ALBERT

Description: Abstract 2972 Thalidomide (T) with melphalan/prednisone (MPT) was defined as a standard treatment in elderly patients with multiple myeloma (MM) based on 5 randomized trials. Treatment with MPT not only showed improved response rate, significantly better time to response as well as quality of response but also a significant improvement of event free survival (EFS), progression free survival (PFS) and overall survival (OS). In one of these trials, HOVON 49, a prospective Health related – Quality of life (HRQoL) was initiated in order to asses the impact of T on QoL. (Wijermans et al, J Clin Oncol 28:3160-6). Patients aged 〉65 years with newly diagnosed symptomatic MM were randomized to receive 8 cycles of MP or MPT, followed by T maintenance in MPT arm. 284 patients were included in this HRQoL side study (MP: n=149, MPT: n=135). HRQoL was assessed with the EORTC core QoL Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24) at baseline and at pre-determined intervals during treatment. Treatment-related toxicity WHO grade 2–4 occurred in 60% of MP and 87% of MP-T treated patients. Most frequently found were neutropenia-related infections, neurotoxicity (mostly T induced peripheral neuropathy) and myelotoxicity. The QLQ-C30 subscales Physical Function (p=0.044) and Constipation (p

Description: The randomized, open-label, phase III trial HOVON-65/GMMG-HD4 was designed to evaluate the efficacy of bortezomib prior to HDM for response and progression-free survival (PFS) in patients with newly diagnosed MM. The trial was performed in 75 referral centers in the Netherlands and Belgium (HOVON group) and Germany (GMMG group). Patients with Salmon & Durie (SD) stage II or III, age 18–65 years inclusive, were randomly assigned to 3 cycles of VAD (vincristine 0.4 mg, adriamycine 9 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, 9–12, and 17–20) or PAD (bortezomib 1.3 mg/m2 days 1,4,8,11, adriamycine 9 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, 9–12, and 17–20). No thrombosis prophylaxis was given. Stem cells were mobilized using the CAD regimen, including cyclophosphamide 1000 mg/m2 iv day 1, and G-CSF. After induction therapy, all patients were to receive 1 or 2 cycles of high-dose melphalan (HDM) 200 mg/m2 with autologous stem cell rescue followed by maintenance with thalidomide 50 mg daily (VAD arm) or bortezomib, 1.3 mg/m2 once every 2 weeks (PAD arm) for 2 years. Between May 4, 2005 and May 16, 2008, 833 patients were randomized. After the trial was closed, we here report the planned interim analysis data on response after induction and HDM-1 of the initial 150 (75 per arm) randomized patients. The data of the initial 300 registered patients (150 per arm) will be available by November 1, 2008 and presented. The 2 randomization arms were equal for SD stage of disease, ISS stage, and distribution of chromosomal abnormalities. 134 patients (89%) completed PAD/VAD and 130 patients (87%) completed HDM-1, with no difference between the treatment arms. Full dose bortezomib could be administered in 95 % (PAD1), 79 % (PAD2) and 85 % (PAD3) of patients. Successful stem cell apheresis was achieved in all 132 patients who received CAD. Adverse events CTC grade 2–4 during PAD vs VAD included neurologic or polyneuropathy (PNP) 38% vs 21 %, constitutional symptoms 30 % vs 24 %. PNP of CTC grade 1–4 was more frequent in the PAD arm (p=0.01), while DVT/pulmonary embolism was diagnosed in 10 % during VAD and 6 % during PAD. Responses were assessed according to EBMT criteria including VGPR after PAD/VAD, after HDM-1 and best response on protocol treatment. Complete Response (CR), Very Good Partial Response (VGPR) and Partial Response (PR) in both arms were compared by logistic regression (table 1) Response ITT (%) PAD VAD p-value PAD+ HDM-1 VAD+ HDM-1 p-value CR 5 0 0.06 15 4 0.05 ≥VGPR 41 17 0.001 59 47 0.14 ≥PR 80 64 0.03 92 77 0.01 The (preliminary) overall complete response rate including maintenance was 27 % (PAD arm) and 5% (VAD arm) (p=0.001). Deletion of chromosome 13q did not have a significant impact on response. We conclude that PAD induces significantly more PR+VGPR+CR as compared with VAD, and that this effect is sustained after HDM-1. This trial was supported by the Dutch Cancer Foundation (EudraCT nr 2004-000944-26), the German Federal Ministry of Education and Research and a grant from Johnson and Johnson

Description: Tosedostat (TSD, CHR-2797) is an aminopeptidase inhibitor that selectively depletes amino acid pools in malignant cells, resulting in anti-proliferative, pro-apoptotic and antiangiogenic effects. In a phase I study, treatment with TSD resulted in complete remission in a number of refractory AML patients. The primary objective of this phase II study was to determine whether TSD was a sufficiently effective therapy to warrant pivotal studies. Methods. This was an open label, single agent, phase II study to assess clinical activity of TSD in elderly and/or previously treated patients with AML/MDS. Patients were treated with once daily oral doses of the maximum acceptable dose (130 mg) of TSD for up to 84 days. Further treatment was allowed if, in the opinion of the investigator, this was considered to be beneficial. Clinical responses were assessed by monthly bone marrow aspirates and weekly hematological assessments. Results. Of the 41 TSD-treated patients with AML (n=38) or MDS (n=3), who were enrolled between March and October 2007, 27 were male, 14 female, with a mean age of 67 years (range 34–82). The median performance status (ECOG) at baseline was 1 (range 0–2). Twelve (31.6%) AML patients and 2 (66.7%) MDS patients were chemotherapy naïve, and 9 (23.7%) AML patients had either secondary disease or adverse cytogenetics. For 16 (39%) patients, treatment with TSD was a second or later salvage attempt. Thirty two patients (30 AML, 2 MDS-RAEB1 and 2) received ≥28 days treatment, and 21 (51.2%) patients completed the formal 84-day study period (19 AML, 2 MDS). Nine (22%) of the patients (7 AML, 2 MDS) continued treatment with TSD after 84 days, and 6 (15%) patients were on TSD in total for more than 6 months (4 AML, 2 MDS). Ten (26.3%) of the AML patients responded to treatment; amongst these, 2 patients received TSD as 2nd/3rd salvage therapy, and a further 2 patients did not show a complete response (CR) after 2 previous induction courses of chemotherapy. Three AML patients achieved a CR (〈 5% blasts in bone marrow), of whom 2 were in durable remission (232 days, continuing*; 171 days), and 7 had a partial response (PR, 5–15% blasts) lasting approximately 1–3 months. Two (66.7%) of the MDS patients also responded to treatment with TSD; these patients maintained stable disease for more than 6 months. All responders (CR, PR and SD) were 〉60 years at the time of the first dose. Median overall survival in AML patients was 130 days (range 8 – 478 days*). The most frequently reported adverse events were: fatigue (61%), thrombocytopenia (49%), pyrexia (39%), peripheral edema (39%) and diarrhea (34%); 9 (22%) patients withdrew due to drug related toxicity. TSD had no effect on hemoglobin or neutrophils. Conclusions. This study in patients with advanced AML/MDS with adverse prognosis demonstrates the anti-leukemic activity of TSD in elderly AML patients, as measured by CR and decreases in leukemic blasts. In addition, 2 relapsed high risk MDS patients achieved disease stabilization. TSD at 130mg qd is also very well tolerated over a long period of exposure (6–10 months). These results support further pivotal studies with TSD in elderly AML and MDS patients.