ALBERT

Description: Increased drug delivery through enhanced formulations of standard acute lymphoblastic leukemia (ALL) therapies may improve outcomes while producing less toxicity. Preclinical and Phase 1 and Phase 2 clinical studies of vincristine sulfate encapsulated in liposomes (VSLI, Marqibo®) have shown enhanced efficacy and acceptable tolerability in a variety of solid and hematologic malignancies. A maximum tolerated dose (MTD) of 2.25 mg/m2 with no dose cap has been established for VSLI, which contrasts with the 2 mg dose cap for conventional vincristine (VCR). Pharmacokinetic studies have shown that altered distribution and elimination phases may lead to increased exposure versus traditional VCR and may account for the increased efficacy observed in nonclinical models. The current Phase 2 trial is evaluating VSLI in adult (Ph-) subjects with ALL in second relapse or after progression following two prior ALL therapies. Subjects are receiving intravenous (IV) 2.25 mg/m2 VSLI weekly with no dose cap for up to 12 months. The study will enroll approximately 56 subjects with response rate as the primary endpoint. To date, 23 subjects have received at least one dose of IV VSLI. Preliminary reports indicate that five of these subjects achieved responses (CR/CRi/CRp). While data review is not complete, preliminary signs of efficacy in this underserved patient population warrant discussion: Two subjects had fewer than 5% lymphoblasts; one on Day 28 and the other on Days 28 and 56 after initial VSLI treatment and subsequently underwent stem cell transplant. The latter subject achieved a CR to a single agent (VSLI) in her first relapse (systemic and extramedullary) after a prior allogeneic transplant. One subject achieved a CR with no residual blasts (normocellular bone marrow) and resolution of extramedullary disease including resolution of bilateral pleural effusions without thoracentesis and marked decrease of an anterior mediastinal mass by Day 28. Her chest pain resolved after the first dose of VSLI. This subject subsequently went on to receive a second stem cell transplant. One subject with extramedullary disease of the kidney achieved a CR with no residual blasts detected in the kidney or bone marrow. This subject achieved a true CR (2 confirmed kidney biopsies one month apart) after 11 doses VSLI. One subject with bone marrow disease achieved a CR that was durable for approximately 5 months. Although these data are preliminary in this patient population, these findings are encouraging given that this is a single agent chemotherapy being given to a heavily pretreated leukemic population. The drug appears well tolerated to date with no reports of subjects experiencing Grade 4 toxicity. VSLI appears to have a safety profile similar to conventional VCR. Common AEs include neutropenia, fatigue, constipation, peripheral neuropathy, and nausea. In the previous VSLI (Marqibo) Study VSLI-06, VSLI appeared to be highly effective in second relapsed subjects achieving a CR rate of 29% with a limited sample size (2 out of 7 subjects). The preliminary CR (CR/CRi/CRp) rate from this study further corroborates this result: the CR rate is 28% among patients who completed study treatment and is at least 22% (≥5/23 subjects) among all subjects including those who just started receiving VSLI. The projected rate of activity in this ongoing trial supports these previous Phase 1 study results and confirms the importance of VSLI (Marqibo) in this patient population. These preliminary results are extremely encouraging, as VSLI was given as a single agent to a patient population that typically has a very low response rate to anti-leukemia therapies. Phase 3 combination studies are planned.

