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Purpose: This Phase I study assessed the feasibility of concomitant arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (Velcade™) (AAV) for patients with relapsed/refractory multiple myeloma., Experimental Design: ATO (0.25 mg/kg) and AA (1 g) were given with an escalating dose of bortezomib (1 mg/m(2) or 1.3 mg/m(2) IV bolus on days 1 and 8 of a 21-day cycle)., Results: Ten patients (median age 62 years), with a median of 3 prior regimens, were enrolled. Four (40%) patients achieved clinical benefit, with one patient achieving a durable partial response. No formal DLTs were encountered., Conclusion: AAV combination was feasible and demonstrated some benefits in this heavily pretreated population.

Patients with chronic lymphocytic leukemia (CLL) with deletion or mutation of TP53 have exceedingly poor clinical outcomes. Cenersen, an oligonucleotide targeting TP53, has been shown to abrogate the activity of TP53 gain-of-function mutants and to increase sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. We combined cenersen with fludarabine, cyclophosphamide and rituximab (FCR) as treatment for patients with high-risk CLL. The purpose of this phase II study was to determine the overall response rate, response duration and toxicity of cenersen administered in combination with FCR. Twenty patients with relapsed or high-risk CLL were evaluated. Nineteen patients were previously treated. The complete response rate was 18%; the overall response rate was 53%. Median progression-free and overall survival was 5.3 and 10.6 months, respectively. The most common serious adverse events were neutropenia and thrombocytopenia. In this single arm phase II study, cenersen combined with FCR yielded clinical responses with acceptable toxicity in patients with high-risk CLL.

Purpose: VEGF, mTOR, and EGFR inhibitors have demonstrated anti-tumor and anti-angiogenic effects alone and in combination with each other. This study evaluated the safety, tolerability, and pharmacokinetics of bevacizumab, everolimus, and erlotinib combination., Methods: Doublet therapy consisted of bevacizumab at 10 mg/kg every 14 days and everolimus 5 mg daily which escalated to 10 mg daily. Erlotinib 75 mg daily was added to the phase II dose recommended phase II dose (RPTD) of bevacizumab and everolimus. Dose-limiting toxicity (DLT) was assessed in cycle 1., Results: Forty-eight patients with advanced solid malignancies were evaluable for DLT and efficacy. No DLTs were observed in the doublet dose escalation. Two DLTs (grade 3 mucositis and grade 3 rash) were observed with the addition of erlotinib 75 mg daily. Consequently, triplet doses were adjusted and were better tolerated. Four patients had a partial response. Median progression-free survival (PFS) for the doublet therapy was 6.0 months (0.5 to 32+ months) and 5.5 months (0.8 to 27+ months) for the triplet therapy. Systemic exposure of everolimus was significantly higher in combination with erlotinib (476 ± 161 ng h/mL) compared to when given alone (393 ± 156 ng h/mL; P = 0.020)., Conclusions: The RPTD for the doublet therapy is bevacizumab 10 mg/kg every 14 days and everolimus 10 mg daily, and the RPTD for the triplet therapy is bevacizumab 5 mg/kg every 14 days, everolimus 5 mg and erlotinib 75 mg daily. Prolonged disease stability was demonstrated in tumors known to respond to mTOR inhibition and potentially resistant to VEGF blockade.

We present a study of the prevalence of genetic polymorphisms and expression of genes encoding the drug-resistance proteins glutathione S-transferases (GSTs) in order to gain insights into the pattern of failure evident in mantle cell lymphoma. We note a high preponderance of genetic alterations conferring resistance to standard chemotherapy in this illness. Concurrent with this investigation, we present a series of patients who were provided dose-dense and intense chemotherapy to circumvent these drug-resistance mechanisms. High responses were noted, though durable remissions were few, indicating non-traditional chemotherapy options are important to investigate in this illness.

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.)

