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.

Update of a Phase I Study of Sorafenib in Patients with Refractory/Relapsed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 893-893 ◽  
Author(s):  
John Delmonte ◽  
Hagop M. Kantarjian ◽  
Michael Andreeff ◽  
Stefan Faderl ◽  
John J. Wright ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Maximal Response ◽  
Daily Dose ◽  
Grade 3 ◽  
Acute Myeloid

The critical importance of the Ras, VEGF, and FLT3 pathways in the pathogenesis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) has been well established. FLT3 abnormalities, internal tandem duplication (ITD) and point mutations, occur in about 30% of pts with AML and the FLT3-ITD mutation independently confers poor prognosis. Sorafenib is an oral multikinase inhibitor targeting the above pathways and is highly potent against FLT3-ITD mutants (IC50 1–3 nM) (ASH abstract, 2006). We are conducting a phase I trial to evaluate the safety and efficacy of two different schedules of sorafenib. To date, 21 patients (pts) with refractory/relapsed AML (n=20) and high risk MDS (n=1) have been enrolled. Pts were randomized to sorafenib for 5 days per week for 21 days (arm A; n=11) or for 14 days every 21 days (arm B; n=10). In both arms the starting dose level (DL) is 200 mg twice daily. Successive dose levels are 600, 800, and 1200 mg daily in a standard 3+3 design. Peripheral blood (PB) and bone marrow (BM) samples were obtained for evaluation of FLT3 status and phosphorylated and total FLT3 and ERK expression. Median age is 62 years (range, 33–82), number of prior therapies 2 (range, 1–5), time from diagnosis to sorafenib treatment 9 months (range, 2–46), and median duration on study was 1.2 months (range, 0.1–3.4). Twenty pts are evaluable. 9/20 (45%) pts received ≤ 1 cycle of sorafenib because of disease progression (n=6), self-discontinuation (n=2), or no benefit (n=1), of whom 5 (56%) were FLT3-ITD negative, 3 (33%) were FLT3-ITD positive, and 1 (11%) was not tested. In contrast, 11/20 (55%) pts received > 1 cycle of sorafenib, of whom 8 (73%) were FLT3-ITD positive and 3 (27%) were FLT3-ITD negative; reasons for discontinuation were disease progression (n=5), self-discontinuation (n=2), stem cell transplant (n=2), or no benefit (n=2). Sorafenib has been well tolerated with 1 pt achieving a DLT of grade 3 hyperbilirubinemia at the 800 mg daily dose in arm B, but the MTD has not been reached; this cohort has been expanded. The only other grade 3 toxicity has been pleural effusion at the 600 mg daily dose in arm A, not considered a DLT because it occurred during cycle 2. A ≥ 50% reduction in PB or BM blasts was obtained in 11/20 (55%) pts. 9/11 (82%) pts harbored the FLT3-ITD mutation and had a median duration of response of 42 days (range, 15–87). In these 9 pts, the median PB absolute blast count at baseline and after maximal response to sorafenib was 10.3 (range, 0.2–18.7) and 0 (range, 0–1)(p=0.008). Median BM blast percentage at baseline and after maximal response to sorafenib was 72% (range, 14–96) and 42% (range, 12–58) (p=0.002), with 1 pt achieving a morphologic complete remission in the BM. Serial determinations of phosphorylation status following sorafenib (at 0, 2, 24,120 hours) in pts with the FLT3-ITD mutation demonstrated inhibition of phospho-FLT3 in 3/3 and phospho-ERK in 5/5 pts. In conclusion, sorafenib administration is safe in AML and appears to preferentially target the FLT3-ITD mutation. This study continues to accrue pts to define the MTD and it will be followed by combination studies of standard chemotherapy with sorafenib, with an emphasis on targeting pts with AML expressing the FLT3-ITD mutation.

