A Phase I Dose Finding Study of Panobinostat in Children with Hematologic Malignancies: Initial Report of TACL Study T2009-012 in Children with Acute Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3705-3705 ◽  
Author(s):  
John M Goldberg ◽  
Julia Glade-Bender ◽  
Maria Luisa Sulis ◽  
Rebecca A Gardner ◽  
Jessica A. Pollard ◽  
...  

Abstract Background: Approximately 3540 children are diagnosed with leukemia in the United States yearly (Bhatia and Robison, Oncology of Infancy and Childhood, 2008). Cooperative group trials have increased survival, particularly for acute lymphoblastic leukemia (ALL), but successful treatment of recurrent leukemia remains an unmet medical need. Resistance pathways and epigenetic alterations suggest a role for histone deacetylase (HDAC) inhibitors in children with leukemia (Burke and Bhatla, Frontiers in Pediatrics, 2014). Panobinostat is an orally administered pan-deacetylase inhibitor with activity against HDACs at concentrations in the nanomolar range (Atadja, Cancer Letters, 2009), and for which there is pre-clinical evidence of activity in pediatric leukemia (Stubbs, et al., ASH 2010). Panobinostat shows promise in a variety of adult hematologic malignancies (Khot et al., Expert Opinion on Investigational Drugs, 2013). We undertook a phase I trial of panobinostat in children with recurrent hematologic malignancies, and herein report the safety and pharmacokinetics (PK) from enrolled children with leukemia. Methods: T2009-012 is a first-in-child study coordinated by Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL). Children with relapsed or refractory leukemia between the ages of 1 and 21 years were enrolled to a multi-center, single agent trial of panobinostat dosed once per day three days per week for four successive weeks. Dose escalation was a standard 3+3 design with three dose levels planned. Subjects underwent lumbar puncture with prophylactic chemotherapy at treatment start and after a 28 day course. Blood was sampled pre-dose, at 0.5, 1, 6, 24 and 28-48 hours following the first dose. PK was obtained from blood on patients concurrently with optional specimens obtained from cerebrospinal fluid (CSF) on Day 29. Subjects who received fewer than 11 of the 12 planned doses and did not experience a dose limiting toxicity (DLT) were considered not evaluable for DLT, but were included in the summary of toxicities. Serial ECGs were monitored. Results: Seventeen subjects were enrolled with a diagnosis of acute leukemia, 10 with ALL and 7 with acute myelogenous leukemia (AML). Five were enrolled at dose level 1, 24 mg/m2/dose, 6 at dose level 2, 30 mg/m2/dose, and 6 at dose level 3, 34 mg/m2/dose. There have been no DLTs. Nine subjects are evaluable for DLT and 4 subjects were taken off study early due to increasing blast count. No subjects required removal from protocol therapy for QTc prolongation. One subject with infant ALL was removed early for progressive Aspergillus infection, 1 subject only received 10 doses owing to electrolyte abnormalities, and 2 subjects had nausea and vomiting after administration of 4 doses and did not continue. Grade 3/4 adverse events occurring in more than 20% of subjects included anemia in 82%, diarrhea in 24%, febrile neutropenia in 65%, hypokalemia in 41%, and hypophosphatemia in 24%. Concentration-time profiles were obtained from 9 subjects ages 16 months to 14 years in the 3 dose levels. Mean ± SE of PK for all subjects were Cmax 28.8 ± 6.1 ng/mL, Tmax 2.0 ± 0.8 hours, and T1/2 12.8 ± 3.0 hours. Two toddlers had the highest dose-normalized AUC0-inf and lowest oral clearance. Apparent oral clearance proportionally increased with increase in BSA. To date, 4 CSF specimens have been evaluated and found to have panobinostat below the lower limit of the quantification of 0.1 ng/mL, despite appreciable levels in the plasma. Two subjects on dose level two began a second cycle of therapy; one completed a second cycle for MLL rearranged leukemia and one discontinued study participation in the second cycle to undergo hematopoietic stem cell transplant for secondary AML after achieving a CRp in the first cycle. Conclusions: Panobinostat was tolerated these heavily pre-treated patients without unanticipated toxicities. PK in larger children and adults appears similar but PK in smaller children needs to be further explored. Penetration of panobinostat into the CSF was negligible. Two of 17 patients were able to receive a second cycle of therapy, but 4 had to be withdrawn early because of rapid increase in blast counts. Future trials will explore combination therapy in children with refractory hematologic malignancies, particularly those known to be driven by epigenetic mechanisms, in order to better control risk of rapid progression and improve efficacy through synergy. Disclosures Off Label Use: panobinostat for leukemia. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Thomson:Epizyme, Inc: Employment.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3651-3651 ◽  
Author(s):  
Mark Kirschbaum ◽  
Ivana Gojo ◽  
Stuart L Goldberg ◽  
Lisa Kujawski ◽  
Ehab Atallah ◽  
...  

