Phase I/II Clinical Study of Tosedostat, an Inhibitor of Aminopeptidases, in Patients With Acute Myeloid Leukemia and Myelodysplasia

2010 ◽  
Vol 28 (28) ◽  
pp. 4333-4338 ◽  
Author(s):  
Bob Löwenberg ◽  
Gareth Morgan ◽  
Gert J. Ossenkoppele ◽  
Alan K. Burnett ◽  
Pierre Zachée ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Platelet Count ◽  
Phase I ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Antileukemic Activity ◽  
Once Daily ◽  
Acute Myeloid

Purpose To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor. Patients and Methods In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome. Results In phase I, 16 patients were treated in four cohorts with tosedostat (60 mg to 180 mg) for 28 days. Three patients reported dose-limiting toxicities: two with reversible thrombocytopenia (> 75% reduction in platelet count) at 180 mg (MTD) and one with a Common Toxicity Criteria (CTC) grade 3 ALT elevation at 130 mg (MAD). In phase II, 41 patients were treated with 130 mg tosedostat. In phases I and II, the most common severe (CTC grades 3 to 5) adverse event was a reduction in the platelet count. Of the 51 AML patients in this study, seven reached complete marrow response (< 5% marrow blasts), with three achieving complete remission, and a further seven patients reaching a partial marrow response (between 5% and 15% marrow blasts). The overall response rate was therefore 27%. All responders were age > 60 years, and 79% had either relapsed or refractory AML. Conclusion This phase I/II study demonstrates that oral once daily dosing with 130 mg tosedostat is well tolerated and has significant antileukemic activity. The favorable risk-benefit profile suggests that further clinical trials are warranted.

Early Results Of a Phase I/II Trial Of Midostaurin (PKC412) and 5-Azacytidine (5-AZA) For Patients (Pts) With Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3949-3949
Author(s):  
Paolo Strati ◽  
Hagop M Kantarjian ◽  
Aziz Nazha ◽  
Gautam Borthakur ◽  
Naval G. Daver ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) affect primarily elderly pts. Their treatment with aggressive chemotherapy is frequently challenging. Moreover, pts with FLT3 mutations have very poor prognosis. We hypothesized that the combination of midostaurin, a FLT3 inhibitor, and 5-AZA, a hypomethylating agent, may be an effective and safe regimen. Methods Both untreated (8) and previously treated (36) pts with AML or MDS were eligible for this study, regardless of FLT3 mutation and prior exposure to FLT3 inhibitors. Pts received 5-AZA 75 mg/mq subcutaneously or intravenously on day 1-7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter, for 12 cycles of 28 days duration. Cytogenetic risk was defined according to MRC criteria. Differences between categorical variables were compared by the chi2 test. CR duration (CRD) was calculated from the time of CR achievement until relapse and estimated by the Kaplan-Meier method and compared by the log-rank test. Results Fourty-four pts were enrolled, 13 included in Phase I and 31 in Phase II. Baseline pts’ characteristics are shown in the Table. Thirty-eight pts (86%) received 50 mg bid of midostaurin, and 6 (14%; Phase I) received 25 mg bid. The median number of administered cycles was 2 (1-9). Grade 3-4 hematological toxicities consisted of 95% neutropenia, 64% anemia and 93% thrombocytopenia. Grade 3-4 non-hematological toxicities consisted of 45% infections, 23% hypokalemia, 16% hyponatremia, 7% reduction in ejection fraction, 7% hyperuricemia, 4% hyperglycemia, 4% nausea/vomiting, 4% QTc prolongation, 4% hyperbilirubinemia, and 4% elevated AST. Eleven pts (25%) achieved a CR, 9 with incomplete platelet recovery (20%), after a median time of 13 (10-16) weeks from treatment start. Five (11%) of these pts relapsed after achieving CR. Two pts (5%) received an allogeneic stem cell transplant while on study, one in CR and one primary refractory (after a blast count drop from 27 to 7%), and they are both still in CR and alive. Among 26 pts with FLT3 ITD and no D835 mutation, 9 (35%) achieved CR/CRp. Six of 18 (33%) pts not previously exposed to FLT3 inhibitors responded. There was no significant correlation of dose with response (24% with 50 mg bid vs 33% with 25 mg bid, p=0.63). After a median follow-up of 15 (3-72) weeks, 20 pts (64%) died, 3 (7%) while on study (2 died of sepsis, 1 of unknown causes with progressive disease). The median CRD was 16 (9-23) months. Factors significantly associated with a longer CRD were male sex (p=0.04), age older than 65 years (0.03) and use of 50 mg bid of midostaurin (p=0.02). Conclusions The combination of midostaurin and 5-AZA is safe and well tolerated. Its efficacy is most noticeable among pts with FLT3 mutations. A longer response duration is observed using midostaurin at 50 mg bid dose and in elderly male pts. Disclosures: Ravandi: CELGENE: Honoraria; NOVARTIS: Honoraria. Cortes:ARIAD: Consultancy, Research Funding; ASTELLAS: Research Funding; AMBIT: Research Funding; AROG: Research Funding; NOVARTIS: Research Funding.

