Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Leukemia

Preleukemia

Myelodysplastic Syndromes

Leukemia, Erythroblastic, Acute

Bone Marrow Diseases

Hematologic Diseases

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Myeloproliferative Disorders

Acute Graft Versus Host Disease

Chronic Myeloproliferative Disorders

Antineoplastic Agents

All Drugs and Chemicals

Fludarabine

Fludarabine phosphate

Azacitidine

Melphalan

Alemtuzumab

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Patients will be given a five day course of subcutaneous 5-azacytidine, followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor.

Patients will be given a five day course of subcutaneous 5-azacytidine followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor. 5-Azacytidine 75 mg/m2 subcutaneously daily at the same time on days -11, -10, -9,

-8 and -7. This will be administered on an outpatient basis if possible.

5-Azacytidine

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Fludarabine will be given at 40 mg/m2 intravenously daily at the same time over 30 minutes on days -6,-5,-4,-3.

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Melphalan will be given at 140 mg/m2 IV on day -3.

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Alemtuzumab will be given at 30 mg subcutaneously on Days -4 and -2 for unrelated donors, and Day -2 for related donors.

Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Total Body Irradiation (TBI) will be given at 2 doses of 200 cGy each on one day of the conditioning regimen (between days -6 and -3).

Total Body Irradiation

Sebastian Mayer, MD

The purpose of this study is to determine whether 5-Azacytidine priming before the conditioning regimen for subjects receiving a hematopoietic stem cell transplant is an effective treatment for high risk myeloid malignancies in complete remission (CR).

This open label two-step phase II study is designed to determine the safety and efficacy of epigenetic priming with 5-Azacytidine immediately prior to reduced intensity conditioning for an in vivo T-cell depleted hematopoietic stem cell transplantation for high risk myeloid malignancies in complete remission (CR).

Subjects will be given a five day course of subcutaneous 5-azacytidine, followed by a reduced intensity conditioning regimen of fludarabine, melphalan and total body irradiation (TBI) prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated Human Leukocyte Antigen (HLA) matched donor.

The effect of 5-azacytidine on global gene methylation will be assessed. Evaluations for safety, in particular for graft failure, transplant related mortality and acute graft versus host disease will be made on a weekly basis. Efficacy, as defined by disease free survival, will be evaluated with a bone marrow biopsy at the standard time points, which are one-, three-, six-, and twelve-months after transplant and upon clinical suspicion within regular follow-up visits - weekly for the first 3 months, then biweekly for 3 months, then monthly until one-year post-stem cell transplant. Thereafter, unless otherwise dictated by the clinical scenario, the follow up visits will be every 3 months.

Azacytidine Prior to in Vivo T-cell Depleted Allo Stem Cell Transplant for Patients With Myeloid Malignancies in CR

Epigenetic Priming With 5-Azacytidine Prior to in Vivo T-cell Depleted Allogeneic Stem Cell Transplantation for Patients With High Risk Myeloid Malignancies in Morphologic Remission

Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 1 year post-transplant.

Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 6 months post-transplant

Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 2 years post-transplant.

Number of participants alive at 6 months post-transplant

Number of participants alive at 1 year post-transplant

Number of participants alive at 2 years post-transplant

Number of patients who experience graft failure, defined as the absence of neutrophil engraftment by Day +21 or a drop in the absolute neutrophil count to \<0.3 cells/microL for five consecutive days occurring after initial neutrophil engraftment within the first 3 weeks post-transplantation.

Number of patients who develop acute graft-versus-host disease of any grade.

Number of patients who develop high-risk extensive chronic graft-versus-host disease. Extensive chronic GVHD is defined as generalized skin or multiple organ involvement. High risk chronic GVHD is defined as platelet count of less than 100k/microL

Weill Medical College of Cornell University

All adverse events were first documented by the study transplant physicians and thereafter collated and graded by two independent reviewed according to CTCAE version 4.0. Per protocol, events reported were all infectious events and Grade 3 and higher events for non-infectious events

Patients will be given a five day course of subcutaneous 5-azacytidine, followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation (TBI) prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor.

5-Azacytidine: Patients will be given a five day course of subcutaneous 5-Azacytidine followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor. AZA 75 mg/m2 subcutaneously daily at the same time on days -11, -10, -9, -8 and -7. This will be administered on an outpatient basis if possible.

Fludarabine (conditioning regimen): Fludarabine will be given at 40 mg/m2 intravenously daily at the same time over 30 minutes on days -6,-5,-4,-3.

Melphalan (conditioning regimen): Melphalan will be given at 140 mg/m2 IV on day -3.

Alemtuzumab (conditioning regimen): Alemtuzumab will be given at 30 mg subcutaneously on Days -4 and -2 for unrelated donors, and Day -2 for related donors.

TBI (conditioning regimen): TBI will be given at 2 doses of 200 cGy each on one day of the conditioning regimen (between days -6 and -3).

5 Azacytidine

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Hematologic malignancy that allogeneic hematopoietic stem cell transplant is intended to treat

Disease

Donor relationship to participant for allogeneic stem cell transplant

One participant was removed from the study before stem cell transplantation and is therefore unevaluable for this baseline measure

Donor Relationship

1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant.

