Donor Stem Cell Transplant in Treating Patients With High Risk Acute Myeloid Leukemia

March 28, 2018 updated by: University of Southern California

HLA-mismatched Allogeneic Cellular Therapy (HMMACT) After Chemotherapy in High Risk Acute Myeloid Leukemia

This phase I trial studies the side effects of donor stem cell transplant in treating patients with high risk acute myeloid leukemia. Giving low doses of chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells when they do not exactly match the patient's blood. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect)

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To assess the feasibility of cytarabine based chemotherapy and human leukocyte antigen (HLA)-mismatched allogeneic cellular therapy (HMMACT) in patients with high risk acute myeloid leukemia (AML), with feasibility measured by induction mortality (IM) and complete response rate.

SECONDARY OBJECTIVES:

I. To obtain preliminary estimates of clinical outcome following cytarabine based chemotherapy and HMMACT in patients with high risk AML, as measured by event free survival (EFS) and overall survival (OS).

II. To further evaluate the safety outcomes of induction and consolidation of cytarabine and HMMACT in terms of serious infections (grade 4), time to recovery of absolute neutrophil counts and platelets and incidence of graft versus host disease (GvHD).

III. To further evaluate the feasibility of this approach in terms of identifying a suitable donor in this elderly population.

IV. To compare in preliminary manner the clinical outcomes of cytarabine and HMMACT in patients with high risk AML as measured by complete response rate (CRR), event free survival (EFS) and overall survival (OS) by donor/recipient HLA-C1 vs C2 pairs.

V. To characterize in a preliminary manner, the numbers of suppressor regulatory T cells (Tregs), T helper 17 cells (Th17), and cytotoxic T cells during pre and post HMMACT treatment, and with clinical outcomes in leukemia.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive mitoxantrone hydrochloride intravenously (IV) on days 1-3 and cytarabine IV on days 1-7.

HMMACT: Patients receive filgrastim (G-CSF) mobilized peripheral blood stem cells (G-PBSC) on day 9. After completion of study treatment, patients are followed up monthly for 3 years.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90033
        • USC Norris Comprehensive Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients must have a histologically and cytological confirmed acute myeloid leukemia, high risk AML defined as:

    • Age > 60, or
    • Presence of complex cytogenetic abnormalities (with > 3 cytogenetic abnormalities), del (7q, -5, -7), t(9,22), 11q(23) or high risk mutations by FISH eg MLL, FLT-3 +
    • Secondary AML, or
    • A white blood cell count of > 50 x10^9/L
  • Patients must be medically ineligible for allogeneic stem cell transplant (alloSCTx) or not have a known fully HLA matched sibling for planned sibling transplant.
  • Patients must have measurable or evaluable disease

  • Diagnosis of AML according to World Health Organization (WHO) diagnostic criteria (at least 20% blasts in the peripheral blood or bone marrow), with French-American-British Cooperative group (FAB) classification other than M3 (acute promyelocytic leukemia), documented by bone marrow aspiration and biopsy performed within 14 days prior to administration of 1st dose of remission induction chemotherapy; if a bone marrow aspirate and biopsy were obtained within 28 days prior to the first dose of remission induction therapy then these tests may be submitted for review at University of Southern California (USC) and a repeat screening bone marrow does not need to be conducted;

    • Cohort A: newly diagnosed AML, no prior cytotoxic chemotherapy
    • Cohort B: newly diagnosed AML, failed to achieve Complete remission (CR) with single standard Induction chemo.
  • Patient has at least one medically fit family member expected to be HLA mismatched at 1-9/10; more commonly and preferred: 4-6/10 loci (parent, sibling, niece/nephew, etc but adult children preferred)
  • Absolute neutrophil count (ANC) > 1500, unless due to direct bone marrow involvement of disease
  • Platelets > 75,000, unless due to direct bone marrow involvement of disease
  • Hemoglobin > 8.0 gm/dL, transfusion allowed
  • Serum creatinine < 2.0 x the upper limits of institutional normal (ULN)
  • Total bilirubin < 1.5 x the upper limits of institutional normal
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT )< 2.5 x the upper limits of institutional normal (=< 5 x ULN for patients with liver involvement of leukemia)
  • Cardiac left ventricular ejection fraction (LVEF) > 45%
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Estimated survival of at least 3 months
  • Patients must be able to understand and agree to sign an Institutional Review Board (IRB)-approved informed consent form
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry, for the duration of study, and for two months after study participation
  • DONOR: Donor screening; all donors will meet the standard blood donor criteria established by the participating local blood center, American Association of Blood Banks (AABB)
  • DONOR: Donors will be selected from among the subject's relatives, adult children preferred
  • DONOR: Infectious disease testing will be done per Hemacare policy and AAAB guidelines
  • DONOR: Donor and intended recipient red cell type and compatibility will be determined
  • DONOR: Donors will be pre-selected on the basis of HLA haploidentity
  • DONOR: If patient is cytomegalovirus (CMV)-negative, donors who are CMV-negative will be preferred; CMV serology of the donor will be tested prior to the allogeneic cell donation; donations from CMV-positive donors to CMV-negative recipients will be given if no CMV negative donor is available, and CMV surveillance and pre-emptive treatment given