Abstract Epigenetic therapies, eg decitabine (dec) a DNA methyltransferase inhibitor (MTI), have added treatment options for myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). However, response rates remain relatively low. Preclinical and clinical data suggest that broadening epigenetic targeting by adding HDAC inhibitors to MTIs may improve responses. Preclinical data suggest that outcomes may differ according to the sequence in which epigenetic agents are combined. We present preliminary data from a phase I, open-label, multicenter, dose-escalating study, aiming to find the maximum-tolerated dose and recommended phase II dose of vorinostat combined concurrently or sequentially with dec in patients (pts) with MDS or AML. Other endpoints included tolerability and exploratory assessments of activity. Pts diagnosed with intermediate-high risk MDS, refractory or relapsed AML (≥18 years), or untreated AML(≥60 years; unsuitable for standard chemotherapy), with an ECOG performance status of ≤2 were eligible. See table for vorinostat dosing schedules. Dec 20 mg/m2 IV was administered over 1 h, daily on days 1–5. Therapy continued up to 24 months or until progressive disease (PD). 63 pts were randomized to treatment: median age (range, years) 68 (18–85); 65% males; 9 pts with MDS; 27 pts with untreated AML; 24 pts with relapsed/refractory AML. 35 pts have discontinued due to PD/lack of efficacy (n=19), withdrawal of consent (n=8), adverse events (AEs) (n=6), physician decision (n=1), and protocol deviation (n=1). AEs were reported by 50 pts (79.4%), mainly mild to moderate and commonly included nausea (n=19), fatigue (n=18), constipation (n=16), leukopenia (n=16), diarrhea (n=15), and vomiting (n=12). 37 AEs were treatment related. 42 pts (66.7%) had serious AEs, including febrile neutropenia (n=22), grade 3/4 neutropenia (n=7), and pneumonia (n=9). 12 deaths occurred during the study. In 60 pts evaluable for response, the median (range) number of cycles received were 2 (1–4), 6 (4–7), 3 (1–5), 2 (2–5), 2 (1–2), and 1 (1–7) for dose levels 1, 2, 3, 1a, 2a, and 3a, respectively. Dose levels 3 and 3a were expanded. Complete response (CR) was achieved by 22% pts with MDS, 26% with untreated AML, and 8% with relapsed/refractory AML. Hematologic improvement (HI) was reported in 4% and 22% of pts with untreated AML and MDS, respectively. A similar proportion of pts achieved stable disease (SD) in all disease groups (range 30–46%). Overall, best responses recorded in evaluable pts were: CR, n=11 (3 cytogenic CR); partial response (PR), n=1; HI, n=3; SD, n=25. PD was reported in 6 pts. Best response for 14 pts not yet reported. A best response of CR, PR, HI, and SD was achieved in 26%, 3%, 6%, and 32% of pts treated with concurrent therapy, and 10%, 3%, and 45% of pts receiving sequential regimens reported a best response of CR, HI, and SD, respectively. In pts with untreated AML receiving concurrent therapy, CR was achieved in 8 pts, PR in 1 pt, HI in 2 pts, and SD in 10 pts. In those receiving sequential therapy, CR was achieved in 3 pts, HI in 1 pt, and SD in 13 pts. Preliminary data indicate that the combination of vorinostat with dec, either concurrently or sequentially, is possible without significant toxicity. In addition, the combination shows promising activity in MDS and untreated AML. Concurrent initial schedule (28-day cycle) Sequential initial schedule (28-day cycle) Dose Level 1:Vorinostat 400 mg QD for 7 days (days 1–7) Dose Level 1a:Vorinostat 400 mg QD for 7 days (days 6–12) Dose Level 2: Vorinostat 400 mg QD for 14 days (days 1–7 and days 15–21) Dose Level 2a: Vorinostat 400 mg QD for 10 days (days 6–15) Dose Level 3: Vorinostat 400 mg QD for 14 days (days 1–14) Dose Level 3a: Vorinostat 400 mg QD for 14 days (days 6–19)


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17098-17098 ◽  
Author(s):  
K. H. Dragnev ◽  
J. R. Rigas ◽  
W. M. Disalvo ◽  
S. A. Simeone ◽  
A. E. Hagey ◽  
...  