A Phase I Study of Idarubicin Dose Escalation for Remission Induction Therapy in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1344-1344
Author(s):  
Mark Lee ◽  
Sung-Yong Kim
Keyword(s):  
Acute Myeloid Leukemia ◽  
Platelet Count ◽  
Phase I ◽  
Dose Level ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Level 1 ◽  
Level 2 ◽  
Acute Myeloid

Abstract The maximum tolerated dose (MTD) of idarubicin has been acknowledged to be 12-15 mg/m2/day for 3 days for acute leukemias. Its MTD should be reevaluated in the treatment of acute myeloid leukemia (AML) in the era of granulocyte colony-stimulating factor and better supportive care. We conducted a phase I study to investigate the safety of escalating doses of idarubicin in combination with cytarabine 100 mg/m2/day for 7 days for previously untreated AML. The starting dose of idarubicin was 12 mg/m2/day for 3 days with dose escalations by 3 mg/m2/day. Cohorts of three patients were treated at each dose level, and the idarubicin dose was escalated up to 18 mg/m2/day until at least two patients among a cohort of three to six patients experienced the dose-limiting toxicities (DLTs) (traditional 3+3 design for phase I clinical trials: J Natl Cancer Inst 2009;101:708). Hematologic DLTs were defined as the time to recovery of neutrophils {absolute neutrophil count (ANC) ≥500/μL} or platelets (platelet count ≥20,000/μL) exceeded 42 days after the start of induction therapy (J Clin Oncol 2004;22:4290). Non-hematologic DLTs were defined as grade 4 or 5 toxicities (Leukemia 1998;12:865). We adopted the NCI CTCAE v3.0 to grade the hematologic and non-hematologic toxicities. Thirteen adult patients were enrolled in the study, but two and two were excluded at level 1 and level 2, respectively, because they received reinduction therapy for resistant disease within 4 weeks after the start of the assigned induction therapy. Consequently, nine patients were evaluable for the phase I study. The median times to recovery of neutrophils (ANC ≥500/μL) after the start of induction therapy at level 1, level 2, and level 3 were day 20 (range, 19-22), day 19 (range, 17-20), and day 25 (range, 21-26), respectively. The median times to recovery of platelet (platelet count ≥20,000/μL) at each level were day 20 (range, 19-23), day 20 (range, 16-34), and day 24 (range, 20-35), respectively. Therefore, grade 4 hematologic toxicities were observed at all 3 levels; however, these hematologic toxicities did not meet the criteria of the hematologic DLTs as defined in this study. There was any instance of grade 4 non-hematologic toxicity at each dose level. No death associated with the induction treatment was observed in this trial. Hematologic and non-hematologic DLTs as defined above were not observed at all 3 dose levels; therefore, idarubicin 18 mg/m2/day for 3 days could be defined as the MTD for this trial. Disclosures No relevant conflicts of interest to declare.

scholarly journals First-In-Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia

2011 ◽  
Vol 29 (8) ◽  
pp. 979-985 ◽  
Author(s):  
Eric J. Feldman ◽  
Jeffrey E. Lancet ◽  
Jonathan E. Kolitz ◽  
Ellen K. Ritchie ◽  
Gail J. Roboz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Hypertensive Crisis ◽  
Maximum Tolerated Dose ◽  
Molar Ratio ◽  
Phase Ii Trials ◽  
Platelet Recovery ◽  
Acute Myeloid

Purpose This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351. Patients and Methods CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m2 with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred. Results The maximum-tolerated dose was 101 units/m2. DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m2. Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours. Conclusion The recommended dose of CPX-351 for phase II study is 101 units/m2. Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.

