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Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC). Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK -positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible. Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK -positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%. Conclusions: Ensartinib was active and generally well tolerated in patients with ALK -positive NSCLC. Clin Cancer Res; 24(12); 2771-9. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Abstract Because of the importance of the phosphoinositide 3-kinase (PI3K)/AKT pathway in chronic lymphocytic leukemia (CLL), we evaluated in vitro cytotoxicity induced by perifosine, an AKT inhibitor, in CLL lymphocytes and found that the mean 50% effective dose (ED50) was 313 nM. We then performed a phase II trial of perifosine in patients with relapsed/refractory CLL to assess response, outcomes, toxicity and ex vivo correlative measures. After 3 months of treatment, six of eight patients showed stable disease, one achieved a partial response and one had progressive disease. Median event-free survival and overall survival in all patients treated were 3.9 and 9.7 months. Adverse events included hematologic, infectious/fever, pain, gastrointestinal and constitutional toxicities. Unexpectedly, AKT phosphorylation in CLL lymphocytes from treated patients was not correlated with response. Additionally, perifosine did not inhibit AKT phosphorylation in cultured CLL lymphocytes. Perifosine is cytotoxic to CLL cells in vitro, and largely induces stabilized disease in vivo, with an AKT-independent mechanism.

The purpose of this study was to evaluate the efficacy and safety of short-course bortezomib, melphalan, prednisone (VMP) in previously untreated multiple myeloma as frontline therapy for transplant-ineligible patients and induction prior to autologous stem cell transplantation (ASCT). Patients received up to 6 28-day cycles of bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11, plus melphalan 6 mg/m(2) and prednisone 60 mg/m(2), days 1-7. After 2-6 cycles, eligible and consenting patients could proceed to ASCT. Responses were assessed by International Uniform Response Criteria. The primary endpoint was complete response (CR) rate with VMP. Forty-five patients were enrolled. Among 44 evaluable patients, response rate was 95%, including 18% >or=CR (9% stringent CR), 27% very good partial responses (VGPR), and 50% partial responses (PR). Twenty patients proceeded to ASCT. Stem cell collection was successful in all; median yield was 5.6 x 10(6) CD34(+) cells/kg. Posttransplant response rates were 30% >or=CR (10% stringent CR), 65% VGPR, and 5% PR. After median follow-up of 14.0/14.6 months, median time to progression and progression-free survival were both 19.8/27.9 months in non-ASCT/ASCT patients. Seven patients have died; 1-year survival rates were 82%/95% in non-ASCT/ASCT patients. The most common grade 3/4 toxicities were thrombocytopenia (20%), neutropenia (28%), and infection (9%). Peripheral neuropathy grade 2-4 was the most common nonhematopoietic side effect occurring 17 patients (38%), although it was typically reversible, and only 5 patients (11%) discontinued therapy as a result of it. Short-course VMP is highly effective and generally well tolerated, both as initial treatment in non-ASCT patients and induction prior to ASCT. VMP did not negatively affect stem cell collection. Longer follow-up and prospective phase III trials are required to validate these initial observations., (Copyright (c) 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Rituximab in combination with chlorambucil or radiation therapy may be an effective and less-toxic therapeutic alternative for patients with lymphocyte predominance Hodgkin's disease (LPHD). We treated 6 patients with LPHD with weekly rituximab at 375 mg/m2 for 4 weeks, followed by either radiation therapy or chlorambucil. Four patients had previously untreated disease and 2 had relapsed LPHD. All patients had no evidence of disease progression at a median follow-up time of 12.5 months after receiving rituximab therapy (range, 6-39 months) and a median follow-up time of 6.5 months after completion of chlorambucil or radiation therapy (range, 3-25 months). Further follow-up is warranted to evaluate response duration and late toxicity of this novel treatment strategy