17098 Background: NSCLC is the leading cause of cancer mortality for men and women in the United States. More effective treatments are needed to prolong survival and improve quality of life. Platin-containing chemotherapy doublets are commonly used in NSCLC treatment. ABT-751 is a novel oral anti-microtubule agent targeting the colchicine binding site. As single agent, it was well-tolerated and showed a preliminary signal of activity in previously treated NSCLC. In vivo studies demonstrated additive activity between ABT-751 and cisplatin in a NSCLC xenograft model. Methods: A phase I trial of ABT-751 and C was conducted in pts with advanced previously treated NSCLC. Primary objective - maximum tolerated dose (MTD). Secondary objectives - toxicities, efficacy, and surrogate markers of response (cell cycle changes and cyclin D1 expression) in buccal swabs from pts at the phase II dose. Six dose levels - 1: ABT-751 100mg bid, C AUC 4.5; 2: ABT-751 125 mg bid, C AUC 4.5; 3: ABT-751 125 mg bid, C AUC 6; 4: ABT-751 150 mg bid, C AUC 6; 5: ABT-751 175 mg bid, C AUC 6; 6: ABT-751 200 mg bid, C AUC 6. ABT-751 was taken orally twice a day for 14 days in a 21 day cycle, C was administered intravenously on day 4 during cycle 1 and on day 1 on subsequent cycles. Rapid dose escalation was used for the first 3 dose levels followed by cohorts of at least 3 patients for the remaining dose levels. Results: Eight pts were enrolled, all stage IV NSCLC, 4 women, median age 62 (47–73), all KPS 80, 6 had one and 2 had 2 prior therapies. A median of 3.5 (1–4) cycles was administered. Dose-limiting toxiticies of grade 3 fatigue and grade 4 thrombocytopenia and neutropenia were observed in 2/5 patients on dose level 4. Common grade 2 toxicites were constipation and peripheral sensory neuropathy (levels 2–4). MTD was dose level 3. Seven pts were evaluable for response, 2 had partial responses (levels 2 and 4, both had one prior therapy), 4 had stable disease, 1 had disease progression. Median time to progression was 18.7 weeks (6–24+). Pharmacokinetic analyses and buccal swabs are being performed. Conclusions: The recommended phase II doses are ABT-751 125 mg twice daily for 14 days and carboplatin AUC 6 on a 21-day cycle. This regimen is well tolerated and shows preliminary evidence of activity for previously treated NSCLC. [Table: see text]


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 883-883 ◽  
Author(s):  
Nobuko Hijiya ◽  
Paul Gaynon ◽  
Manuel Fernandez ◽  
Michael Rytting ◽  
Roland Chu ◽  
...  

Abstract Clofarabine as a single agent has demonstrated activity in childhood acute leukemia. In the current phase I/II study, clofarabine was added to the widely used combination of etoposide and cyclophosphamide. The phase I component of the study is completed. Patients between 1 and 21 years old with refractory or relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) were enrolled in phase I. A standard 3+3 design was followed to determine the safest dose when used in combination. All 3 drugs were administered via IV infusion daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients received up to 2 induction cycles (depending on the response following cycle 1), followed by consolidation (up to a maximum of 8 cycles, including induction). The initial doses (cohort 1) were: clofarabine 20 mg/m2/day, etoposide 75 mg/m2/day and cyclophosphamide 340 mg/m2/day. Clofarabine was increased to 30 mg/m2/day in cohort 4 and 40 mg/m2/day in cohort 5 after cyclophosphamide and etoposide were escalated to their respective target dose levels (440 mg/m2/day and 100 mg/m2/day) in cohorts 2 and 3. Twenty-five patients (ALL: 20 patients; AML: 5 patients) were enrolled in the 5 cohorts, and response data based on investigator’s assessment are available on the first 22 patients (ALL: 18 patients; AML: 4 patients). The median number of prior induction regimens was 2, and 3 patients had a prior hematopoietic stem cell transplant (HSCT). Data show complete remission (CR) in 7 patients (ALL: 7 patients; AML: 0 patients) and complete remission without platelet recovery (CRp) in 6 patients (ALL: 2 patients; AML: 4 patients) for an overall response rate of 59% (ALL: 50%; AML: 100%). Four patients proceeded to HSCT after treatment. One patient in cohort 4 experienced a dose-limiting toxicity (DLT) that resolved (grade 3 elevation of lipase and abdominal pain). In addition, a second patient in cohort 4 experienced a lipase elevation that did not meet DLT criteria, leading to a cohort expansion to 10 total patients. One patient in cohort 5 (n=6) experienced a DLT of prolonged bone marrow aplasia leading to cohort expansion. Common toxicities observed in ≥20% of patients included febrile neutropenia, abdominal pain, diarrhea, nausea, vomiting, pyrexia, anorexia, hypokalemia, headache, anxiety and rash. As determined by the independent data monitoring committee, the recommended phase II doses of clofarabine, cyclophosphamide, etoposide 40mg/m2/day, 440 mg/m2/day, and 100 mg/m2/day, respectively. Encouraging preliminary efficacy results and an acceptable safety profile of the combination regimen warrants continuation of the phase II portion of the study, which is actively enrolling patients.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3292-3292 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Charles Chuah ◽  
George Wilding ◽  
Julie Chang ◽  
Srdan Verstovsek ◽  
...  