Phase I Dose Escalating Trial of Bortezomib (Velcade®) in Combination with Idarubicin and Cytarabine in Patients with Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1799-1799 ◽  
Author(s):  
Eyal C. Attar ◽  
Daniel J. DeAngelo ◽  
Karen K. Ballen ◽  
Emily Learner ◽  
Elizabeth G. Trehu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Science Studies ◽  
Leukemia Cell ◽  
Maximum Tolerated Dose ◽  
Synergistic Cytotoxicity ◽  
Acute Myeloid

Abstract Conventional therapy for acute myeloid leukemia (AML) consists of a combination of cytarabine and an anthracycline such as idarubicin. Currently, most patients ultimately fail treatment due to leukemia cell resistance to drug therapy. In vitro experiments have shown that the addition of a proteasome inhibitor to an anthracycline results in synergistic cytotoxicity to leukemia cells. Hence, we initiated this phase I trial in patients to see if bortezomib could be safely added to conventional treatment. Patients over age 60 with AML or any patient 18 or older with relapsed disease after a remission of at least 3 months (not refractory) were eligible. All patients received idarubicin 12 mg/m2 on days 1–3 and cytarabine 100 mg/m2 by continuous infusion days 1–7. In addition, patients received bortezomib by IV bolus on days 1, 4, 8, and 11. Cohorts of 3 to 6 patients were entered using increasing doses of bortezomib in order to determine the maximum tolerated dose (MTD). The first cohort received 0.7 mg/m2 of bortezomib with each bolus. If dose limiting toxicity (DLT) was encountered, then cohort advancement was restricted. DLTs included prolonged myelosuppression, neuropathy, and other grade 3 or 4 toxicities. Dose escalation would proceed to 1.0 mg/m2 and then to 1.3 mg/m2 if tolerated. No escalation was planned beyond 1.3 mg/m2. To date 14 patients have been entered on this study. In the first cohort of 3 patients with bortezomib at 0.7 mg/m2, a DLT due to prolonged neutropenia was encountered, so an additional 3 patients were entered at this dose level. No DLTs were encountered among these additional patients, so 3 more patients were entered with bortezomib at 1.0 mg/m2. One of these patients experienced prolonged thrombocytopenia and thus 3 additional patients were enrolled at 1.0 mg/m2. No DLTs were encountered among these additional patients, and thus the next cohort of patients with bortezomib at 1.3 mg/m2 was opened. To date, two patients have been enrolled at this dose level. The plan is to enroll a third patient at this level and to assess for possible DLTs. Among the 12 patients evaluable for response, there have been 4 patients achieving complete remission, 3 patients achieving remission without complete recovery of platelet count (CRp defined as having met criteria for CR but with 25,000–99,000 platelets/μl), 2 patients achieving a partial remission (CR but with 5–24% bone marrow blasts), and 3 patients failing to respond. In conclusion, bortezomib at 0.7 mg/m2 and 1.0 mg/m2 in the day 1, 4, 8, and 11 schedule can be added to idarubicin and cytarabine with acceptable toxicity. This study continues in an attempt to determine whether bortezomib can be escalated safely to 1.3 mg/m2 in this combination. Additional patients will be enrolled at the candidate MTD to gain confidence in the safety and activity at this level. Correlative science studies are planned.

