Clinical Trials /

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

NCT01801046

Description:

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)

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Donor Stem Cell Transplant in Treating Patients With High Risk Acute Myeloid Leukemia
  • Official Title: HLA-mismatched Allogeneic Cellular Therapy (HMMACT) After Chemotherapy in High Risk Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 9L-11-8
  • SECONDARY ID: NCI-2013-00447
  • NCT ID: NCT01801046

Conditions

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia in Remission
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Childhood Acute Erythroleukemia (M6)
  • Childhood Acute Megakaryocytic Leukemia (M7)
  • Childhood Acute Monoblastic Leukemia (M5a)
  • Childhood Acute Monocytic Leukemia (M5b)
  • Childhood Acute Myeloblastic Leukemia With Maturation (M2)
  • Childhood Acute Myeloblastic Leukemia Without Maturation (M1)
  • Childhood Acute Myeloid Leukemia in Remission
  • Childhood Acute Myelomonocytic Leukemia (M4)
  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Interventions

DrugSynonymsArms
mitoxantrone hydrochlorideCL 232315, DHAD, DHAQ, NovantroneTreatment (chemotherapy, G-PBSC)
cytarabineARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinosideTreatment (chemotherapy, G-PBSC)

Purpose

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)

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy, G-PBSC)ExperimentalINDUCTION 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.
  • mitoxantrone hydrochloride
  • cytarabine

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Induction mortality
Time Frame:Up to 8 weeks
Safety Issue:
Description:Exact 95% confidence intervals will be constructed.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Will be summarized in terms of type, severity, attribution, time of onset, duration, reversibility, and outcome.
Measure: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
Safety Issue:
Description:Will be summarized using cumulative incidence curves.
Measure: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
Safety Issue:
Description:Will be summarized using cumulative incidence curves.
Measure:Incidence of GvHD
Time Frame:Up to 3 years
Safety Issue:
Description: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).
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:University of Southern California

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