scholarly journals Phase I Study of Ixazomib in Addition to Chemotherapy for the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4059-4059
Author(s):  
Philip C. Amrein ◽  
Eyal C. Attar ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
Gabriela S. Hobbs ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Remission Rate ◽  
Secondary Aml ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Introduction: Treatment of acute myeloid leukemia (AML) has remained largely unchanged for several decades despite the emergence of new agents. Long-term survival for patients aged >60 years is less than 10% (median survival 10.5 months). Targeting the proteasome in treating AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). Preclinical studies in leukemia cell lines revealed synergistic cytotoxicity when bortezomib, a proteasome inhibitor, was combined with the standard agents daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although neurotoxicity was noted among treated patients, 12% grade 3 sensory (Attar, …, Amrein, et al. Clin Cancer Res 2008, Attar, … Amrein, J Clin Oncol 2012). The next generation proteasome inhibitor, ixazomib, which is less frequently associated with neurotoxicity, was therefore selected for combination with conventional chemotherapy in this phase I trial. The primary objective was to determine the maximum tolerated dose (MTD) in the combination, initially in induction, and then in combination with consolidation in a subsequent portion of the overall study. We report here the results of the induction portion of the study, which has been completed. Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. The induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3; ixazomib orally at the cohort dose, Days 2, 5, 9, and 12 A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction and subsequently in consolidation. The dose of 3.0 mg/day was the maximum planned for this study. The determined MTD of ixazomib in the first portion of the trial would be used during induction in the second portion, which seeks to test dose escalation of ixazomib during consolidation. Secondary objectives included rate of complete remission and disease-free survival. Results: Fourteen patients have been analyzed for toxicity and activity during the induction portion of the study. There were 4 (28%) patients with either secondary AML or treatment related AML, 9 (64%) were male, and the median age was 67 years (range 62-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 3 thrombocytopenia) indicated at the highest dose level. There has been no neurotoxicity with ixazomib to date. Among the 14 patients, there have been 10 complete remissions (CR's) and 1 CRi for a remission rate of 79%. Conclusions: The highest dose level planned for this portion of the trial, 3.0 mg of ixazomib, was reached with 1 DLT and is the recommended dose for induction in the next portion of this study, which will seek to determine a safe ixazomib dose in combination with conventional consolidation therapy. That no neurotoxicity was encountered was reassuring, and the remission rate in this older adult population is favorable. Table. Table. Disclosures Amrein: Takeda: Research Funding. Attar:Agios: Employment, Equity Ownership. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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.

scholarly journals A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome

Haematologica ◽  
2021 ◽  
Author(s):  
Mahesh Swaminathan ◽  
Hagop M Kantarjian ◽  
Mark Levis ◽  
Veronica Guerra ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3 ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.