A Phase I Study of CHR-2797, an Orally Active Aminopeptidase Inhibitor in Elderly and/or Treatment Refractory Patients with Acute Myeloid Leukemia or Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 443-443 ◽  
Author(s):  
Faith Davies ◽  
Gert Ossenkoppele ◽  
Pierre Zachee ◽  
Richard Noppeney ◽  
Alan Burnett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Active Metabolite ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Once Daily ◽  
Grade Iii ◽  
Acute Myeloid

Abstract Background. CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, NOXA. CHR-79888 is an active metabolite of CHR-2797. Methods. This was an open label, single agent, dose escalating phase I salvage study to assess tolerance, MTD/DLT, activity, and pharmacokinetics of CHR-2797 in patients with hematological malignancies. Elderly patients and/or relapsed patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM) were eligible. Patients were treated with escalating once daily doses (60–180 mg) for up to 84 days or until progressive disease (PD). Clinical responses were assessed by monthly bone marrow aspirates in AML/MDS patients and by M-protein levels in MM patients. Results. Sixteen adults (4 women, 12 men) of median age 70 yrs, (range 45–84 yrs) were accrued between May 2006 and Jan 2007: 13 patients with AML, 1 with MDS, and 2 with MM. Thirteen patients finished the dose finding phase of 28 days and 6 patients continued for at least 84 days. CHR-2797 was well tolerated and, except for one patient with grade III ALT elevation, no grade III/IV drug related non-hematological toxicity was observed during the first 28 days of treatment. Two patients on 180 mg developed DLT that was considered drug related: >75 percent reduction in platelet count. CHR-2797 had no influence on hemoglobin or neutrophils in this trial. Overall the most frequently reported adverse events were thrombocytopenia (6.7%), diarrhea (4.5%), dizziness (3.9%), and fatigue (3.9%). Five AML patients died in the first 3 months of the trial or within 4 weeks of discontinuing CHR-2797: 3 due to disease progression and 2 following a MI (not related to drug). Bone marrow studies revealed complete responses (< 5% blasts in bone marrow) in 3/12 AML patients after 1–3 months of therapy (60 and 130mg), one of which was also a cytogenetic response. One of the 2 responding patients on 130 mg was evaluated as a CRp at 3 months; this patient was in remission for 3 months following platelet recovery after the drug was stopped. One further AML patient (60 mg) became completely transfusion independent and remained so for 6 weeks. Good exposure to CHR-2797, including levels of the active metabolite CHR-79888 has been observed on days 1 and 28 with a terminal half life (for 79888) of 8– 11 hours. Conclusions. Oral once daily CHR-2797 in AML/MDS/MM patients with adverse prognostic risk was well tolerated. MTD for maintenance therapy was reached at 180 mg. Single agent CHR-2797 therapy showed encouraging clinical activity (incl. 3/12 CRs) in these elderly and poor risk AML patients who were able to continue therapy for at least 28 days. Because of the favorable results a phase II study with CHR-2797 in advanced AML is currently in progress.

Phase I/II Study of Tipifarnib and Bortezomib in the Treatment of Poor Risk Adult Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2982-2982 ◽  
Author(s):  
Stefania Paolini ◽  
Emanuela Ottaviani ◽  
Barbara Lama ◽  
Federica Salmi ◽  
Cristina Clissa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Treatment Response ◽  
Stable Disease ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Maximum Tolerated Dose ◽  
Expression Ratio ◽  
Real Time Quantitative Pcr ◽  
Acute Myeloid