Description: Novel formulations of standard chemotherapy allowing increased drug delivery without additional toxicity may improve outcomes for patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Vincristine sulfate liposomes injection (VSLI, Marqibo®) is VCR encapsulated in sphingomyelin (55%)/cholesterol (45%) nanoparticle liposomes called Optisomes™. Pharmacokinetic studies have shown that the altered distribution and elimination phases of VSLI may lead to increased VCR exposure compared to traditional VCR, and may account for the increased efficacy observed in preclinical models. Activity of VCR is dose and time-dependent, but neurotoxicity limits dosing to 1.4 mg/m2 (capped at 2.0 mg). VSLI, however, may be given without dose capping. We conducted a phase 1, open-label, dose-escalation study of VSLI in adults with relapsed or refractory ALL to determine the safety, maximum tolerated dose (MTD), and activity of this formulation. Subjects received VSLI intravenously weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2. Dexamethasone 40 mg was given days 1–4 and 11–14 of each 4 week cycle. Thirtysix eligible subjects, all of whom had been previously treated with VCR, received at least 1 dose of VSLI. All were Philadelphia chromosome negative except for one. Median number of doses received for all subjects was 4; total medium cumulative dose was 9.09 mg/m2 (19.20 mg). MTD of VSLI was 2.25 mg/m2 based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure and grade 4 hepatotoxicity observed in 1 subject each at the 2.4 mg/m2 dose level. The most common toxicities (constipation [67%], fatigue [61%], pyrexia [50%], anemia [50%], peripheral neuropathy [50%; mostly grade 1–2]) were as expected. Complete response (CR) was achieved in 7 of 36 (19%) subjects based on intent to treat analysis (Table). Overall response rate (including 1 PR) was 22%. Four subjects (11%) achieved hematologic improvement, 13 (36%) had stable disease, and 9 (25%) progressed. CR rate was 29% for the 7 subjects treated with VSLI as second salvage. Five of 7 subjects who achieved CR were able to undergo allogeneic stem cell transplant (SCT). In conclusion, VSLI appears to be an effective therapeutic option which may permit potentially curative SCT. A phase 2 international multi-center trial of single agent VSLI in subjects with relapsed ALL is currently accruing. Table. VSLI Clinical Activity (CR) by Dose Level and Salvage Status 1.5 mg/m2 n = 5 1.825 mg/m2 n = 3 2 mg/m2 n = 3 2.25 mg/m2 n = 18 2.4 mg/m2 n = 7 Total n = 36 1st salvage 1/1 0/1 -- 2/7 1/4 4/13 (31) 2nd or later salvage 1/4 1/2 0/3 1/11 0/3 3/23 (13)

Description: ABT-869 is an orally bioavailable, potent and specific inhibitor of multiple receptor tyrosine kinases (RTKs) including vascular endothelial and platelet growth factor, FLT3, STAT5, and ERK receptors. Since multiple RTKs, particularly FLT3, are commonly expressed and activated in AML/MDS, ABT-869 may prove to be an attractive therapeutic option. The current multi-center, two arm, dose-escalation study was designed to assess the safety, pharmacodynamics, pharmacokinetics (PK) and preliminary anti-tumor activity of ABT-869 as monotherapy in arm A, and to determine the PK, safety profile and potential of a PK or PD mediated drug interaction in patients with AML or MDS treated with ABT-869 plus Cytosine arabinoside (Ara-C) in arm B. No dose was administered on D7 (arm A) and D12 (arm B). In single-agent Arm A enrollment is complete (N=29) with 9, 4, 12 and 4 patients enrolled in each of the 10, 12.5, 15, and 20 mg cohorts, respectively. Dosing began with the 10 mg/day cohort and escalated to the 20 mg/day cohort to define a recommended phase 2 dose (RP2D) of 15 mg. During dose escalation, in the 10 mg cohort, 2 patients experienced DLTs of fatigue while in the 20 mg cohort, 3 patients experienced DLTs of fatigue and 1 patient experienced a DLT of proteinuria. In currently enrolling arm B (N=17), ABT-869 was administered in combination with Ara-C. ABT-869 was initiated on day 6 following administration of Ara-C at 1.5 mg/m2 on days 1–3 (patients ≥64 years old) or days 1–4 (patients