Aim: To determine the maximally tolerated dose (MTD), recommended phase II dose (RPTD) and toxicity profile of gemcitabine plus irinotecan combination., Patients and Methods: Thirty-nine evaluable patients with advanced solid tumors were treated with gemcitabine (Gem) and irinotecan (Iri) on days 1, 8 and 15 of a 28-day cycle. Dose levels included Gem/Iri 700/50, 900/50, 900/75, 500/50 mg/m(2) respectively. Dose-limiting toxicity (DLT) was assessed during cycle one; toxicity evaluation was closely monitored throughout the course of treatment. Treatment continued until disease progression or unacceptable toxicity., Results: DLTs primarily consisted of grade > or = 3 thrombocytopenia lasting > or = 4 days often accompanied by grade > or = 3 neutropenia. Other grade > or = 3 toxicities included vomiting, diarrhea, fatigue and elevated alkaline phosphatase. Three patients had a partial response. Stable disease as best response was seen in 16 patients, ranging from 2-18 months., Conclusion: The MTD/RPTD is gemcitabine 500 mg/m(2) plus irinotecan 50 mg/m(2) on days 1, 8 and 15 of a 28-day cycle. Given the toxicity profile and negative results of phase III studies, no further testing of this treatment combination is recommended.

Non-cross resistant drugs given at high-dose intensity may maximise tumor cell kill leading to improved patient outcomes. We investigated the feasibility and efficacy of administering ifosfamide, carboplatin and etoposide +/- rituximab as sequential high-dose single agents. Twenty-two patients with relapsed/refractory Hodgkin lymphoma (n = 9) or non-Hodgkin (n = 13) lymphoma (NHL) were included. Therapy included: cycle 1 ifosfamide (15 g/m(2)), cycle 2 etoposide (900 mg/m(2)) and cycle 3 carboplatin (area under the curve 15). Patients with NHL received rituximab (375 mg/m(2)) with cycles 1 and 2. Blood stem cell collection was performed after etoposide. Primary endpoints were overall response (complete response (CR) + PR) and ability to mobilise stem cells after etoposide. Secondary endpoints were to assess the toxicity of the regimen and to evaluate the ability of patients to proceed to stem cell transplant (SCT). Overall response rate was 54% with CR in 4/22 (18%) subjects and PR in 8/22 (36%). Median progression-free survival was 15 months and overall survival has not been reached at 40 months. Thirteen participants proceeded to SCT. Grade 3/4 thrombocytopenia and neutropenia occurred in 58% of cycles and 91% of subjects respectively. Forty-five percent of patients required hospitalisation for toxicity and two patients died from complications of therapy. Sequential dose intense ifosfamide, etoposide, carboplatin +/- rituximab was more toxic and no more effective than the same drugs given in a conventional fashion.

Purpose: The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer., Experimental Design: Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m(2) every 21 days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity., Results: Thirty-one patients were enrolled over three docetaxel dose levels (8 at 60 mg/m(2), 19 at 70 mg/m(2), and 4 at 75 mg/m(2)) including dose expansion at 70 mg/m(2). The maximum tolerated dose of docetaxel was 70 to 75 mg/m(2). Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95% CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy., Conclusions: The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m(2). Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.

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/m(2)/day intravenously on Days 1 and 2 (total cycle dose 4 gm/m(2)), doxorubicin 35 mg/m(2)/day as a continuous infusion on Days 1 and 2 (total 70 mg/m(2)), vincristine 1.4 mg/m(2) (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.

Purpose: The treatment of early-stage Hodgkin's disease (HD) has evolved from radiotherapy alone (RT) to combined-modality therapy (CMT) because of concerns about late adverse effects from high-dose subtotal nodal irradiation (STNI). However, there is little information regarding the long-term results of CMT programs that substantially reduce the dose and extent of radiation. In addition, lowering the total radiation dose may reduce the complication rate without compromising cure. This retrospective study compares the long-term results of STNI with CMT using modestly reduced RT dose in the treatment of early-stage HD., Patients and Methods: Between 1982 and 2002, 111 patients with stage IA and IIA HD were treated definitively with RT (mean dose, 37.9 Gy); 70 patients were treated with CMT with low-dose involved-field radiotherapy (LDIFRT; mean dose, 25.5 Gy). Median follow-up was 11.7 years for RT patients and 8.1 years for the CMT group., Results: There was a trend toward improved 20-year overall survival with CMT (83% v 70%; P = .405). No second cancers were observed in the CMT group; in the RT group the actuarial frequency of a second cancer was 16% at 20 years. There was no difference in the frequency of cardiac complications (9% v 6%, RT v CMT)., Conclusion: In this retrospective review, CMT with LDIFRT was effective in curing early-stage HD and was not associated with an increase in second malignancies. For RT alone, a moderate dose seemed to reduce cardiac complications but did not lessen second malignancies compared with higher doses used historically.