Abstract Background. Outcome of elderly acute myeloid leukemia (AML) patients is dismal. Tipifarnib (Zarnestra, Z) and Bortezomib (Velcade, V) are new, targeted-treatments that might improve current results. In particular, Z is a farnesyltransferase inhibitor effective in AML, allowing complete remission (CR) rates ranging from 8 to 22%. Notably, the response rate appeared superior among patients with higher RASGRP1/APTX gene expression ratio. V is a proteasome inhibitor, possibly effective in AML as for phase I studies. Interestingly, Z and V appeared synergistic in AML cell lines. Aim. We designed a phase I/II study aiming to assess the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of V in association with standard doses of Z and the efficacy and toxicity of the combination, in AML patients &gt;18 years, unfit for conventional therapy, or &gt;60 years, in relapse. Furthermore, we aimed to assess the correlation between RASGRP1/APTX ratio and treatment response. Methods. V was administered as weekly infusion for three consecutive weeks (days 1, 8, 15), starting from 0.7 mg/m2 and increasing by 0.3 mg/m2 until the DLT was reached. Z was administered at the daily dose of 600 mg BID for 21 consecutive days. Response was assessed at the end of each cycle (28 days). Patients’ withdrawn was planned in case of progression or stable disease after six cycles. Real-time quantitative PCR (q-PCR) was used for RASGRP1/APTX genes evaluation. Results. 45 patients were enrolled: 12 in the phase I and 33 in the phase II. 11/12 patients were evaluable in the phase I. Five patients received V at the dose of 0.7 mg/m2 without reporting DLT. Conversely, DLT was reached at the dose of 1.0 mg/m2 due to grade III SNC toxicity, recorded in 1/6 patients. 22/45 patients were evaluable for treatment response; transient reduction of peripheral blasts (&gt; 50% to baseline) was observed in 20/22 cases. 2 patients achieved CR and 1 obtained a partial response (PR). 1 patient had a haematological improvement (HI), 12/22 had a stable disease (SD) and 5/22 showed progressive disease (PD). Interestingly, the 4 responders (CR+PR+HI) had a significant higher RASGRP1/APTX ratio respect to non responder (p=0.017). Conclusion. We conclude that the MTD of V in association with Z is 1.0 mg/m2. The association seemed to be safe, with response rate (18%) similar to what reported for Z alone. Finally, though in few cases, RASGPR1/APTX ratio was confirmed to be associated to treatment response.

A Phase I/II Trial of Combination of Midostaurin (PKC412) and 5-Azacytidine (5-AZA) for the Treatment of Patients with Refractory or Relapsed (R/R) Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3587-3587 ◽  
Author(s):  
Aziz Nazha ◽  
Hagop M. Kantarjian ◽  
Gautam Borthakur ◽  
Guillermo Garcia-Manero ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Response Rate ◽  
Allelic Ratio ◽  
Bone Marrow Blasts ◽  
Acute Myeloid

Abstract Abstract 3587 Background: Midostaurin (PKC412) is a potent orally bioavailable FLT3 inhibitor with activity in acute myeloid leukemia (AML). 5-azacytidine (5-AZA) is a hypomethylating agent that plays an important role in the treatment of AML and MDS. We hypothesized that adding midostaurin to 5-AZA may improve the response rate with limited toxicity profile. Materials and Methods: Patients ≥18 years with MDS, chronic myelomonocytic leukemia (CMML) or AML, who failed prior therapies with performance status ≤ 2, adequate liver (bilirubin ≤ 2 × ULN, ALT ≤ 2.5× ULN) and renal (creatinine ≤2× ULN) functions were eligible. Patients were included in phase I regardless of FLT3 mutation status; only FLT3 mutated patients were included in phase II. Patients received 5-AZA 75 mg/m2 subcutaneously or intravenously for 7 days of each cycle (Days 1–7) and midostaurin at 25 mg (cohort 1) and 50 mg (cohort 2; target dose) orally twice daily for 14 days (Days 8–21) per cycle. Patients were planned to receive up to 12 cycles if benefit from treatment. Supportive care was standard. The study was approved by institutional IRB and conducted in accordance of the declaration of Helsinki. Results: 20 patients have been enrolled: 13 included in phase I (6 in cohort 1 and 7 in cohort 2) and 6 patients in phase II. One patient in cohort 1 was inevaluable for DLT (withdrawal before completing cycle #1). One patient in cohort 2 received midostaurin dose as per cohort 1 dose by patient error. Patients' characteristics and responses are summarized in table 1. Overall response rate (ORR) in phase I was 3/13 (21%) (2 CRi and 1 patient decreased BM blasts from 27% to 7% after 2 cycles and went to transplant). ORR in phase II was 2/6 (33%) (1 patient with AML achieved CRi, 1 patient with CMML {received prior sorafenib} achieved CR). In addition, 1 AML patient had bone marrow blasts improved form 77% to 10% after 1 cycle, completed 3 cycles of therapy and then refused further treatment, and 1 AML patient had bone marrow blasts improve from 34% to 7 % and was continued on treatment). A total of nine patients with FLT3-ITD mutations enrolled in the trial: four patients in phase I with a median allelic ratio of 0.44 (range, 0.219–0.726); 1/4 (25%) achieved CRi, 2 of the non-responders had received prior FLT3 inhibitors (1 had developed FLT3-D835). Five patients in phase II had FLT3-ITD (median allelic ratio 0.06, range 0.014–0.279; one with concomitant D835 mutation) and one patient had FLT3-D835 mutation only (allelic ratio 0.238). 4/6 patients in phase II had failed prior FLT 3 inhibitors. In total, the ORR among patients with FLT3-ITD mutations was 3/9 (33%). All toxicities were grade 1 and 2 with no difference between the 2 dose schedules of midostaurin. No DLT or deaths were identified. Conclusion: The combination of midostaurin/5-AZA is safe and well tolerated at the intended doses (midostaurin 50 mg PO twice daily). Good ORR in high risk patients with relapsed or primary refractory FLT3-ITD positive AML was observed. Schedule is being amended to allow uninterrupted midostaurin administration. Phase II study continues to enroll patients with FLT3 mutations and updated results will be presented at the meeting. Disclosures: Off Label Use: 5-azacytidine in AML. Cortes:Novartis: Consultancy, Research Funding; Celgene: Research Funding; Ambit: Research Funding.

