Early Allogeneic Hematopoietic Cell Transplantation in Treating Patients With Relapsed or Refractory High-Grade Myeloid Neoplasms

NCT02756572 | Completed Phase 2 Results DMC

• 4 other identifiers: 9567NCI-2016-00477P30CA015704RG1016011
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This clinical trial studies how well early stem cell transplantation works in treating patients with high-grade myeloid neoplasms that has come back after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as filgrastim, cladribine, cytarabine and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a donor peripheral blood cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells. Early stem cell transplantation may result in more successful treatment for patients with high-grade myeloid neoplasms.

Conditions

Blasts 10 Percent or More of Bone Marrow Nucleated Cells; Chronic Myelomonocytic Leukemia-2; High Grade Malignant Neoplasm; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts-2; Myeloid Neoplasm; Previously Treated Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Feasibility of Early Allogeneic Hematopoietic Cell Transplant Assessed by Enrollment and Incidence of Early Transplant

  Success will be defined as enrollment of at least 30 patients with transplants occurring in 15 of these 30 (50%) within 60 days of enrollment or start of induction chemotherapy with G-CLAM, whichever is earlier.

  Up to 60 days after start of chemotherapy

• Feasibility of Early Allogeneic Hematopoietic Cell Transplant Assessed by Relapsed-free Survival 6 Months After Transplant

  Success will be defined as observing a 40% of higher 6-month relapse-free survival among patients who received early transplant on study.

  6 months after early allogeneic HCT on study

Secondary Outcomes (17)

• Response Assessments After Early Allogeneic Hematopoietic Cell Transplant, Day 28

  Approximately 28 days after early allogeneic HCT

• Response Assessments After Early Allogeneic Hematopoietic Cell Transplant, Day 84

  Approximately 84 days after early allogeneic HCT

• Relapse-free Survival (RFS) Among Patients Who Received Early Transplant

  Up to 100 days post-transplant

• Relapse-free Survival (RFS) Among Patients Who Received Early Transplant

  Up to 6 months post-transplant

• Event-free Survival (EFS) Among Patients Who Received Early Transplant

  Up to 100 days post-transplant

Study Arms (1)

Treatment (chemotherapy, HCT)

EXPERIMENTAL

See Detailed Description

Drug: Cladribine; Drug: Cyclosporine; Drug: Cytarabine; Biological: Filgrastim; Drug: Fludarabine Phosphate; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Other: Laboratory Biomarker Analysis; Drug: Melphalan; Drug: Mitoxantrone Hydrochloride; Drug: Mycophenolate Mofetil; Other: Questionnaire Administration; Drug: Sirolimus; Radiation: Total-Body Irradiation; Drug: Melphalan Hydrochloride

Interventions

Cladribine DRUG

Given IV

Also known as: 2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251

Treatment (chemotherapy, HCT)

Cyclosporine DRUG

Given PO

Also known as: 27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya

Treatment (chemotherapy, HCT)

Cytarabine DRUG

Given IV

Also known as: .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453

Treatment (chemotherapy, HCT)

Filgrastim BIOLOGICAL

Given SC

Also known as: FILGRASTIM, LICENSE HOLDER UNSPECIFIED, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tevagrastim

Treatment (chemotherapy, HCT)

Fludarabine Phosphate DRUG

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Treatment (chemotherapy, HCT)

Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Undergo allogeneic hematopoietic stem cell transplantation

Also known as: Allogeneic Hematopoietic Stem Cell HSCT, Allogeneic Stem Cell Transplantation, HSC

Treatment (chemotherapy, HCT)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (chemotherapy, HCT)

Melphalan DRUG

Given IV

Also known as: Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine nitrogen mustard, Sarcoclorin, Sarkolysin, WR-19813

Treatment (chemotherapy, HCT)

Mitoxantrone Hydrochloride DRUG

Given IV

Also known as: CL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, Pralifan

Treatment (chemotherapy, HCT)

Mycophenolate Mofetil DRUG

Given PO

Also known as: Cellcept, MMF

Treatment (chemotherapy, HCT)

Questionnaire Administration OTHER

Ancillary studies

Treatment (chemotherapy, HCT)

Sirolimus DRUG

Given PO

Also known as: AY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217

Treatment (chemotherapy, HCT)

Total-Body Irradiation RADIATION

Undergo TBI

Also known as: Total Body Irradiation, Whole-Body Irradiation

Treatment (chemotherapy, HCT)

Melphalan Hydrochloride DRUG

Given IV

Also known as: 241286, 3-(p-(bis(2-chloroethyl)amino)phenyl)-L-Alanine, Hydrochloride, Alkeran, Alkerana, Evomela

