Strair, Roger

BackgroundExtracorporeal photopheresis (ECP) is an immunomodulatory cellular therapy which has been shown to induce a tolerogenic state in patients with acute and chronic graft‐vs‐host disease. ECOG‐ACRIN explored the activity of ECP as a part of a reduced intensity conditioning regimen in two multicenter trials in patients with MDS (E1902) and lymphomas (E1402). While both studies closed before completing accrual, we report results in 23 patients (17 MDS and 6 lymphoma).Study Design and MethodsPatients received 2 days of ECP followed by pentostatin 4 mg/m2 /day for two consecutive days, followed by 600 cGy of total body irradiation prior to stem cell infusion. Immunosuppression for aGVHD was infusional cyclosporine A or tacrolimus and methotrexate on day +1, +3, with mycophenolate mofetil starting on day 100 for chronic GVHD prophylaxis.ResultsAll patients engrafted, with median time to neutrophil and platelet engraftment of 15‐18 days and 10‐18 days respectively. Grade 3 or 4 aGVHD occurred in 13% and chronic extensive GVHD in 30%.ConclusionsThese studies demonstrate that ECP/pentostatin/TBI is well tolerated and associated with adequate engraftment of neutrophils and platelets in patients with lymphomas and MDS.

Abstract Background: MDX-060 is a fully human anti-CD30 IgG1k monoclonal antibody that induces Fc-receptor mediated killing of CD30 expressing cell lines and inhibits the growth of CD30-expressing tumor cells in a murine xenograft model. We previously reported data from the first 31 patients in a Phase I/II open-label, dose escalation study of MDX-060 in patients with relapsed or refractory CD30+ lymphomas. The purpose of the study is to determine the safety and tolerability profile of the drug, and to preliminarily evaluate efficacy. We now update the findings of this study, including reporting the results of a new higher dose cohort. Methods: In the Phase I portion of the study, MDX-060 was administered intravenously at dose levels of 0.1, 1, 5, or 10 mg/kg weekly for 4 weeks to cohorts of 3–6 patients. In the Phase II portion of the study additional patients were administered MDX-060 intravenously at 10 (n=10) or 15 (n=17) mg/kg weekly for 4 weeks. Responses were assessed at month 2. Results: To date, MDX-060 has been administered to 48 patients; 40 with Hodgkin’s disease (HD), 6 with anaplastic large cell lymphoma (ALCL) and 2 with other CD30 positive lymphomas. MDX-060 has been well tolerated, and a maximum tolerated dose has not been identified. There were 2 drug-related serious adverse events, 1 patient in the 1 mg/kg dosing cohort had Grade 3 elevated liver transaminase, and 1 patient in the 15 mg/kg cohort had Grade 3 pneumonia/Grade 4 ARDS. Objective clinical responses have been observed in 5 patients. Two patients had complete responses; 1 patient with ALCL in the 1 mg/kg cohort lasting 100 days, and 1 patient with HD in the 15 mg/kg cohort lasting 117 days. Retreatment of the ALCL patient with MDX-060 resulted in a second complete response. Three patients had partial responses; 1 patient with HD in the 5 mg/kg cohort lasting 92 days, and 1 patient with HD in the 15 mg/kg cohort, which is continuing at 176 days. In addition, 1 patient with ALCL in the 15 mg/kg cohort had a partial response. Stable disease was observed in 17 patients following MDX-060 administration with a median duration of 132 days (range:15–387 days). Baseline soluble CD30 levels in the plasma were evaluated, but did not appear to correlate with clinical outcome. Conclusions: Preliminary evidence indicates MDX-060 to be well tolerated in heavily pre-treated patients with CD30+ lymphomas, with minimal toxicity, and with clinical activity observed at 1 mg/kg, 5 mg/kg and 15 mg/kg. Additional patients are being accrued at 1 mg/kg and 5 mg/kg to more accurately assess efficacy at these dose levels.