Abstract Abstract 3292 Background: SB939 is a novel orally bioavailable inhibitor of class 1, 2 and 4 histone deacetylases. In human tumor cell lines SB939 inhibits proliferation and promotes apoptosis at an IC50 of 0.1 – 1.3mM. Antitumor activity has been demonstrated in xenograft models of AML (MV4-11) and B-cell lymphoma (Ramos), as well as solid tumors. A phase I, open label, dose escalation study in patients with advanced hematologic malignancies was conducted to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary efficacy of SB939. Methods: SB939 was administered orally every other day 3 times a week for 3 consecutive weeks, in a 4-week cycle. Cohorts of patient were treated with escalating doses of SB939 starting from 10 mg. The MTD was defined as the lowest dose level with less than 2 DLTs. The recommended Phase 2 dose level was defined as one dose level below the MTD. PK and PD (Acetylated Histone 3 in PBMCs) samples were collected in the first cycle. Results: A total of 44 patients were enrolled. 23 patients during dose escalation at dose levels of 10 mg (n=1), 20 mg (n=1), 40 mg (n=6), 60 mg (n=3), 80 mg (n=3), 100 mg (n=3) and 120 mg (n=6). An additional 21 patients were enrolled as part of a cohort expansion at 100 mg. The median age was 70 yr (range 37–84 yr), 57% were male, 61% were caucasian and 27% asian. Median number of prior therapies was 2 (range 0–9), 16 % had a prior transplant. 89% had ECOG performance score of 0–1. The median number of doses received was 17. DLTs included prolonged QTc at 40 mg and neutropenic sepsis at 120 mg. The MTD as defined was not reached; 120 mg was declared as MTD due to the requirement for dose reduction after multiple cycles of treatment. 100 mg was determined to be the recommended Phase II dose. 24 patients, MDS (n=11), AML (n=12), and lymphoma (n=1) were treated at the 100 mg dose level. SB939 was generally well tolerated. Grade 1–2 events included nausea (45%), fatigue (44%), diarrhea (36%), anorexia (34%) and vomiting (30%). Grade 3–4 adverse events included thrombocytopenia (39%), anemia (23%), pneumonia (23%), febrile neutropenia (20%), fatigue (16%), hypokalemia (11%), and neutropenic sepsis (11%). Samples for pharmacokinetics were drawn prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 ± 2 and 30 ± 2 hours after dosing on days 1 and 15 of Cycle 1. Levels of SB939 in plasma were determined using a validated LC-MS/MS method and Non-Compartmental Analysis used WinNonlin, version 5.2 (Pharsight). SB939 was rapidly absorbed with mean Tmax ranging between 0.5–1.3 h; the mean elimination half-life ranged between 6–17 hrs. The Cmax and AUC (0-∞) increased dose-proportionally in the range of doses tested. There was no accumulation of SB939 on day 15 following repeated dosing. Concentrations above IC50 of SB939 for HDAC 1, 2, and 4 were reached at all doses and increased acetylation of H3 was observed in PBMCs across all dose levels. 1 PR (80 mg) and 1 CR (120 mg) were observed in 2 patients with AML with durations of 362 and 206 days respectively. Stable disease for more than 2 cycles was seen in 7 patients, 3 with IPSS intermediate or high risk MDS (duration 72–134 d) and 4 with AML (duration 56–354 d). Conclusions: SB939 demonstrated excellent PK properties and target inhibition and was generally very well tolerated. Toxicities were mild to moderate and similar to some but not all toxicities seen with other HDAC inhibitors. The MTD as defined for this regimen of SB939 in patients with hematologic malignancies was not reached and 100mg is the recommended dose, indicating a favorable therapeutic index. Response data particularly in higher risk MDS and AML encourage further exploration of the therapeutic benefit of SB939 in combination with other anti-cancer therapies. Disclosures: Ethirajulu: S*BIO: Employment. Zhu:S*BIO: Employment.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3756-3756 ◽  
Author(s):  
Ronan T Swords ◽  
Andrew H Wei ◽  
Simon Durrant ◽  
Anjali S. Advani ◽  
Mark S Hertzberg ◽  
...  

Abstract Background: EphA3 is a novel drug target involved in cell positioning in fetal development. In adults it is an oncofetal antigen, that is re-expressed in hematologic malignancies (blood and bone marrow, leukemic stem cells) and solid tumors. It is also upregulated in diseases characterized by abnormal proliferation and fibrosis, such as idiopathic pulmonary fibrosis and diabetic kidney disease. KB004 is a Humaneered® high affinity antibody (KD = 610 pM) targeting EphA3 with at least 3 possible mechanisms of action: direct apoptosis in tumor cells, activation of ADCC and disruption of tumor vasculature. Objectives: The primary objectives of the Phase I study component are to determine safety and MTD for KB004 in patients with hematologic malignancies, refractory to or unfit for chemotherapy. Secondary objectives are to characterize PK, immunogenicity, and preliminary clinical activity of KB004. Exploratory objectives include evaluation of EphA3 expression on tumor, stromal, and endothelial cells. Methods: Multicenter Phase I/II study. Key eligibility criteria: unsuitable for standard of care or relapsed or refractory hematologic malignancy, ECOG PS 0-1, adequate organ function, platelets ≥ 10,000/uL (untransfused for 7 days) and normal coagulation times. KB004 was administered as a 1-2 hr intravenous infusion on days 1, 8, and 15 of each 21-day cycle, at incremental doses of 20, 40, 70, 100, 140, 190, 250 and 330 mg. At 70 mg and above infusion reaction prophylaxis included H1 and H2 blockers, acetaminophen and IV steroids. Safety and activity by IWG response criteria were assessed. Peripheral blood and bone marrow biopsies for PK analysis