Description: DNA hypermethylation of promoter-specific CpG islands has been implicated in the pathogenesis and progression of myelofibrosis (MF). We have evaluated Decitabine, a DNA methyltransferase inhibitor in patients (pts) with MF, including primary MF (PMF), and MF arising after polycythemia vera or essential thrombocythemia (post-PV or post-ET MF). This was a multicenter, single stage Phase II trial, with a planned accrual of 20 patients. The regimen would be deemed worthy of further investigation if ≥ 5 pts responded. Eligibility criteria included myelofibrosis associated with anemia (hemoglobin 50% increase in platelet levels) have also been observed. Median time to response was 2 cycles (range 1–6); median duration of response was 5 months (range 2–15). Two pts are maintaining their responses at 2 and 14 months. All responders who developed disease progression did so while off therapy. Analysis of the effects of decitabine on CD34+ cells revealed a 61% reduction (p1%) than non-responders at baseline and post-therapy (p

Description: The fludarabine-melphalan-alemtuzumab combination is a well tolerated conditioning regimen for HCT. Unfortunately recurrence rates are high, particularly for those with active disease entering HCT. Clofarabine (Clo), a second generation nucleoside analog with excellent activity in acute leukemia, might enhance disease control. Here we report the results of a phase I–II study of clofarabine-melphalan-alemtuzumab conditioning for allogeneic peripheral blood HCT. GVHD prophylaxis used tacrolimus. For the phase I cohort, one pt was enrolled per dose level, until the first DLT or until 2 had gr 3 toxicity. Dose level 1 consisted of: clofarabine 10 mg/m2/day on d-7 to -3 and melphalan 100 mg/m2 on day-2. Clo was increased by 10 mg/m2/day per cohort until 40 mg/m2/day. Then, melphalan was increased by 20 mg/m2 until 140 mg/m2. Twelve pts were accrued in the phase I portion. There were four deaths from transplant mortality (TRM); two patients who had failed prior transplant and were pancytopenic prior to conditioning, died of early sepsis unrelated to regimen related toxicity. One early death from multi-organ failure in a patient with t-AML, residual breast cancer and a history of heart disease was attributed to possible regimen related toxicity. One additional pt with multiple comorbidities died at day 159 from sepsis. The phase II dose was established at Clo 40 mg/m2/day × 5 days + melphalan 140 mg/m2. Sixteen pts have been accrued in the ongoing phase II study. For the entire phase I–II cohort, median age was 52 (20–69); 13 had AML, 13 NHL, 1 CML, 1CLL; 23 had high or intermediate and 5 had low risk disease. 5 had relapsed after alloHCT, 4 after autoHCT. HCT-CI was 〉= 3 in 9 and ECOG PS 〉=1 in 11. Sixteen had HLA-identical sibling donors and 12 had 8/8 Matched unrelated donors. All evaluable patients recovered ANC 〉0.5 by d+11 (9–20) and plt count 〉 20 by d+12 (9–27). Median d 30 donor chimerism was 95% (range 14–100) with no late graft failures. In addition to the four transplant related deaths during the phase I portion, two additional transplant related deaths occurred during the phase II portion. One patient with multiple comorbidities died during conditioning from possible regimen related toxicity and one pt who had failed a prior transplant died from GVHD. Other toxicities included: gr 2–3 reversible ALT elevation in 14 pts, between day-2 and day +5; gr 2 reversible bilirubin elevation in 1 pt; gr 2–3 hand-foot syndrome in 9 pts; gr 3 mucositis and pulmonary hemorrhage in 1 pt; gr 2 renal failure in 3 pts. With a median follow-up 140 days (51–412), 3 of 12 pts in the phase I portion and 12 of 16 pts in the phase II portion of the study remain in remission. Estimated day 180 progression-free survival is 47% (95% CI: 26–69) (figure) Conclusions: Clofarabine-melphalan-alemtuzumab conditioning induces durable engraftment in related and unrelated donor HCT. The most common toxicities are reversible elevation of transaminases and hand foot syndrome. Grade II renal failure can occur. There were six transplant related deaths, two attributed to possible regimen related toxicity. All transplant related deaths occurred in patients with high risk disease, prior transplant and/or multiple comorbidities. Response rates and duration of response are encouraging. Figure Figure