Treatment (chemotherapy, HCT)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Relapsed or refractory high-grade myeloid neoplasms, defined as having a blast count of \>= 10% blasts at initial diagnosis; examples include excess blasts (EB)-2, with \>= 10% blasts at initial diagnosis, acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML-2); standard definitions of relapse will apply (i.e., characterized by \>= 5% abnormal blasts or blast equivalents as assessed by multiparameter flow cytometry or morphologic examination; peripheral blood blasts or blast equivalents; or extramedullary granulocytic sarcoma, per European LeukemiaNet \[ELN\] 2017 guidelines); bone marrow aspirate/biopsy will be accepted if performed outside University of Washington/Fred Hutchinson Cancer Research Center (UW/FHCRC); determination of disease status should occur within 30 days of signing informed consent
• R/R high-grade myeloid neoplasm following intensive induction chemotherapy; relapsed high-grade myeloid neoplasm: patients will be classified as relapsed if they have \>= 5% blasts after being in a complete remission (CR) following treatment for high-grade myeloid neoplasm; refractory high-grade myeloid neoplasm: patients may be classified as refractory if they have received at least one prior cycle of induction chemotherapy, whether with cladribine cytarabine mitoxantrone (GCLAM) or another regimen
• \*\* Patients may have received up to two courses of intensive induction chemotherapy during initial treatment prior to enrollment on this protocol; for example, patients who have received two courses of granulocyte colony stimulating factor (G-CSF) GCLAM (or similar) chemotherapy, with most recent high-dose cytarabine-containing chemotherapy \> 6 months ago and CR lasting \> 6 months, will be eligible for this protocol; regimens "similar to GCLAM" would include cytarabine at doses of 1g/m\^2 for at least 5 doses; examples of regimens "similar to GCLAM" would be GCLA, fludarabine cytarabine granulocyte (FLAG), and FLAG-idarubicin (ida); however, patients who received more than two courses of GCLAM (or similar) chemotherapy, or patients who received two courses of GCLAM and had CR lasting \< 6 months, would not be eligible
• R/R high-grade myeloid neoplasm following less intensive induction chemotherapy. Patients who have received at least three cycles of treatment with a hypomethylating agent (HMA; such as azacitidine or decitabine) and still have \>= 10% blasts will be eligible for the study (they will be considered refractory); similarly, patients who have received three or more cycles of HMA therapy who have had a response (e.g., achieving CR with \< 5% blasts), but who then progress using standard definitions of relapse, will also be eligible (they will be considered relapsed)
• Potentially eligible for reduced intensity conditioning based on known organ function (formal organ function testing may occur after consent)
• Caregiver capable of providing post-HCT care
• Written informed consent
• Identified donor (see DONOR SELECTION below for further details)
• Matched related or unrelated (one allele mismatch in HLA-A, B, or C OK) donor according to institutional standards
• Unrelated volunteer donor who is mismatched with the recipient (i.e. 9/10 match)
• Caregiver capable of providing post-HCT care, who will be present once induction therapy with filgrastim, cladribine, cytarabine, mitoxantrone hydrochloride (GCLAM) begins
• Written informed consent for transplant
• Either bone marrow or peripheral blood is allowed

You may not qualify if:

• Prior allogeneic HCT
• More than two prior courses of induction chemotherapy
• Relapse after minimal residual disease (MRD)-negative CR within 3 months of most recent GCLAM chemotherapy
• Low likelihood of being eligible for reduced intensity conditioning HCT based on known information
• Cardiac ejection fraction \< 40% or symptomatic coronary artery disease or uncontrolled arrhythmia, as assessed by multigated acquisition (MUGA) or transthoracic echocardiography (TTE) within previous 3 months and since the most recent anthracycline exposure
• Corrected diffusing capacity of the lungs for carbon monoxide (DLCOc) \< 40% or forced expiratory volume in 1 second (FEV1) \< 50%
• Estimated glomerular filtration rate (GFR) \< 40 ml/min
• Need for supplemental oxygen
• Direct bilirubin or alanine aminotransferase (ALT) \> 2 x upper limit of normal, unless these abnormalities are thought to be related to Gilbert's disease or leukemic infiltration of hepatic parenchyma
• Known human immunodeficiency virus (HIV) positivity
• Pregnant or nursing (to be confirmed with quantitative human chorionic gonadotropin \[HCG\] testing)
• Invasive solid tumor within 5 years; non-melanoma skin cancer or in situ malignancies are allowed
• Evidence of serious uncontrolled infection
• Eastern Cooperative Oncology Group (ECOG) of 3 or 4
• Donor specific antibodies against donor HLA-DQ or -DP

Sponsors & Collaborators

• University of Washington: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myeloid, Acute

Interventions

Cladribine; Cyclosporine; Cyclosporins; Cytarabine; Filgrastim; Granulocyte Colony-Stimulating Factor; fludarabine phosphate; Melphalan; Mitoxantrone; Mycophenolic Acid; Sirolimus; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Proteins; Biological Factors; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Quinones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Macrolides; Lactones; Radiotherapy; Therapeutics; Investigative Techniques

Limitations and Caveats

Some patients did not move on with transplant on study within 60 days of chemotherapy due to issues with scheduling pre-transplant evaluations, donor searches, and donor availability which caused delays. Some patients were also taken off this study to enroll onto other, more appropriate transplant clinical trials.

Results Point of Contact

• Title: Mary-Elizabeth Percival, MD, MS
• Organization: University of Washington/Seattle Cancer Care Alliance

mperciva@seattlecca.org

206-606-1320

Study Officials

• Mary-Elizabeth Percival

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Division of Hematology

Study Record Dates

• First Submitted: April 21, 2016
• First Posted: April 29, 2016
• Study Start: September 22, 2016
• Primary Completion: March 1, 2020
• Study Completion: July 1, 2020
• Last Updated: November 8, 2021
• Results First Posted: March 22, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)