and EphA3 expression were also collected. Results: A total of 50 patients (AML 39, MDS 7, DLBCL 1, MF 3) received KB004 in the phase I/dose finding component of the study, which has been completed. The most common toxicities were transient grade 1 and grade 2 transient infusion reactions (IRs) in 79% of patients. IRs were characterized by chills, elevated temperature, fever, rigors, back pain, nausea, vomiting, hypotension, hypertension and transient hypoxia (in 2 cases). No other significant KB004 related toxicity was observed. Two patients discontinued KB004 due to an IR. One of these (grade 3) defined a DLT at the 330mg dose level. A second patient at 330mg had grade 2 infusion reactions associated with multiple infusion delays. These observations prompted expansion of the next lowest dose cohort, 250mg. Six evaluable patients were treated at this dose level. No clinically significant IRs or DLTs were observed. This is therefore the recommended phase 2 dose (RP2D). At all dose levels observed Cmax for KB004 was approximately dose proportional. Sustained exposure above the predicted effective concentration (1ug/mL) to cover the 7-day interval between doses was achieved above 190mg. Responses according to IWG criteria were observed in patients with AML, MF and MDS at the 20 mg, 140g and 250mg dose levels, respectively. At 20mg, a 78 yr-old patient with relapsed AML achieved CRp. Remission was sustained for over 18 months and relapse was preceded by a rise in EphA3 expression. Serial bone marrow biopsies with KB004 treatment show decreased reticulin and collagen fibrosis. At 140mg, a 67 yr old patient with JAK2 V617F mutant previously untreated myelofibrosis whose predominant clinical problem at diagnosis was anemia achieved Clinical Improvement [CI]. Transfusion independency (both RBC and platelets) has been sustained for 8+ months with improvement in constitutional symptoms and improved splenomegaly. At 250 mg an 84 yr-old patient with MDS/MPN (intermediate risk) achieved a Hematologic Improvement [HI, erythroid]. A > 50% reduction in marrow blast percentage was seen in 8 patients. Bone marrow biopsies positive for EphA3 expression with a cut-off of 10% of nucleated cells were obtained in greater than 70% of AML patients. Of 20 patients for whom EphA3 expression data exists with time, 7 (35%) had at least a 50% reduction in expression with treatment. Conclusion: KB004 is a novel agent targeted against EphA3 that is well tolerated when given as a weekly 2 hour infusion. The promising clinical activity profile is postulated to be consistent with the antifibrotic mechanism. The Phase II component of the study is ongoing in which the activity of KB004 will be characterized in disease specific cohorts including AML, MDS and MF at the RP2D of 250mg. Disclosures Durrant: KaloBios: Research Funding. Advani:KaloBios: Research Funding. Greenberg:Celgene: Research Funding; Novartis: Research Funding; GSK: Research Funding; Onconova: Research Funding; KaloBios: Research Funding. Cortes:KaloBios: Research Funding. Yarranton:KaloBios: Employment; Glaxo: Equity Ownership; EnGen: Equity Ownership, Science Advisor, Science Advisor Other; Stemline Therapeutics: Equity Ownership. Walling:KaloBios, Corcept Therapeutics, Prothena, NewGen Therapeutics, Valent Technologies, LBC Pharmaceuticals: Consultancy, Equity Ownership; Amgen, BioMarin: Equity Ownership; Crown BioScience: Membership on an entity's Board of Directors or advisory committees.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2925-2925 ◽  
Author(s):  
Nobuko Hijiya ◽  
Paul S. Gaynon ◽  
Manuel Fernandez ◽  
Lewis B. Silverman ◽  
Blythe Thomson ◽  
...  

Abstract We have previously reported encouraging overall complete remission (CR) rates and an acceptable safety profile using the combination of clofarabine, cyclophosphamide and etoposide in relapsed or refractory childhood acute leukemia. Here, we report follow-up results of the phase I portion of the study and provide an update on phase II which is currently enrolling patients. Patients between 1 and 21 years of age with refractory or relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) (Phase I portion only) were enrolled. A standard 3+3 design was followed to determine the maximally tolerated dose combination in phase I. Five dosing cohorts evaluated escalating doses of clofarabine 20–40 mg/m2/day, etoposide 75–100 mg/m2/day and cyclophosphamide 340–440 mg/m2/day. All 3 study drugs were administered via IV infusion daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients received up to 2 induction cycles, followed by consolidation (up to a maximum of 8 cycles in total). Dose-limiting toxicities in the phase I portion have been previously reported. The recommended phase II doses were clofarabine 40 mg/m2/day, cyclophosphamide 440 mg/m2/day, and etoposide 100 mg/m2/day. The phase II portion of the study is a single-arm open-label study with a planned total enrollment of 33 patients. Twenty-five patients (ALL: 20 patients; AML: 5 patients) were enrolled in the 5 phase I dose cohorts. The median number of prior induction regimens was 2, 7 patients (5 ALL, 2 AML) were refractory to their immediately preceding regimen, and 4 patients (1 ALL, 3 AML) had a prior hematopoietic stem cell transplant (HSCT). Based on investigator’s assessment, data showed complete remission (CR) in 10 patients (9 ALL, 1 AML) and complete remission without platelet recovery (CRp) in 6 patients (2 ALL, 4 AML) for an overall response rate of 64% (ALL: 55%; AML: 100%). Of the 16 responders (CR + CRp), 9 patients proceeded to HSCT after treatment. The median duration of remission (censored at the last known date of follow-up regardless