Phase I Trial of Belinostat and Bortezomib in Patients with Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia in Blast Crisis - One Year Update

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3588-3588
Author(s):  
Beata Holkova ◽  
Prithviraj Bose ◽  
Mary Beth Tombes ◽  
Ellen Shrader ◽  
Wen Wan ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Chronic Myelogenous Leukemia ◽  
Dose Level ◽  
Phase I Trial ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Acute Leukemias

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.

Phase I Trial of Belinostat and Bortezomib in Patients with Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia in Blast Crisis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2598-2598
Author(s):  
Beata Holkova ◽  
Mary Beth Tombes ◽  
Ellen Shrader ◽  
Sheryl S. Cooke ◽  
Wen Wan ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Chronic Myelogenous Leukemia ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Level 3

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.

scholarly journals Phase I trial of SAR103168, a novel multi-kinase inhibitor, in patients with refractory/relapsed acute leukemia or high-risk myelodysplastic syndrome

2014 ◽  
Vol 56 (2) ◽  
pp. 395-400 ◽  
Author(s):  
Gail J. Roboz ◽  
H. Jean Khoury ◽  
Elias Jabbour ◽  
Wilena Session ◽  
Ellen K. Ritchie ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Phase I Trial ◽  
Kinase Inhibitor

scholarly journals Characterization of Thy-1 (CDw90) expression in CD34+ acute leukemia

Blood ◽  
1995 ◽  
Vol 86 (1) ◽  
pp. 60-65 ◽  
Author(s):  
JT Holden ◽  
RB Geller ◽  
DC Farhi ◽  
HK Holland ◽  
LL Stempora ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Acute Leukemias ◽  
Hematopoietic Stem

Thy-1 (CDw90) is a phosphatidylinositol-anchored cell surface molecule which, when coexpressed with CD34 in normal human bone marrow, identifies a population of immature cells that includes putative hematopoietic stem cells. To date, the characterization of Thy-1 expression has been confined largely to normal tissues and cell lines. In this study, we evaluated the frequency and intensity of Thy-1 expression as defined by reactivity with the anti-Thy-1 antibody 5E10 in 38 cases of CD34+ acute leukemia (21 acute myelogenous leukemia [AML], 8 chronic myelogenous leukemia [CML] in blast crisis, and 9 acute lymphoblastic leukemia [ALL]). In 34 of 38 cases (89%) the CD34+ cells lacked expression of the Thy-1 antigen. High-density Thy-1 expression was found in 1 case of CML in lymphoid blast crisis, and low- density Thy-1 expression was identified on a portion of the leukemic cells in 2 cases of AML with myelodysplastic features, and 1 case of CML in myeloid blast crisis, suggesting a possible correlation between Thy-1 expression and certain instances of stem cell disorders such as CML and AML with dysplastic features. In contrast, the dissociation of Thy-1 and CD34 expression in the majority of acute leukemias studied suggests that the development of these leukemias occurs at a later stage than the hematopoietic stem cell. Characterization of Thy-1 expression in acute leukemia may eventually provide insights into the origin of the disease. In addition, separation of leukemic blasts from normal stem cells based on Thy-1 expression may prove useful in assessing residual disease, as well as in excluding leukemic blasts from stem cell preparations destined for autologous bone marrow or peripheral stem cell transplantation.

Phase I Study of Vorinostat in Combination with Decitabine in Patients with Relapsed or Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3651-3651 ◽  
Author(s):  
Mark Kirschbaum ◽  
Ivana Gojo ◽  
Stuart L Goldberg ◽  
Lisa Kujawski ◽  
Ehab Atallah ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Dose Level ◽  
Preliminary Data ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Best Response ◽  
Acute Myelogenous ◽  
Dose Levels ◽  
Refractory Aml

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)

Final Results of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2894-2894 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian W. Flinn ◽  
Rolondo Enoch ◽  
Paul A. Foster ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
B Cell Malignancies ◽  
Dose Levels

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

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 ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Phase I ◽  
Dose Level ◽  
Hematologic Malignancies ◽  
The United States ◽  
Myelogenous Leukemia ◽  
Cell Transplant ◽  
Oral Clearance ◽  
Initial Report ◽  
Dose Levels

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.

Updated Results of a Phase I Study of Flavopiridol in Acute Leukemias Using a Novel, Pharmacokinetically Derived Schedule: Clinical Activity Including Hyperacute Tumor Lysis Syndrome (TLS), Pharmacokinetics (PK), and Pharmacodynamics (PD).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4578-4578
Author(s):  
William Blum ◽  
Rebecca B. Klisovic ◽  
Cheryl Kefauver ◽  
Amy Johnson ◽  
Mitch Phelps ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Objective Response ◽  
Tumor Lysis Syndrome ◽  
Acute Leukemias ◽  
Tumor Lysis

Abstract Flavopiridol is a cyclin-dependent kinase inhibitor that induces apoptosis in acute leukemia cell lines. In earlier studies with flavopiridol in several malignancies, plasma concentrations of flavopiridol were not reached or maintained at sufficient levels to induce apoptosis due to unexpectedly high levels of bound drug in human serum relative to fetal calf serum used in preclinical studies. PK modeling in chronic lymphocytic leukemia (CLL) cells cultured in human plasma in vitro indicated that administering flavopiridol by 30 minute intravenous (IV) bolus followed by 4 hour continuous IV infusion (CIVI) would achieve sustained in vivo plasma drug concentration and time exposure similar to that necessary to induce apoptosis. We designed a phase I dose escalation trial in acute leukemias of single agent flavopiridol given as a 30 minute bolus followed by a 4 hour CIVI on days 1–3 with the ability to repeat cycles every 21 days; 16 patients (pts) have been enrolled to date. Dose escalation was as follows (bolus dose/4 hr CIVI dose in mg/m2): 20/30 (n=3), 30/35 (n=7), 30/50 (n=3), and 40/60 (n=3). Based on prior experience with flavopiridol at our institution in CLL, aggressive measures for the prevention and management of hyperacute tumor lysis syndrome (TLS) were employed. Pts had relapsed/refractory AML (N=12) and ALL (N=4), and were 25–78 yrs old (median age 64 yrs). Average plasma levels were 1.0–2.5 μM at the first three dose levels during the infusion (N=13) and declined with terminal half-lives comparable to previously reported 72 hr and more recent 4.5 hr infusions. Clinically significant TLS occurred in 2/16 pts with chemical evidence of lysis in 4 additional pts. A dose-limiting toxicity (renal failure) occurred at dose level 4 (40 mg/m2 bolus/60 mg/m2 CIVI), and the level is currently being expanded. Treatment was otherwise well tolerated. Downregulation of Mcl-1 protein by standard immunoblotting at 4 and/or 24 hrs was demonstrated in blood and/or bone marrow cells of 6/10 patients Anti-leukemic activity including transient reductions in WBCs/circulating blasts (n=7), bone marrow blasts (n=2), and platelet transfusion independence (n=1) was observed. Two received a second course of therapy, but no pt experienced an objective response by standard criteria. The current dose level exceeds that previously given in ongoing CLL studies; dose escalation to identify the maximum tolerated dose using this pharmacokinetically derived schedule in acute leukemia continues. Given the activity of this drug as a single agent, combination studies with conventional chemotherapy or other novel agents in acute leukemias should be considered.

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