Twenty-three adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) were treated for up to 12 weeks with the anti-CD52 monoclonal antibody alemtuzumab. Patients were a median of six years from diagnosis and had been treated with a median of four chemotherapy regimens (median of 24 total cycles) prior to enrollment. Fourteen patients (61%) had received prior monoclonal antibody therapy with rituximab. Adverse symptoms were primarily mild to moderate fever, rigor/chills, nausea/vomiting, or fatigue/malaise in up to 86% of patients. Patients with low blood counts at the initiation of alemtuzumab tolerated therapy well. A total of 17 patients were evaluable for disease response. Nine patients (53%) responded with complete remissions in the peripheral blood. Of these nine, five were evaluated by bone marrow biopsy with four complete responses (CR) and one partial response. Six of the nine presented with nodal disease at the start of alemtuzumab therapy with three CRs and three partial responses. Alemtuzumab is a monoclonal antibody that offers effective treatment for chemotherapy refractory CLL and PLL and is generally well tolerated in the outpatient setting.

Purpose: To ascertain the maximum tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with mitoxantrone at 12 mg/m(2) daily for 3 days in the treatment of acute leukemia., Patients and Methods: Thirty-four patients were enrolled. Stratum I consisted of 26 patients, median age 50 years (range, 25 to 71 years), with relapsed or refractory leukemia. Stratum II contained eight patients, median age 62.5 years (range, 38 to 83 years), who had received fewer than three cycles of myelotoxic therapy for chronic myeloid leukemia or myelodysplasia that had evolved into leukemia. Patients received mitoxantrone at 12 mg/m(2) daily for 3 days. After the first mitoxantrone dose, gemcitabine was provided intravenously at 10 mg/m(2)/min with the duration adjusted by following a continuous reassessment model., Results: Severe myelosuppression, and stomatitis or esophagitis were the most common hematologic and nonhematologic dose-limiting toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours (7,200 mg/m(2)). The mean steady-state concentration of gemcitabine was 24.72 micromol/L and varied over a fivefold range among patients. Overall response rates in this phase I trial for strata I and II were 42% and 63%, respectively., Conclusion: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m(2)/min for 12 hours with 12 mg/m(2)/d mitoxantrone for 3 days is a tolerable induction regimen and achieves plasma concentrations sufficient for maximal intracellular activation. Stomatitis or esophagitis should be anticipated; however, this regimen may induce significant responses in patients with difficult-to-treat leukemias.

Cyclophosphamide and doxorubicin, two important drugs in the treatment of lymphoma, exhibit a relationship between dose and fractional cell kill, and because of their toxicity profiles, they are candidates for significant dose escalation. We performed a phase II trial to determine the response rate, toxicity, and feasibility of escalated doses of both drugs as part of high dose CHOP in diffuse aggressive lymphoma. Patients who had advanced, previously untreated diffuse aggressive lymphomas (IWF E-H) and an International Prognostic Index of intermediate to high risk were eligible. Treatment was cyclophosphamide 2 gm/m2/day intravenously on Days 1 and 2 (total cycle dose 4 gm/m2), doxorubicin 35 mg/m2/day as a continuous infusion on Days 1 and 2 (total 70 mg/m2), vincristine 1.4 mg/m2 (maximum 2 mg) on Day 1 and prednisone 100 mg/day orally on Days 1 - 5 repeated every 3 weeks for a total of four cycles. G-CSF, prophylactic antibiotics, and mesna were provided. A total of 99 patients were enrolled; 98 received therapy. Major toxicities were Grade 4 neutropenia and thrombocytopenia occurring in 97% and 92%, respectively. Serious infections occurred in 53%. Treatment-related mortality was 2%. The overall response rate is 85%, and two-year failure free and overall survival are 39% and 64%, respectively. Persistent or relapsed lymphoma was the overwhelming cause of death. Six patients have developed AML or MDS. In view of the substantial toxicity accompanying high dose CHOP, the observed outcome suggests that its efficacy is not sufficient to make further study feasible. [ABSTRACT FROM AUTHOR]