scholarly journals Genome-Wide CRISPR Screening Identifies MAPK and Mtorc Pathways As Regulators of Sorafenib Resistance in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2557-2557
Author(s):  
Alisa Damnernsawad ◽  
Tamilla Nechiporuk ◽  
Daniel Bottomly ◽  
Stephen E Kurtz ◽  
Christopher A. Eide ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Drug Sensitivity ◽  
Mek Inhibitors ◽  
Genetics Research ◽  
Genome Wide ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a fast progressing blood malignancy with impaired differentiation and proliferation of myeloid precursors. It is one of the most common leukemias in adults and is known for its molecular and biological heterogeneity, with a variety of genetic lesions implicated in the disease. Among these variants, internal tandem duplication (ITD) or point mutations in the tyrosine kinase domain (TKD) of FLT3 tyrosine kinase are found in around 30% of AML patients. Sorafenib, a multi-kinase inhibitor that targets FLT3, RAF, VEGFR, FGFR, KIT and RET, is approved for use in hepatocarcinoma, renal cell carcinoma, and thyroid carcinoma treatments. Addition of different FLT3 inhibitors such as sorafenib to standard-of-care chemotherapy treatment prolongs AML patient survival with or without FLT3 mutations, although relapse caused by drug resistance remains a clinical challenge. Understanding the mechanisms of resistance to FLT3-targeted drugs, therefore, is necessary to improve treatment options and patient outcomes in AML. We aimed to elucidate resistance mechanisms to sorafenib by subjecting MOLM13 AML cells to genome-wide CRISPR screening to identify genes whose loss-of-function contributes to reduced drug sensitivity. Using Mageck along with an internally developed tiering system for screen hit prioritization, we identified negative regulators of MAPK as well as mTOR pathways as main players in sorafenib resistance. We validated prioritized hit genes using individual sgRNAs to generate single gene deficient cell models for LZTR1, NF1, TSC1 or TSC2. Drug sensitivity assays confirmed an increase in sorafenib resistance in these knockout cells. LZTR1-, TSC1- or TSC2-deficient cells also exhibited reduced sensitivity to a panel of additional FLT3 inhibitors. RNA sequencing results from 271 AML patient peripheral blood or bone marrow samples revealed a correlation between sorafenib sensitivity and lower expression of LZTR1, NF1, TSC1, and TSC2. MOLM13 cell lines resistant to crenolanib, quizartinib, and sorafenib were independently generated by incremental increase in concentration of each drug in cell culture media. Similarly, western blot analysis demonstrated up-regulation of MAPK and/or mTORC1 activity in these resistant cell lines. In addition, these cells were sensitive to MEK inhibitors, and the combination of FLT3 + MEK inhibitors showed synergistic efficacy over single agents in both resistant and parental cells. Taken together, our work identifies the contribution of the MAPK and PI3K/mTOR pathways to FLT3 inhibitor resistance in AML and suggests the combination of FLT3 + MEK inhibitors may be effective for AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors. Disclosures Tyner: Aptose: Research Funding; Array: Research Funding; Agios: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Syros: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Array: Research Funding; Constellation: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Gilead: Research Funding; AstraZeneca: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Syros: Research Funding; Aptose: Research Funding; Petra: Research Funding; Seattle Genetics: Research Funding; Petra: Research Funding; Constellation: Research Funding; AstraZeneca: Research Funding; Agios: Research Funding.

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]

A Phase I Combination Study of Ribavirin and Low Dose Cytarabine Arabinoside (ara-C) in M4/M5 Acute Myeloid Leukemia (AML) and AML with High eIF4E,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3606-3606
Author(s):  
Sarit Assouline ◽  
Biljana Kraljacic-Culjkovic ◽  
Eftihia Cocolakis ◽  
Abdellatif Amri ◽  
Julie Bergeron ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Pharmacodynamic Profile ◽  
Acute Myeloid

Abstract Abstract 3606 The conventional therapy for acute myeloid leukemia (AML), including cytarabine and an anthracycline with or without transplant, results in a durable remission in only a minority of AML patients. Furthermore, half of all newly diagnosed AML patients are over the age of 65, and many are poor candidates for high dose chemotherapy due to comorbidities and poor performance status. Thus, new effective treatment strategies are needed. Overexpression of the eukaryotic translation initiation factor 4E (eIF4E) occurs in greater than 30% of all cancers including M4 and M5 subtypes of AML. eIF4E is an oncogene that selectively regulates expression post-transcriptionally, both at the levels of mRNA translation and export, for genes that are critical for cell division, growth and angiogenesis. Novel strategies to target eIF4E are entering clinical development and have shown some promising activity in cancer. We have identified ribavirin as an inhibitor of eIF4E with anti-cancer activity in patients with AML. Ribavirin is a well-characterized and well-tolerated anti-viral drug. We have shown that it inhibits oncogenic transformation mediated by overexpression of eIF4E and reduces clonogenic potential of cancer cells with elevated levels of eIF4E. Our phase II proof-of-principle clinical trial examining the efficacy of ribavirin treatment in elderly or relapsed M4 and M5 AML patients was the first clinical study to target eIF4E in human malignancy, and demonstrated that ribavirin effectively targets eIF4E in patients, leading to clinical improvement. Unfortunately, all patients who achieved a response acquired resistance and relapsed shortly thereafter. We have found that ara-C and ribavirin have an additive effect on primary leukemia specimens in vitro. Hence, a Phase I trial was commenced combining low dose ara-C with ribavirin in AML patients. The primary objective of the trial was to determine the maximum tolerated dose and recommended phase II dose of ribavirin and low dose ara-C. Additional objectives were to determine safety and to examine molecular correlates and the pharmacokinetic/pharmacodynamic profile of the combination treatment. A total of 17 patients were enrolled on study and evaluated for safety. No dose limiting toxicities have been observed to date. The current dose being tested is 4400 mg/day of ribavirin and ara-C 20 mg subcutaneous twice a day for 10 days and dose escalation continues. We have observed that ribavirin plasma levels are substantially lower than obtained in the monotherapy trial. In addition, of the 12 patients who completed at least one cycle of therapy, we have seen one complete response (CR), 2 blasts responses, and one stable disease. The patient with CR had treatment-related AML due to breast cancer therapy and had relapsed shortly after an allogeneic stem cell transplantation. She achieved a CR after 5 cycles of low dose ara-C and ribavirin. After 6 cycles, the patient was put on maintenance ribavirin monotherapy and continues to be in remission after 16 cycles. Interestingly, in this patient, toxicities due to ara-C led to its dose reduction that correlated with a near doubling of plasma ribavirin levels prior to achieving remission, suggesting that ara-C may alter absorption of ribavirin. A full molecular response was observed in patients with clinical response and none in patients that did not respond, indicating that ribavirin levels were sufficient to affect eIF4E localization and levels. Further safety, pharmacokinetic, pharmacodynamic, and response data will be presented. Disclosures: Off Label Use: Use of investigational agent Ribavirin for the treatment of AML. Bergeron:Celgene: Research Funding; Merck: Research Funding; Roche: Honoraria.

