Eric H. Kraut

Low-dose deoxycoformycin in lymphoid malignancy.

Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase (ADA), was explored for its antineoplastic potential in 28 patients with advanced lymphoid malignancy. Both normal and malignant B lymphocytes have low levels of ADA activity, and low doses of dCF profoundly inhibit this enzyme in the peripheral blood of patients with chronic lymphocytic leukemia (CLL). The low doses of dCF administered in this trial (4 mg/m2) were not associated with prohibitive toxicity. Five of 28 patients had an objective response. Four additional patients had clinical improvement. No significant difference in the pretreatment ADA activity existed between responding patients and treatment failures. The demonstration of responses to dCF following failure on standard alkylating agents suggests that dCF may not be cross-resistant with current agents used to treat CLL. Additional studies should be pursued using low-dose dCF in patients with advanced malignancy.

Flavopiridol, Fludarabine, and Rituximab in Mantle Cell Lymphoma and Indolent B-Cell Lymphoproliferative Disorders

PURPOSE Flavopiridol downmodulates antiapoptotic proteins associated with resistance to fludarabine and rituximab and is effective against p53-mutated chronic lymphocytic leukemia (CLL). We conducted a phase I study of flavopiridol, fludarabine, and rituximab (FFR) in patients with mantle-cell lymphoma (MCL), indolent B-cell non-Hodgkins lymphomas (B-NHL), and CLL to determine the activity of FFR. PATIENTS AND METHODS Therapy included fludarabine 25 mg/m(2) intravenously (IV) days 1 to 5 and rituximab 375 mg/m(2) day 1 every 28 days for 6 cycles. We administered flavopiridol 50 mg/m(2) by 1-hour IV bolus (IVB) day 1 (n = 15); day 1 to 2 (n = 6); 20 mg/m(2) 30-minute IVB + 20 mg/m(2) 4-hour IV infusion (n = 3); or 30 mg/m(2) + 30 mg/m(2) (n = 14). RESULTS Thirty-eight patients (median age, 62 years) with MCL (n = 10); indolent B-NHL including follicular (n = 9), marginal zone (n = 4), lymphoplasmacytic (n = 1), or small lymphocytic lymphoma (n = 3); and CLL (n = 11), were enrolled. Twenty-two patients were previously untreated; 16 had received one to two prior therapies. Two patients in cohort 2 developed grade 3 dose-limiting toxicity (seizures, renal insufficiency). The median number of treatment cycles was 4, with cytopenias (n = 10) and fatigue (n = 3) the most common reasons for early discontinuation. Overall response rate was 82% (complete response, 50%; unconfirmed complete response, 5%; partial response, 26%), including 80% of patients with MCL (median age, 68; seven complete responses, one partial response). Median progression-free survival (PFS) was 25.6 months. Median PFS of patients with nonblastoid variant MCL (n = 8) was 35.9 months. CONCLUSION FFR was active in MCL, indolent B-NHL, and CLL and should be studied for older patients with MCL who are not candidates for aggressive chemotherapy.

Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma.

In a phase II trial, 16 patients with relapsed refractory multiple myeloma received temsirolimus 25mg I.V. weekly until progression. One partial response and 5 minor responses were observed for a total response rate of 38%. The median time to progression was 138 days. Grade 3-4 toxicity included fatigue (n=3), neutropenia (n=2), thrombocytopenia (n=2), interstitial pneumonitis (n=1), stomatitis (n=1) and diarrhea (n=1). Clinical activity was associated with a higher area under the curve (AUC) and maximal reduction in phosphorylated p70(S6)K and 4EBP1 in peripheral blood mononuclear cells. At the dose and schedule used, temsirolimus had low single agent activity. Investigation of alternate dosing schedules and use in combinations is indicated.

A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia: Southwest Oncology Group Study☆

The aim of this study is to determine whether the addition of mitoxantrone to high dose cytarabine improves the outcome of treatment in patients with relapsed or refractory acute myeloid leukemia (AML). One hundred and sixty-two eligible patients, 14-76 years of age, with AML either in first relapse or that failed to respond to initial remission induction therapy, with no CNS involvement were randomized to receive therapy with cytarabine 3 gm/M2 i.v. over 2 h every 12 h for 12 doses on days 1-6 (Arm I) (HIDAC); or HIDAC plus mitoxantrone 10 mg/M2 i.v. daily on days 7 9 (Arm II) (HIDAC + M). Patients achieving complete remission were treated with three courses of consolidation including HIDAC (Ara-C 3 gm/M2 i.v. 12 h days 1 3; 2 gm/M2 over age 50) alone (ARM I) or with mitoxantrone (10 mg/M2 i.v. day 1) (ARM II). Among 162 patients (81 HIDAC, 81 HIDAC + M) evaluated for induction toxicity, there were 10 (12%) induction deaths with HIDAC and 13 (17%) with HIDAC + M (2-tailed P = 0.65). Most early deaths were due to infection and/or hemorrhage. Among 162 patients evaluated for responses to induction therapy, 26/81 (32%) HIDAC and 36/81 (44%) HIDAC + M patients achieved complete remission (two-tailed P = 0.15). Although this difference was not statistically significant in univariate analysis, it was after adjusting for the effects of WBC and PMN percentage in multivariate analysis (P=0.013). Median survivals from study entry were 8 months (HIDAC) and 6 months (HIDAC + M); 2-tailed logrank P = 0.58. Among 48 patients registered for consolidation, the median disease-free survivals from that registration were 8 months with HIDAC and 11 months with HIDAC + M (P = 0.60). There were three treatment-related deaths during consolidation (1 HIDAC, 2 HIDAC + M), all due to infections. In this randomized trial, the addition of mitoxantrone to high-dose cytarabine was associated with a trend toward a higher CR rate. There was less evidence for an advantage in disease-free or overall survival, although any such conclusion is limited by the size of the study.