Disease Free Survival at 1 Year Post-transplant

Disease Free Survival at 6 Months Post-transplant

Disease Free Survival at 2 Years Post-transplant

Overall Survival at 6 Months Post-transplant

1 participant was unevaluable as they were removed from study before undergoing hematopoietic stem cell transplant

Overall Survival at 1 Year Post-Transplant

Clopper-Pearson (exact) 95% confidence interval provided for the survival proportion.

Overall Survival at 2 Years Post-Transplant

Graft Failure

Acute Graft-versus-Host Disease (GVHD)

High-Risk Extensive Chronic Graft-versus-Host-Disease

Overall Study

Leukemia, Myelomonocytic, Acute

Leukemia, Monocytic, Acute

Leukemia, Megakaryoblastic, Acute

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Anti-Infective Agents

Cytarabine

Idarubicin

Antiviral Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Will receive volasertib combined with idarubicin plus cytarabine in a 3+7 schedule as induction chemotherapy. Volasertib dose will be given on day 4 in a dose escalation schedule over 3 dose levels (140 mg/m2, 170 mg/m2, 200 mg/m2) in successive cohorts.

Non-hematologic toxicity will be determined using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria for adverse events. Hematologic toxicity will be determined by days to absolute neutrophil count (ANC) and platelet recovery.

Addition of single dose of volasertib intravenously (IV) on Day 4 of treatment protocol.

Volasertib

Given IV daily on Days 1-3 of treatment protocol.

Given IV daily as 24-hour continuous infusion on Day 1-7 of treatment protocol.

Joseph Brandwein, MD

This is a Phase I clinical trial to determine the maximum tolerated dose (MTD) of the polo-like kinase-1 inhibitor volasertib which can be safely combined with idarubicin plus cytarabine induction chemotherapy for previously untreated patients with acute myeloid leukemia. (AML).

Main inclusion criteria:

1. AML, any subtype except acute promyelocytic leukemia (APL)
2. At least one of the following features:

   i. Age 18-75 with adverse risk cytogenetics ii. Age 18-75 with antecedent myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD), or therapy-related AML iii. Age 60-75, regardless of risk category
3. No prior therapy for AML other than hydroxyurea
4. Judged by treating physician to be medically fit for induction chemotherapy
5. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2
6. Normal left ventricular ejection fraction

Subjects will receive induction chemotherapy consisting of idarubicin 12 mg/m2 on Days 1-3 plus cytarabine 200 mg/m2 (age 18-59) or 100 mg/m2 (age 60-75) as a continuous IV infusion x 7 days. Volasertib will be administered on day 4 in a dose-escalation schedule, using a standard 3+3 dose escalation design, over 3 dose levels. Once the MTD has been determined, an additional dose expansion cohort will be accrued.

A Study of Volasertib Plus Induction Chemotherapy for Acute Myeloid Leukemia

A Phase I Study of Volasertib Combined With Standard Induction Chemotherapy for Previously Untreated Patients With Acute Myeloid Leukemia (VIAC)

Anonymized data will be made available to Boehringer-Ingelheim.

Non-hematologic toxicities will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Hematologic toxicities will be assessed by determining number of days to neutrophil (ANC) recovery to \>0.5 x10(9)/L or platelet recovery to \>20 x10(9)/L.

DLT is defined as grade 3-4 non-hematologic toxicity (except grade 3 nausea, vomiting, mucositis or creatinine elevation due to tumor lysis syndrome, and grade 3-4 neutropenic infections and electrolyte abnormalities) using CTCAE version 4.0.Hematologic DLT is defined as ANC recovery to \>0.5 x10(9)/L or platelet recovery to \>20 x10(9)/L of \> 42 days.

MTD is defined as maximum dose of volasertib associated with \< 2/6 DLTs at a given dose level.

Complete response (CR) defined as \<5% marrow blasts with ANC \> 1.0 x10(9)/L and platelets \>100 x 10(9)/L, with no extramedullary disease. CRi defined as same, but ANC \<1.0 and/or platelets \<100.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Azacytidine Prior to in Vivo T-cell Depleted Allo Stem Cell Transplant for Patients With Myeloid Malignancies in CR	NCT02497404	Leukemia, Eryth... Myelodysplastic...	5-Azacytidine Fludarabine Melphalan Alemtuzumab Total Body Irra...	18 Years -	Weill Medical College of Cornell University
Azacytidine Prior to in Vivo T-cell Depleted Allo Stem Cell Transplant for Patients With Myeloid Malignancies in CR	NCT02497404	Leukemia, Eryth... Myelodysplastic...	5-Azacytidine Fludarabine Melphalan Alemtuzumab Total Body Irra...	18 Years -	Weill Medical College of Cornell University
Azacytidine Prior to in Vivo T-cell Depleted Allo Stem Cell Transplant for Patients With Myeloid Malignancies in CR	NCT02497404	Leukemia, Eryth... Myelodysplastic...	5-Azacytidine Fludarabine Melphalan Alemtuzumab Total Body Irra...	18 Years -	Weill Medical College of Cornell University
A Study of Volasertib Plus Induction Chemotherapy for Acute Myeloid Leukemia	NCT02527174	Leukemia, Myelo... Leukemia, Monoc... Leukemia, Myelo... Leukemia, Eryth... Leukemia, Megak...	Volasertib Idarubicin Cytarabine	18 Years - 75 Years	University of Alberta

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