of alternative therapy) for the 16 responders was 18.2 weeks (range 6.6 to 61.4 weeks) (ALL: median 31.4 weeks, range 6.6 to 61.4 weeks; AML: median 15.6 weeks, range 7.3 to 48.9+ weeks), including 31.4 weeks for the 10 patients with CR and 15.3 weeks for the 6 patients with CRp. At the last known date of follow-up, 7 of the 16 responders were alive and 4 of these remained in CR (three of these had undergone post-therapy HSCT). One patient with ALL completed 8 cycles of therapy, with a duration of remission of 61.4 weeks. In phase II, 3 of the first 8 ALL patients enrolled achieved a response (1 CR, 2 CRp). However, 4 patients developed severe hepatotoxicity (3 veno-occlusive disease, 1 hyperbilirubinemia). The study was amended to exclude patients with prior HSCT, viral hepatitis and/or cirrhosis, or elevated conjugated bilirubin levels. Four additional patients have since been enrolled in the amended phase II portion of the study and no cases of severe hepatotoxicity have been observed to date. In summary, the combination of clofarabine, cyclophosphamide and etoposide induced durable remission in children with relapsed or refractory acute leukemia. The recommended phase II doses of clofarabine, cyclophosphamide, and etoposide were 40 mg/m2/day, 440 mg/m2/day, and 100 mg/m2/day, respectively, each given for 5 days in induction. The phase II portion of the study is now actively enrolling patients with ALL without a history of prior HSCT following development of hepatoxicity in 4 patients. An update of all patients enrolled in phase II will be presented at the meeting.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3588-3588
Author(s):  
Beata Holkova ◽  
Prithviraj Bose ◽  
Mary Beth Tombes ◽  
Ellen Shrader ◽  
Wen Wan ◽  
...  

Abstract Abstract 3588 Although reports of synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in acute leukemias have been limited, they are well described in B-cell malignancies (e.g., myeloma and lymphoma). Nevertheless, preclinical findings have shown striking synergism between the HDAC inhibitor belinostat (previously PXD-101) and the proteasome inhibitor bortezomib, administered at low (sub-micromolar) concentrations, in cultured and primary acute myeloid leukemia (AML) and acute lymphocytic leukemia cells (Dai Y et al. Br J Haematol. 2011). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC). To date, 25 patients with the following disease types have been treated: acute leukemia (n=19), MDS (n=4), and CML-BC (n=2). The male:female ratio was n=11 (44%):14 (56%); the median age was 62 (range 27–83) years; ECOG performance scores ranged from 0–2; and the median number of prior therapies was 2 (range 1–5). The schedule of administration was belinostat, 30 minutes intravenous (IV) infusion, on days 1–5 and 8–12; and bortezomib, IV bolus, preceding belinostat on days 1, 4, 8, 11; on a 21-day cycle. Dose levels were, in mg/m2(bortezomib/belinostat): 1.0/500 (n=6); 1.3/500 (n=6); 1.3/650 (n=4); 1.3/850 (n=3); 1.3/1000 (n=4); 1.3/1200 (n=2). The study is currently enrolling to dose level 6 (1.3/1200). No dose-limiting toxicities (DLTs) have been observed to date. Non-DLT ≥ grade 2 (CTCAE version 4) treatment-related adverse events have included: fatigue (grade 2, 36%), leukopenia (grade 4, 12%), nausea (grade 2, 12%), peripheral sensory neuropathy (grade 2, 12%), and thrombocytopenia (grade 3, 20%). No serious adverse events have occurred at an unexpected frequency or severity. Two deaths have occurred due to disease progression, and one death has occurred due to a cerebrovascular accident that was related to pre-existing comorbidities and not to study-therapy. Of the 25 patients treated, 22 have been evaluable for response, 2 are too early to evaluate, and 1 patient was not evaluable for response. There have been 2 partial responses (PRs) and 1 complete response (CR) in this heavily pretreated population. The CR was achieved at dose level 1 in a patient with biphenotypic acute leukemia refractory to 7+3 and Flag-IDA. The patient proceeded to allogeneic hematopoietic stem cell transplantation (SCT) after 4 cycles of treatment. In addition, 1 patient with CML-BC had stable disease (SD) by protocol criteria but a CR with incomplete blood count recovery (CRi) by standard criteria, and is undergoing evaluation for allogeneic hematopoietic SCT. The patient is currently in cycle 8 at dose level 4. One of the PRs was achieved in a patient with AML transformed from MDS (2 prior regimens); after 4 cycles of treatment at dose level 5, the patient proceeded to allogeneic hematopoietic SCT. The second PR was achieved in an AML patient after cycle 2; a bone marrow biopsy revealed chronic myelomonocytic leukemia, and the response was deemed sufficient to proceed to allogeneic hematopoietic SCT. Also of note, a patient with AML transformed from MDS is currently on treatment in cycle 5 at dose level 5 with SD. An additional 6 patients have had SD, and 11 patients have had progressive disease. Correlative studies examining pre- and post-treatment leukemic blast expression of nuclear RelA, Bim, Bcl-xL, and XIAP are ongoing. Collectively, these findings indicate that a regimen combining belinostat and bortezomib is well tolerated in patients with relapsed or refractory acute leukemia, MDS, or CML-BC and shows evidence of activity. The MTD has not yet been reached. Pending identification of the MTD, phase II evaluation of this therapeutic strategy, should determine its activity more definitively. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 263-263 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hagop Kantarjian ◽  
Blanca Sanchez-Gonzalez ◽  
Stefan Faderl ◽  
Srdan Verstovsek ◽  
...  