Ponatinib in patients with acute myeloid leukemia (AML): Preliminary findings from a phase I study in hematologic malignancies.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 6518-6518 ◽  
Author(s):  
M. Talpaz ◽  
N. P. Shah ◽  
M. W. Deininger ◽  
M. J. Mauro ◽  
I. W. Flinn ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Hematologic Malignancies ◽  
Acute Myeloid

scholarly journals First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia

2020 ◽  
Vol 38 (36) ◽  
pp. 4260-4273
Author(s):  
Olga Salamero ◽  
Pau Montesinos ◽  
Christophe Willekens ◽  
José Antonio Pérez-Simón ◽  
Arnaud Pigneux ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Antileukemic Activity ◽  
Open Label ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

PURPOSE Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML). METHODS This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor. RESULTS Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm. CONCLUSION Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).

A phase I/II trial of combination of PKC412 and 5-azacytidine (AZA) for the treatment of patients with refractory or relapsed (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6589-6589
Author(s):  
Aziz Nazha ◽  
Hagop Kantarjian ◽  
Gautam Borthakur ◽  
Tapan M. Kadia ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Clinical Activity ◽  
Flt3 Inhibitors ◽  
To Receive ◽  
Acute Myeloid

6589 Background: Midostaurin (PKC412) is a FLT3 kinase inhibitor with activity in acute myeloid leukemia (AML). Hypomethylating agents play an important role in the treatment of AML and MDS. We investigated the safety (phase I) and clinical activity (phase II) of combination of 5-azacytidine (AZA) and PKC412 in pts with R/R AML and MDS. Method: Pts ≥18 years with MDS, CMML or AML, who failed prior therapies with performance status <2, adequate liver (bilirubin < 2x ULN, ALT ≤ 2.5x ULN) and renal (creatinine < 2x ULN) functions were eligible. Pts received AZA 75 mg/m2 subcutaneously or intravenously for 7 days of each cycle (Days 1-7) and PKC412 at 25 mg (cohort 1) and 50 mg (cohort 2; target dose) orally twice daily for 14 days (Days 8-21). Pts were to receive up to 12 cycles if benefit from treatment. Supportive care was standard. Results: 14 pts were included in phase I. 1 pt was inevaluable for DLT (withdrawal before completing cycle#1). 6 pts treated in cohort 1 and 7 in cohort 2. 1 pt in cohort 2 received PKC412 dose as per cohort 1 dose by pt error. Pt characteristics and responses are summarized in the Table. The overall response rate (ORR) was 3/13(21%) (2 with CRi, 1 pt dropped BM blasts form 27% to 7% after 2 cycles and went to transplant. 1/4 with FLT3-ITD achieved CRi, 2 of the non-responders received prior FLT3 inhibitors (1 had developed FLT3 D835). All toxicities were grade 1 (nausea 1 pt, vomiting 1 pt, dry skin 1 pt, and rash 1 pt) with no difference between the 2 groups. No DLT was identified. Conclusions: PKC412+AZA is safe and well tolerated at the intended doses with good ORR in high risk pts with R/R AML. Phase II study is enrolling pts with FLT3-ITD. Updated result will be presented. [Table: see text]

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