scholarly journals Interim Results from the Phase I Deplethink Trial Evaluating the Infusion of a NKG2D CAR T-Cell Therapy Post a Non-Myeloablative Conditioning in Relapse or Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3844-3844
Author(s):  
A. Samer Al-Homsi ◽  
Enkhtsetseg Purev ◽  
Philippe Lewalle ◽  
Maher Abdul-Hay ◽  
Daniel A Pollyea ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Advisory Committees ◽  
Car T ◽  
Acute Myeloid

CYAD-01 cells are engineered T-cells expressing a chimeric antigen receptor (CAR) based on the natural full-length human natural killer group 2D (NKG2D) receptor fused to the intracellular domain of CD3ζ. NKG2D binds to 8 ligands (MICA, MICAB, and ULBP1-6) over-expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Phase I DEPLETHINK study (NCT03466320) evaluates the safety and preliminary efficacy of a single CYAD-01 infusion (inf.) after lymphodepletion with cyclophosphamide and fludarabine in patients with relapsed or refractory (r/r) AML and MDS. A second cycle of 3 CYAD-01 infusions without preconditioning could be administered in absence of progressive disease (PD) following the 1st infusion. Three dose-levels (DLs; 1x108, 3x108 and 1x109 cells/inf.) are evaluated in the dose escalation segment. The first DL is also evaluated at two different intervals between preconditioning and CYAD-01 infusion (T7: seven days interval; T3: three days interval) in order to mitigate for any potential increased toxicity due to the administration of lymphodepletion. As of end of July 2019, 6 patients (4 AML and 2 MDS) were enrolled in the first 2 cohorts which evaluated DL1 (1x108 cells/inf. at T3 or T7) and 3 patients (3 AML) were enrolled in the cohort 3 evaluating DL2 (3x108 cells/inf. at T3). The blasts in the bone marrow of 8 out of 9 patients ranged between 3% and 48% at baseline. Of the 6 patients treated at DL1 (with lymphodepletion administered up to 7 or 3 days before first CYAD-01 infusion), 3 patients experienced grade (G) 1 toxicity (cytokine release syndrome or CRS and diarrhea), or G2 CRS (uncleaned database). The patient with G2 CRS following the first infusion also experienced G4 CRS and G3 CAR T-cell-related encephalopathy syndrome (CRES) during the second inf. at 3x109 cells/inf. One other patient experienced G1 CRS during the second cycle. At DL2, only 1 patient experienced G1 related AEs (diarrhea and CRS) after the first CYAD-01 infusion. Another patient experienced G3 CRS during the second cycle. All patients recovered with treatment including tocilizumab and, when indicated, steroids. At DL1, two out of 5 evaluable patients reached a stable disease (SD) at day (d) 36, allowing the initiation of the 2nd cycle. At DL2, one patient out of 3 reached SD. The DEPLETHINK study is currently enrolling at DL3 (T3). Preliminary correlative studies show that the area under the curve at d36 (AUC D1-D36) after a single infusion of CYAD-01 with prior lymphodepletion is better than without preconditioning. Furthermore, the T3 interval between the preconditioning and CYAD-01 provides better engraftment than the T7 interval. In conclusion, to date, the results demonstrate the safety and tolerability for CYAD-01 doses 1x108 and 3x108 cells/infusion with a prior lymphodepletion in patients with r/r AML and MDS. The T3 interval was therefore chosen for further CYAD-01 evaluations. The improved persistence of CYAD-01 with lymphodepletion, in particular 3 days before infusion, could lead to improved clinical responses. The study is ongoing and further data will be provided at the meeting. Disclosures Al-Homsi: Celyad: Membership on an entity's Board of Directors or advisory committees. Abdul-Hay:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pollyea:Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lequertier:Celyad: Employment. Alcantar-Orozco:Celyad: Employment. Borghese:Celyad: Employment. Lonez:Celyad: Employment. Braun:Celyad: Employment. Renard:Celyad: Employment. Flament:Celyad: Employment.