Abstract DAC is a potent hypomethylating agent with clinical activity in patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). VPA is a histone deacetylase inhibitor used as an antiepileptic agent. In vitro, the combination of DAC with VPA results in synergistic antileukemia activity at doses of VPA above 1mM. Based on this data, we have developed a phase I/II study of this combination for pts with leukemia. The phase I of the study followed a classic 3+3 design. The dose of DAC was fixed: 15 mg/m2 iv daily for 10 days. This was based on a previous phase I study (Blood2004;103:1635) that indicated that this schedule had an optimal toxicity-response profile in this population. Three dose levels of VPA were selected: 20, 35 and 50 mg/kg. VPA was given orally for 10 days concomitantly with DAC. 22 pts have completed the phase I portion of the study (median age 56 years, range 4–78, 20 pts AML, 2 MDS). At dose level 1 (20 mg/kg of VPA) no grade III-IV toxicity was observed. At dose level 2 (VPA 35 mg/kg), 2 out 6 pts developed grade III neurotoxicity. Both pts were receiving high doses of other neurotropic agents. After IRB approval, 3 mores pts were treated at this dose level with no significant toxicity. Subsequently, 3 pts were treated at the highest planned dose level (50 mg/kg) with no toxicity observed. This cohort was then expanded to a total of 10 pts. One pt developed grade III neurotoxicity. No other severe drug-related toxicities were observed, but 5 patients at all dose levels developed grade II sedation/somnolence. Pancytopenia was induced in all pts. At dose level 1, one pt with refractory AML achieved complete remission (CR) after the second course of therapy. This is now maintained for 5 courses. At dose level 2, a patient with HIV disease and relapsed AML achieved CR after the third course of therapy, and 2 pts with relapsed AML achieved complete marrow responses (marrow blasts less then 5%, no recovery of peripheral counts). Of 3 pts evaluable for response at dose level 3, 1 pt with MDS has achieved CR after 1 course, and 1 with relapsed AML a complete marrow response. Median free VPA levels pretreatment were 0, and 25 mg/L on both days 5 and 10 and returned to 0 prior to next course. Histone acetylation measured by Western blot was observed in 3 pts (25%), all at doses above 20 mg/kg of VPA. Reactivation of p21 expression was induced in 4 out 11 pts analyzed. Global hypomethylation measured using a bisulfite PCR LINE assay was induced in 1 out 3 pts so far studied. Based on the toxicity observed, the phase II portion of the study was initiated. This is restricted to pts with AML/MDS. Seven pts have been accrued to this phase, and 8 out the 10 pts at dose level 3 of the phase I are also evaluable. The response data of this pts will be updated at the meeting. In summary, the combination of low dose DAC and VPA up to doses of 50 mg/kg can be safely administered to pts with leukemia although it may be complicated by neurotoxicity. Clinical and biological activity was observed at all dose levels.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2598-2598
Author(s):  
Beata Holkova ◽  
Mary Beth Tombes ◽  
Ellen Shrader ◽  
Sheryl S. Cooke ◽  
Wen Wan ◽  
...  

Abstract Abstract 2598 Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors, particularly in B-cell malignancies (e.g., myeloma and lymphoma). However, investigation of this strategy in acute leukemias has been limited. Very recent preclinical findings have shown marked synergism between the HDAC inhibitor belinostat and the proteasome inhibitor bortezomib administered at very low (sub-micromolar) concentrations, in various cultured and primary acute myelogenous leukemia and acute lymphocytic leukemia specimens (Dai Y et al. Br J Haematol. 2011). These interactions were associated with multiple perturbations in survival signaling proteins, including inactivation of NF-kappa B, down-regulation of Bcl-xL and XIAP, and up-regulation of the pro-apoptotic protein Bim. These findings prompted initiation of a phase I trial with the primary objective of determining the recommended phase II doses (RPTDs) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC). To date, 13 patients have been enrolled. Patients with the following disease types have been treated: acute leukemia (n=9), MDS (n=3), and CML-BC (n=1). Patient characteristics include male/female ratio n = 6 (46%)/7 (54%), with a median age of 59 years [range 27–75]. ECOG performance score 0–2. The median number of prior therapies was 2 [range 2–5]. The schedule of administration was belinostat 30 minutes intravenous (IV) infusion on days 1–5 and 8–12; and bortezomib IV bolus preceding belinostat on days 1, 4, 8, 11; on a 21 day cycle. Dose level enrollment was: Level 1 = bortezomib 1.0 mg/m2, belinostat 500 mg/m2 (n=6); Level 2 = bortezomib 1.3 mg/m2, belinostat 500 mg/m2 (n=6); and Level 3 = bortezomib 1.3 mg/m2, belinostat 650 mg/m2 (n=1). The study is currently enrolling to dose level 3. No dose-limiting toxicities (DLTs) have been observed to date. Non-DLTs (CTCAE v4) include: leukopenia (grade 4, 23%), thrombocytopenia (grade 3, 15%), and peripheral sensory neuropathy (grade 2, 23%). No serious adverse events have occurred at unexpected frequency or severity. Two deaths have occurred due to disease progression. Of the 13 patients treated, 12 have been evaluable for response. There has been 1 complete response in this heavily pretreated population. This response was achieved in a patient with biphenotypic acute leukemia, refractory to 7+3 and Flag-Ida. The patient proceeded to allogeneic hematopoietic stem cell transplantation. Four patients had stable disease, and 7 patients had progressive disease. Correlative studies examining leukemic blast expression of nuclear RelA, Bim, Bcl-xL, and XIAP pre- and post-treatment are ongoing. Collectively, these findings indicate that a regimen combining belinostat and bortezomib is well tolerated in patients with relapsed or refractory acute leukemia, MDS, or CML-BC. The maximum tolerated dose (MTD) has not been reached. Pending identification of the RPTDs, phase II evaluation of this therapeutic strategy, if warranted, should define its activity more definitively. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 959-959
Author(s):  
James L. Rubenstein ◽  
Lingjing Chen ◽  
Ranjana Advani ◽  
Jan Drappatz ◽  
Elizabeth Gerstner ◽  
...  