An evaluation of ciclosporin and corticosteroids individually as adjuncts to plasma exchange in the treatment of thrombotic thrombocytopenic purpura

We present the results of two consecutively performed cohort studies that evaluated the clinical effects of corticosteroids or ciclosporin as an adjunct to plasma exchange (PE) for the treatment of an acute episode of thrombotic thrombocytopenic purpura (TTP). In comparing 12 corticosteroid‐treated patients with eight ciclosporin‐treated patients, none of the ciclosporin‐treated patients suffered an exacerbation or recurrence of TTP in the first 30 d after discontinuing PE compared with 6/10 (60%) of the corticosteroid‐treated patients (P = 0·042). These data suggest that ciclosporin may have advantages over corticosteroids as an adjunct to PE therapy in the initial treatment of idiopathic TTP.

Pharmacobiologically Based Scheduling of Capecitabine and Docetaxel Results in Antitumor Activity in Resistant Human Malignancies

PURPOSE Capecitabine and docetaxel have demonstrated preclinical antitumor synergy. This synergy is thought to occur from docetaxel-mediated upregulation of thymidine phosphorylase (dThdPase), an enzyme responsible for the relative tumor selectivity of capecitabine. On the basis of the time-dependency and transiency for this upregulation, we performed a phase I study of capecitabine in combination with weekly docetaxel. We hypothesized that weekly docetaxel would result in sustained dThdPase expression and that capecitabine administration at times of maximum dThdPase upregulation would increase the therapeutic index for this combination. PATIENTS AND METHODS Patients with advanced solid malignancies received docetaxel on days 1, 8, and 15, and capecitabine bid on days 5 to 18, every 4 weeks. Docetaxel was fixed at 36 mg/m(2)/wk, whereas capecitabine was escalated in successive patients cohorts. RESULTS Sixteen patients received 77 courses at capecitabine doses from 950 to 1,500 mg/m(2)/d. The most common toxicities were hand-foot syndrome, diarrhea, nausea/vomiting, and asthenia. Grades 3 to 4 hematologic toxicities were infrequent and no treatment-related hospitalizations occurred. Three of three patients treated at 1,500/36 mg/m(2) capecitabine/docetaxel developed grade 3 hand-foot syndrome or diarrhea during either their first or second course, whereas only two of 13 patients at 1,250/36 mg/m(2) doses developed significant toxicity. Antitumor responses (n = 7) occurred in patients with hepatocellular, non-small-cell lung, and chemotherapy-refractory breast, bladder, and colorectal carcinomas. Prolonged stabilizations occurred in patients with metastatic mesothelioma (n = 2), chemorefractory non-small-cell lung carcinoma, and bronchioloalveolar carcinoma. CONCLUSION Capecitabine in combination with weekly docetaxel is well tolerated. Recommended doses are capecitabine 1,250 mg/m(2)/d (625 mg/m(2) bid) with docetaxel 36 mg/m(2)/wk. The acceptable toxicity profile in this dose schedule, and the antitumor activity observed, warrant further evaluation of this regimen.

A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: A Southwest Oncology Group study 9617

Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.

Phase I Trial of Lenalidomide and CCI-779 in Patients With Relapsed Multiple Myeloma: Evidence for Lenalidomide–CCI-779 Interaction via P-Glycoprotein

PURPOSE Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM. PATIENTS AND METHODS A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions. RESULTS Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate. CONCLUSION The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide.

Ciclosporin and plasma exchange in thrombotic thrombocytopenic purpura: long-term follow-up with serial analysis of ADAMTS13 activity

We hypothesized that ciclosporin (CSA) as adjunct to plasma exchange (PE) improves the efficacy of PE in idiopathic thrombotic thrombocytopenic purpura (TTP) via suppression of the antibody inhibitor of ADAMTS13. Our preliminary findings with CSA and PE as the upfront treatment of TTP suggested that the addition of CSA to PE significantly decreased the exacerbation (disease recurrence within 30 d of the last PE) rates compared to a cohort that received corticosteroids and PE as their upfront therapy of TTP. We present an updated analysis with long‐term follow‐up of 18 patients with idiopathic TTP treated with concurrent CSA and PE with analysis of serial measurements of ADAMTS13 activity, antigen and inhibitor concentration in the context of clinical outcome data. Overall, 16/18 (89%) patients achieved remission, similar to historical remission rates in idiopathic TTP with PE with only one patient suffering an exacerbation. Clinical responses correlated with improvements in ADAMTS13 activity and suppression of the antibody inhibitor of ADAMTS13. These data suggest that the efficacy of CSA is at least in part related to its suppression of the antibody inhibitor of ADAMTS13 and a subsequent improvement in ADAMTS13 activity and antigen.

Phase II study of dolastatin-10 as first-line treatment for advanced colorectal cancer.

Dolastatin-10 is a potent inhibitor of microtubule assembly derived from the sea hare, which displayed significant antitumor activity in preclinical models. We conducted a phase II study of dolastatin-10 in patients with advanced colorectal cancer and no prior chemotherapy for metastatic disease. Fourteen patients received doses ranging from 300 &mgr;g/m2 to 450 &mgr;g/m2 as an intravenous push every 21 days. There were no major objective responses. Toxicity was mainly hematologic, with grade III or IV granulocytopenia occurring in 9 of 42 treatment courses. Other toxic effects were generally mild. Dolastatin-10 lacks clinically significant activity in advanced colorectal cancer when used in this dose and schedule.