ALBERT

Description: Leukemia is the most common type of cancer in pediatric patients (pts). Treatment options for Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) include: risk-adapted chemotherapy, imatinib (im) and stem cell transplant (SCT). Relapsed leukemia has few therapeutic options. Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL, KIT, and SRC kinases that was recently granted approval for adults with CML, and Ph+ ALL with resistance or intolerance to prior therapy. CA180018 is the first trial evaluating dasatinib in pediatric patients pts and Ph+ and in Ph- leukemias. CA180018 is a phase I/II dose-finding study of dasatinib in pts aged 1–20 with CML or relapsed Ph+ ALL resistant or intolerant to im, or Ph- ALL or AML in ≥2nd relapse performed in collaboration with 12 centers (6 countries) from the ITCC Consortium. Preliminary data are available on the first 15 pts treated from March-July 2006 (2 chronic phase (CP) CML, 7 Ph+ ALL, 1 accelerated phase (AP) CML, 3 Ph- ALL, and 2 Ph- AML) at a starting dose of 60 mg/m2 daily (course = 3 weeks). Intra-patient dose escalation was allowed for lack of initial response, and a 3+3 design for maximum tolerated dose (MTD) determination. Hematologic, cytogenetic, and molecular responses, as well as plasma and cerebrospinal fluid (CSF) pharmacokinetic (PK) analysis and BCR-ABL mutational analysis are ongoing. Median age was 11 yrs (range 4–17), median time from diagnosis of leukemia was 19.5 months (range 1.4–89.9). Prior therapy included chemotherapy, im, and stem cell transplant. Median duration on study is 0.69 month (range 0.03–3.45). Intra-patient dose escalation to 80 or 100 mg/m2 occurred in 7 pts. Six pts remain on study. There have been 7 responders: 4 complete hematologic responses (CHR): 1 CP CML, 1 AP CML, 2 Ph+ ALL; 5 cytogenetic responses (CyR): 2 Ph+ ALL complete CyR (CCyR), 1 AP CML CCyR, 1 CP CML partial CyR (PCyR), 1 Ph+ ALL minor CyR who never achieved a CHR, and then progressed; and 2 Ph+ ALL pts with CNS disease who cleared the CSF of leukemic blasts with single agent dasatinib. Preliminary PK in 7 pts showed rapid absorption with a median Tmax of 1.0 h, and mean terminal phase half-life (SD) of 2.7 (1.1) h. There is one dose-limiting toxicity (DLT): grade 4 anaphylactic shock which occurred 5 hours after the first dose. Dasatinib has otherwise been well tolerated up to 100 mg/m2 with toxicities including grade 3/4 thrombocytopenia, and sepsis. Nine pts are off study: 8 for progressive disease (2 Ph+ ALL pts with a resistant T315I BCR-ABL mutation), and 1 DLT. These preliminary results provide evidence supporting the safety and efficacy of dasatinib in pediatric pts with relapsed or refractory leukemia. An updated analysis including further enrollment, safety data, PK, cytogenetic and molecular responses, and mutational analyses will be presented.

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: Multiple Myeloma (MM) is characterized by the presence of a monoclonal protein, immunodeficiency, anemia, renal failure and bone lesions. New agents like Bortezomib (Bor) and Thalidomide (Thal) have shown efficacy in 40% of patients with relapsed/refractory MM, and up to 75% in first-line treatment. Classical prognostic classifications such as serum b2-microglobulin, albumin and chromosomal aberrations, have insufficient predictive power in estimating long-term outcome with these targeted agents. We have performed gene expression profiling (GEP) in newly diagnosed MM patients who were included in a large multicenter, prospective phase III trial (HOVON65) comparing Bor with standard induction prior to high dose therapy (HDT). The aim of this profiling was to gain new insights in the pathogenesis of MM and to design a prognostic index for treatment based on molecular profiling. In 258 patients, CD138 magnetic cell selected (MACS) myeloma plasma cells (PC) obtained at diagnosis with PC purity 〉 80% were used for RNA extraction and applied to the Affymetrix GeneChip U133 plus 2.0 arrays. Data from the gene expression arrays were pre-processed using GCRMA (Bioconductor). Unsupervised gene clustering (Omniviz) using a correlation visualisation matrix could determine the clusters based on the top variably expressed genes, and differential gene expression within these clusters could be determined (BRB-array tools, p