Description: Background: Many patients (pts), particularly minorities, lack matched unrelated donors. Mismatched cord blood (CB) transplantation causes less graft versus host disease (GVHD), but is associated with delayed hematopoietic recovery. We studied an alternative donor regimen using T-cell depleted haploidentical stem cells and unrelated CB pioneered by Magro et al. (Haematologica2006;91:640–8) to confirm engraftment with acceptable rates of GVHD. Patients and Methods: We enrolled 15 pts (7 AML, 1 ALL, 2 MDS, 1 CML, 3 NHL, 1 severe aplastic anemia) lacking HLA identical donors. The median age was 28 years (range, 4–66) and median weight was 75 kg (range, 14–124). Twelve pts had active disease at transplant; 2 had prior autologous transplants. Eight pts were Caucasian; 7 other race or ethnicity. The haploidentical donor was the mother in 3; father in 1; child in 4; sibling in 5; and half-sibling in 2 cases. The median haploidentical CD34+ dose was 2.41 × 106/kg (range, 1.25–6.26); CD3+ cells were 0.8 × 104/kg (range, 0.3–1.3). Single unrelated CB units were matched by low resolution at HLA-A and B and high-resolution at DRB1, and matched 6/6 in 1 pt; 5/6 in 7 pts; 4/6 in 6 pts; 3/6 in 1 pt. Median cord total nucleated cells equaled 2.39 × 107/kg (range, 1.07–9.36); CD34+ cells were 0.14 × 106/kg (range, 0.04–0.75). The conditioning regimen for most pts was fludarabine (Flu) (30 mg/m2 × 5 days), thiotepa (5 mg/kg × 2 days), total-body irradiation (TBI) (12 Gy lateral opposed fields), and Thymoglobulin® (rATG) (1.5 mg/kg × 4 days). Five pts unable to tolerate TBI received Flu, melphalan (70 mg/m2 × 2 days), and rATG. GVHD prophylaxis consisted of tacrolimus (Tac) + methylprednisolone or Tac + mycophenolate. Results: Two pts died early (sepsis, CVA). Twelve of the remaining 13 pts engrafted. One pt failed to engraft and died on day (d)36. Median time to ANC 〉500/mL was 9 days (range, 9–12). Median time to sustained platelets 〉20,000/mL was 24 days (range, 12–63). Early haploidentical engraftment was replaced by durable engraftment of CB by 100 days. In unfractionated peripheral blood or bone marrow cells, median haploidentical chimerism was 95% (range, 0–100) on d14; 76% (range, 0–93) on d30; 36% (range, 0–83) on d55; 0% (range, 0–42) on d100; and 0% on d180. Median unfractionated cord chimerism was

Description: We performed a retrospective comparison of presenting features, planned treatment, complete remission (CR) rate, and outcome of 321 adolescents and young adults (AYAs) ages 16 to 20 years with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated on consecutive trials in either the Children's Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB) from 1988 to 2001. CR rates were identical, 90% for both CALGB and CCG AYAs. CCG AYAs had a 63% event-free survival (EFS) and 67% overall survival (OS) at 7 years in contrast to the CALGB AYAs, in which 7-year EFS was only 34% (P 〈 .001; relative hazard rate [RHR] = 2.2) and OS was 46% (P 〈 .001; RHR = 1.9). While CALGB AYAs aged 16 to 17 years achieved similar outcomes to all CCG AYAs with a 7-year EFS of 55%, the EFS for 18- to 20-year-old CALGB patients was only 29%. Comparison of the regimens showed that CCG AYAs received earlier and more intensive central nervous system prophylaxis and higher cumulative doses of nonmyelosuppressive agents. There were no differences in outcomes of those who reached maintenance therapy on time compared with those who were delayed. Based on these observations, a prospective study for AYAs with ALL using the more successful approach of the CCG has been initiated.