A retrospective review was performed on the toxicity and response to one cycle of dose-intense cyclophosphamide/etoposide, followed by consolidation in patients with refractory or previously untreated, high-risk non-Hodgkin's lymphoma (NHL). Fifty-five patients with refractory NHL and 13 with untreated, high-risk NHL were administered one cycle of daily cyclophosphamide 1.5 g/m2 intravenously on days 1-4 and etoposide 300 mg/m2 intravenously every 12 hours on days 1-3. Responders then received other consolidated regimens. Twenty-seven percent of patients with refractory disease had moderate or severe stomatitis, and 44% had moderate or severe infections with 6 (11%) dying of this complication. Similar complication rates were noted in the previously untreated, high-risk group, but there was no treatment-related mortality. The overall response rate to this one cycle of therapy was 31% in the refractory group, with 18% complete response and 13% partial response. The overall response rate in the previously untreated, high-risk group was 69%, with 54% complete and 15% partial responses. In responders, the 2-year event-free survival was 27% in the refractory group and 56% in high-risk group. Dose-intense cyclophosphamide/etoposide has promising efficacy; however, nonhematologic toxicity can be considerable. The better tolerance, high response rate, and encouraging 2-year survival of this regimen in combination with further dose-dense consolidation in patients with high-risk NHL are encouraging.

Purpose: The purpose of this study was to determine the maximum tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with fludarabine at 25 mg/m(2) daily for 5 days in the treatment of relapsed or refractory acute myelogenous leukemia., Experimental Design: Eighteen patients with relapsed or refractory acute myelogenous leukemia were enrolled. The median age was 54.5 years (range, 21-80 years). Patients received a 30-min infusion of fludarabine at 25 mg/m(2) daily for 5 days. i.v. gemcitabine was given as a single infusion at 10 mg/m(2)/min with the duration adjusted following a modified continuous reassessment method., Results: After 18 patients, the maximum recommended duration of infusion of gemcitabine in combination with fludarabine was selected as a 15-h infusion given at 10 mg/m(2)/min (9,000 mg/m(2)). Severe stomatitis or esophagitis was the most common nonhematological dose-limiting toxicity. Myelosuppression was universal. Febrile neutropenia was common, and 3 of 18 (17%) patients developed bacteremia. Occasional nausea, vomiting, or diarrhea was also reported. There were three complete responses and two partial responses for an overall response rate of 28%., Conclusions: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m(2)/min for 15 h with 25 mg/m(2)/day fludarabine for 5 days is a tolerable induction regimen for relapsed or refractory leukemia. Stomatitis, esophagitis, febrile neutropenia, and myelosuppression should be anticipated; however, this regimen may be beneficial in patients with relapsed or refractory leukemia.

Purpose: To estimate the maximum-tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with irinotecan at 40 mg/m(2) daily for 3 days in the treatment of relapsed or refractory acute leukemia or lymphoma., Patients and Methods: Patients with leukemia or lymphoma were escalated in separate strata. Stratum I consisted of 11 patients, median age of 47 years (range, 18 to 68 years), with relapsed or refractory leukemia. Stratum II contained nine patients, median age of 48 years (range, 39 to 68 years), who had refractory non-Hodgkin's lymphoma. Patients received irinotecan at 40 mg/m(2) daily for 3 days, beginning just before the first dose of gemcitabine. Gemcitabine was given at 10 mg/m(2)/min, with the total duration adjusted following a modified continuous reassessment model., Results: Severe myelosuppression and stomatitis/esophagitis were the most serious hematologic and nonhematologic toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours delivered at 10 mg/m(2)/min (7,200 mg/m(2)). The overall response rate for one cycle of this therapy in this phase I trial for patients with leukemia was 18% (95% confidence interval, 8% to 45%), and for those with lymphoma, 33% (95% confidence interval, 17% to 66%)., Conclusion: A prolonged infusion of gemcitabine at 10 mg/m(2)/min for 12 hours with 3 days of irinotecan at 40 mg/m(2)/d is a tolerable induction regimen for patients with acute leukemia or lymphoma. Stomatitis/esophagitis should be anticipated; however, this regimen may induce responses in patients with difficult-to-treat hematologic malignancies.

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.