Abstract Abstract 1508 Background: Tipifarnib is an orally bioavailable farnesyltransferase inhibitor with well-established antileukemic activity in a minority of unselected patients with AML. Seeking to identify patients most likely to have tipifarnib-responsive AML, we applied a PCR-based quantitative 2 gene expression signature ratio (RASGRP1:APTX), which had been tested and validated retrospectively as a predictor of response and survival in previous large studies of tipifarnib, as a molecular screening tool for selection of patients to this pilot trial. Objectives: 1) primary: to determine the complete response (CR +CRi) rate in AML patients prospectively selected for tipifarnib treatment on the basis of a 2-gene signature (RASGRP1:APTX ratio) in bone marrow aspirates. 2) secondary: to assess safety, overall survival, and immunophenotypic expression of RASGRP1 on baseline bone marrow blasts for correlation with PCR-based detection. Methods: This was a multicenter, open-label, phase 2 study. Key eligibility criteria included 1) patients with previously untreated AML, age ≥65 years and deemed unsuitable for or refusing traditional induction chemotherapy, and 2) RASGRP1: APTX ratio of ≥5.0 (measured in bone marrow aspirate) based upon qRT-PCR. Other inclusion criteria included: ECOG PS 0–2, adequate end-organ function, and WBC < 30,000/microliter. Treatment consisted of Tipifarnib 300 mg BID × 21 days, with 7 days off. Dose escalation to 600 mg BID following cycle 1 was permitted for patients who had stable disease (SD) after cycle 1. Patients who achieved CR/CRi or PR after 2 cycles were eligible to continue treatment for up to 6 cycles maximum. Results: A total of 62 patients were consented to the trial. Of these, 21 (34%) were eligible based upon the required 2-gene ratio. Assay results were reported within 72 hours for all patients. Median age was 75 years. Fourteen (67%) patients had adverse karyotype and 14 (67%) had secondary AML (including 7 patients who received prior therapy for MDS). Three patients were replaced during cycle 1, due to withdrawal of consent or early unrelated death, such that 18 patients were considered evaluable for response. Median RASGRP1:APTX was 14.8. Two patients (11%) achieved CR and 6 (33%) additional patients had both SD and achievement of ≥50% reduction in bone marrow blasts by completion of cycle 2. Two of these 6 patients also had ≥50% increase in peripheral blood neutrophils or platelets. All 8 patients with CR or SD received at least 2 cycles of therapy. There was no correlation between baseline RASGRP1:APTX ratio and response. Overall, tipifarnib was well tolerated. Early death (≤ 30 days) was observed in only 1 patient (5%). The most common therapy-related non-hematologic toxicities (mainly grade 1–2) included: anorexia (33%), nausea (33%), fatigue (28%), febrile neutropenia (23%) and diarrhea (23%). Due to the trial not meeting its primary endpoint of at least 3 CR/CRi after 2 cycles, accrual to the trial was suspended. Conclusion: Monotherapy with tipifarnib in preselected elderly patients with AML and a RASGRP1:APTX ratio of ≥5 was associated with significant antileukemic activity and good tolerance. Although the primary endpoints during the first stage of the trial were not met, this study demonstrated the ability to rapidly and efficiently execute a biomarker-driven trial in an aggressive malignancy. Given the observed antileukemic activity in this selected population, along with a favorable toxicity and bioavailability profile for chronic dosing, further study of tipifarnib with less rigid endpoints than CR/CRi is warranted. Updated survival and RASGRP1 protein expression data will also be presented. Disclosures: Off Label Use: Tipifarnib in AML. Knoblauch:Johnson & Johnson: Employment. Karkera:Johnson & Johnson: Employment.

Purpose MDX-060 is a human anti-CD30 immunoglobulin (Ig) G1κ monoclonal antibody that inhibits growth of CD30-expressing tumor cells in preclinical models. To determine the safety, maximum-tolerated dose (MTD), and efficacy of MDX-060 in patients with relapsed or refractory CD30+ lymphomas, sequential phase I and II studies were performed. Patients and Methods In the phase I portion, MDX-060 was administered intravenously at doses of 0.1, 1, 5, or 10 mg/kg weekly for 4 weeks to cohorts of three to six patients. Twenty-one patients—16 with Hodgkin's lymphoma (HL), three with anaplastic large-cell lymphoma (ALCL), and two with CD30+ T-cell lymphoma—were enrolled. Because of the lack of a defined MTD or dose-response correlation, the phase II portion was amended to include several dose levels. In the phase II portion, an additional 51 patients, 47 with HL and four with ALCL, were treated at doses of 1, 5, 10, and 15 mg/kg. Results MDX-060 was well tolerated, and an MTD has not been identified. Only 7% of patients experienced grade 3 or 4 treatment-related adverse events. Among the 72 patients treated, clinical responses were observed in six. Twenty-five patients had stable disease, including five who remained free from progression 1 year after treatment. Conclusion MDX-060 was well tolerated at doses up to 15 mg/kg. MDX-060 has limited activity as a single agent, but the minimal toxicity observed and the significant proportion of patients with stable disease suggests that further study of MDX-060 in combination with other therapies is warranted.