Abstract Abstract 959 Background: We recently studied the safety and activity of intraventricular rituximab monotherapy in the treatment of recurrent intraocular and CNS non-Hodgkin lymphoma (NHL) (JCO 2007 25: 1350–1356). Rapid dissemination throughout the craniospinal axis was demonstrated and cytologic responses were detected in six out of ten patients. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. The major goals of this current trial are to perform the first study of intraventricular immuno-chemotherapy in humans and to evaluate the safety of two dose levels of intraventricular rituximab as well as its pharmacokinetics in combination with intraventricular methotrexate (MTX). Secondary goals are to obtain information regarding the efficacy of this approach in the treatment of patients with recurrent CNS lymphoma, (brain parenchyma, intraocular or the leptomeningeal compartment). Methods: Thirteen patients with recurrent/refractory CD20+ CNS NHL were treated at UCSF, Dana Farber Cancer Institute and Massachusetts General Hospital on a phase I clinical trial involving twice weekly intraventricular rituximab at 10 mg and 25 mg dose levels, administered over a planned four week schedule. Rituximab is combined with MTX (12 mg) during the second intraventricular injection each week. Patients achieving partial response or better were eligible for a second month of combination intraventricular rituximab plus MTX. Results: No serious treatment-related toxicity has been detected with intraventricular rituximab/MTX at the 10 mg and 25 mg dose levels. The most common treatment-related toxicity was paresthesias (grade 1). One patient exhibited NHL progression outside of the CNS at three weeks and thus was not evaluable for CNS response, and one patient exhibited stable disease. Complete cytologic responses were detected in ten out of thirteen patients at the one-month restaging. Parenchymal responses were detected in three out of six subjects with one partial response within the corpus callosum, and two complete regressions of lesions within temporal lobe and cerebral cortex. One patient with leptomeningeal lymphoma non-responsive to intravenous rituximab and refractory to high-dose intravenous and intrathecal methotrexate, oral temozolomide and intrathecal liposomal cytarabine, obtained a sustained complete response with the intraventricular rituximab/MTX protocol and subsequently was approved for consolidative autologous stem cell transplant. Two patients have participated in extended dosing on protocol without progression for five and eight months respectively. Thus far, there is no evidence for a relationship between FcGR3A polymorphism and therapeutic resistance in a preliminary analysis (n=8 patients). The maximum tolerated dose of intraventricular rituximab with this combination was established as 25 mg. The mean maximum intraventricular rituximab concentration after intraventricular injection of rituximab was 285 microgram/ml at the 10 mg dose level (N=3) and 882 microgram/ml at the 25 mg dose level (N=10); (p<0.038). The rate of Rituximab clearance from the intraventricular compartment at two hours post injection was 30% slower when administered in combination with methotrexate compared to intraventricular rituximab monotherapy (p <0.02). Conclusions: Intraventricular rituximab/MTX appears to be safe in recurrent CNS NHL. Twelve of thirteen patients completed at least one month of therapy, without any treatment-associated serious adverse events at any of the institutions. Intraventricular administration of methotrexate may significantly attenuate rituximab clearance from the leptomeningeal compartment. There is encouraging evidence for significant activity of intraventricular immuno-chemotherapy in the treatment of drug-resistant CNS NHL, refractory or non-responsive to intravenous rituximab. These results provide strong support for further investigation of this novel therapeutic approach. NCT00221325. Supported by Leukemia and Lymphoma Society and NIH Grant CA13908301. Disclosures: Off Label Use: We will discuss the off-label use of rituximab within the leptomeningeal compartment to treat recurrent/refractory CNS lymphomas. Advani:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding.


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