scholarly journals Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Philip C. Amrein ◽  
Eyal C. Attar ◽  
Geoffrey Fell ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Remission Rate ◽  
Conventional Chemotherapy ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Grade 3 ◽  
Acute Myeloid

Introduction: Outcomes for acute myeloid leukemia (AML) among older patients has remained largely unchanged for decades. Long-term survival for patients aged &gt;60 years is poor (median survival 10.5 months). Targeting the proteasome in AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although grade 2 sensory neurotoxicity was noted in approximately 12% of treated patients. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the maximum tolerated dose (MTD) of ixazomib in combination with conventional induction and consolidation chemotherapy for AML. Herein are the initial results of this trial. Methods: Adults &gt;60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidaton or transplant was at the discretion of the treating physician in phase A. In the second phase (B), induction was the same as that with the determined MTD of ixazomib. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). The determined MTD of ixazomib in the first portion (A) of the trial was used during induction in the second portion (B), which sought to determine the MTD for ixazomib during consolidation. Secondary objectives included rate of complete remission, disease-free survival, and overall survival (OS). Results: Thirty-six patients have been enrolled on study, and 28 have completed dose levels A-1 through A-3 and B1 through B-2. Full information on cohort B-3 has not yet been obtained, hence, this report covers the experience with the initial 28 patients, cohorts A-1 through B-2. There were 12 (43%) patients among the 28 with secondary AML, either with prior hematologic malignancy or therapy-related AML. Nineteen patients (68%) were male, and the median age was 68 years (range 61-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There has been no grade 3 or 4 neurotoxicity with ixazomib to date. Among the 28 patients in the first 5 cohorts, 22 achieved complete remissions (CR) and 2 achieved CRi, for a composite remission rate (CCR) of 86%. Among the 12 patients with secondary AML 8 achieved CR and 2 achieved CRi, for a CCR of 83%. The median OS for the 28 patients has not been reached (graph). The 18-month OS estimate was 65% [90% CI, 50-85%]. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction in this trial has been reached safely. For consolidation there have been no serious safety issues in the first 2 cohorts with a dose up to 2.3 mg, apart from 1 DLT in the form of delayed platelet count recovery. The recommended phase 2 dose of ixazomib for induction is 3 mg. Accrual to cohort B-3 is ongoing. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate in this older adult population with the addition of ixazomib to standard chemotherapy appears favorable. Figure Disclosures Amrein: Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Attar:Aprea Therapeutics: Current Employment. Brunner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Hobbs:Constellation: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Fathi:Blueprint: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Forty Seven: Consultancy; Trovagene: Consultancy; Kite: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Amphivena: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy. OffLabel Disclosure: Ixazomib is FDA approved for multiple myeloma. We are using it in this trial for acute myeloid leukemia.

Sign in / Sign up

Export Citation Format

Share Document