Exclusion Criteria:

  • Cohort A: Patients who have received prior cytotoxic chemotherapy, such as anthracyclines and cytarabine not permitted; but prior treatment with demethylating agents (azacytidine or decitabine, lenalidomide, etc) ALLOWED.
  • Cohort B: Patients who have received prior fludarabine, clorarabine or drugs known to target T cells not permitted; but prior standard induction with anthracylines and cytarabine ALLOWED including after demethylating agents.
  • Have uncontrolled systemic infections, coagulation disorders, or other major medical illnesses of the cardiovascular or respiratory systems
  • Pregnant and/or lactating
  • Patients who have had non-biopsy surgery in the last 10 days
  • Active central nervous system (CNS) disease; patients with previously treated leptomeningeal disease without evidence of remaining leukemia cells by spinal fluid will be eligible
  • Known active autoimmune disorder
  • Known to be human immunodeficiency virus (HIV)-positive or have active hepatitis B or C
  • Patients concurrently taking the following drugs are excluded: mycophenolate, cyclosporine, prednisone > 20mg/day, or immunosuppressive agents
  • DONOR: Personal or family history of severe sickle cell disease or variant (unless donor has tested negative); testing for the presence of hemoglobin S is not required
  • DONOR: Positive infectious disease test as dictated by blood collection center's standard operating procedure (SOP)
  • DONOR: Current uncontrolled hypertension
  • DONOR: Diabetes mellitus
  • DONOR: Active peptic ulcer disease
  • DONOR: Pregnant or breast-feeding
  • DONOR: Currently taking lithium therapy
  • DONOR: History of autoimmune disease
  • DONOR: History of coronary disease

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (chemotherapy, G-PBSC)
INDUCTION CHEMOTHERAPY: Patients receive mitoxantrone hydrochloride IV on days 1-3 and cytarabine IV on days 1-7. HMMACT: Patients receive G-PBSC on day 9.
Other: laboratory biomarker analysis
Correlative studies
Drug: cytarabine
Given IV
Other Names:
  • Cytosar-U
  • cytosine arabinoside
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
Drug: mitoxantrone hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
  • Novantrone
Procedure: peripheral blood stem cell transplantation
Undergo HMMACT with G-PBSC
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Induction mortality
Time Frame: Up to 8 weeks
Up to 8 weeks
Complete remission rate (complete remission [CR] or incomplete remission [CRi])
Time Frame: Up to 3 years
Exact 95% confidence intervals will be constructed.
Up to 3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Occurrence of serious infections (grade 4) assessed using National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) v4.0
Time Frame: Up to 3 years
Will be summarized in terms of type, severity, attribution, time of onset, duration, reversibility, and outcome.
Up to 3 years
Time to recovery of absolute neutrophil counts (ANC)
Time Frame: From stem cell infusion to the first of 3 consecutive days in which the ANC is more than 0.5 x 10^9/L, assessed up to 3 years
Will be summarized using cumulative incidence curves.
From stem cell infusion to the first of 3 consecutive days in which the ANC is more than 0.5 x 10^9/L, assessed up to 3 years
Time to recovery of platelets
Time Frame: From stem cell infusion until the first of 3 consecutive days in which the platelet count is more than 30 x 10^9/L, assessed up to 3 years
Will be summarized using cumulative incidence curves.
From stem cell infusion until the first of 3 consecutive days in which the platelet count is more than 30 x 10^9/L, assessed up to 3 years
Incidence of GvHD
Time Frame: Up to 3 years
Will be reported in terms of grade, site, and time of onset (for acute GvHD) and whether limited or extensive, and time of onset (for chronic GvHD).
Up to 3 years
Estimate of clinical outcome as measured by event free survival (EFS)
Time Frame: From the start of induction until documentation of failure to achieve a CR or CRi during induction, initiation of a salvage therapy, disease recurrence/progression (after induction), or death due to any cause, assessed up to 2 years
Kaplan-Meier plots will be used to summarize the EFS observed in this series. The proportion of patients alive and in continuous complete remission will be estimated at 6, 12, 18, and 24 months. 95% intervals will be constructed.
From the start of induction until documentation of failure to achieve a CR or CRi during induction, initiation of a salvage therapy, disease recurrence/progression (after induction), or death due to any cause, assessed up to 2 years
Estimate of clinical outcome as measured by overall survival (OS)
Time Frame: From the start of induction until death due to any cause, assessed up to 2 years
Kaplan-Meier plots will be used to summarize the OS observed in this series. The proportion of patients alive will be estimated at 6, 12, 18, and 24 months. 95% intervals will be constructed.
From the start of induction until death due to any cause, assessed up to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Southern California

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Ann Mohrbacher, University of Southern California

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 6, 2013

Primary Completion (Actual)

July 27, 2017

Study Completion (Actual)

August 20, 2017

Study Registration Dates

First Submitted

February 26, 2013

First Submitted That Met QC Criteria

February 27, 2013

First Posted (Estimate)

February 28, 2013

Study Record Updates

Last Update Posted (Actual)

March 30, 2018

Last Update Submitted That Met QC Criteria

March 28, 2018

Last Verified

March 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 9L-11-8
  • NCI-2013-00447 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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