a partial response that persisted for eight cycles. conclusion: The MTD of docetaxel was 30 mg/m(2) in combination with daily bexarotene at 400mg/m(2). Careful monitoring may be indicated in pts with previously irradiated lung tumors.