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Phase III Randomized Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard Daunorubicin &Amp; Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission Therapy, Followed

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Trial Conditions
  • Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • 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 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)
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia
What is the purpose of this trial?

This randomized phase III trial studies clofarabine to see how well it works compared with daunorubicin hydrochloride and cytarabine when followed by decitabine or observation in treating older patients with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as clofarabine, daunorubicin hydrochloride, cytarabine, and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which chemotherapy regimen is more effective in treating acute myeloid leukemia.

Date & Status

Recruiting

Who can Participate?

Eligibility

Ages:
60 and older

Gender:
Both

Eligibility

Inclusion Criteria:

- Sexually active males must be strongly advised to use an accepted and effective
method of contraception

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< grade 1

- Total bilirubin =< grade 1

- Note: If total bilirubin is 2 to 3 mg/dL, but direct bilirubin is normal, then
the patient will be considered eligible

- Patient must not have a concurrent active malignancy for which they are receiving
treatment (other than myelodysplastic syndromes [MDS])

- Patient must not have an active, uncontrolled infection

- ADDITIONAL INDUCTION ELIGIBILITY CRITERIA:

- Newly-diagnosed AML patients according to World Health Organization (WHO)
classification who are considered candidates for intensive chemotherapy based upon
examination of peripheral blood or bone marrow aspirate specimens or touch
preparations of the bone marrow biopsy obtained within two weeks prior to
randomization; a bone marrow aspirate is required for enrollment; however, on
occasion there is discordance between percentage of myeloblasts on the differential
of the peripheral blood or aspirate; the peripheral blood criteria are sufficient for
diagnosis; confirmatory immunophenotyping will be performed centrally

- NOTE: patients must be registered to E3903 (Ancillary Laboratory Protocol for
the Collection of Diagnostic Material on Patients Considered for Eastern
Cooperative Oncology Group (ECOG) Treatment Trials for Leukemia or Related
Hematologic Disorders) and must undergo eligibility testing for the study by
multiparameter flow cytometry

- NOTE: Southwest Oncology Group (SWOG)/Cancer Trials Support Unit (CTSU)
institutions: E3903 is not open at the CTSU; therefore, baseline submissions
must be submitted on E2906

- ECOG performance status (PS) 0-3 (restricted to ECOG PS 0-2 if >= 70 years of age)

- Patients with acute promyelocytic leukemia (APL) confirmed either by the presence of
t(15;17)(q22;q21) or promyelocytic leukemia (PML)/retinoic acid receptor (RAR) alpha
transcripts will be excluded

- Patients must not have blastic transformation of chronic myelogenous leukemia

- Patients with secondary AML are eligible for enrollment onto the trial; secondary AML
is defined as AML that has developed in a person with a history of antecedent blood
count abnormalities, or myelodysplastic syndrome (MDS), or a myeloproliferative
disorder (excluding chronic myeloid leukemia); or a history of prior chemotherapy or
radiation therapy for a disease other than AML

- NOTE: Prior therapy of MDS with decitabine, low-dose cytarabine, or azacitidine
is excluded

- Patients may not have received prior chemotherapy for AML with the exception of
hydroxyurea for increased blast count or leukapheresis for leukocytosis

- Total serum bilirubin =< 1.5 times upper limit of normal (ULN) (=< grade 1); if total
bilirubin is 2 to 3 mg/dL, but direct bilirubin is normal, then the patient will be
considered eligible

- Patients with a serum creatinine > 1 are eligible if they have a calculated
glomerular filtration rate (GFR) of >= 60 ml/min (i.e. class I or class II chronic
kidney disease ) using the Modification of Diet in Renal Disease (MDRD) formula

- Note: Daily creatinine and MDRD formula are only for the 1st induction cycle

- Cardiac ejection fraction >= 45% or within institutional normal limits; a nuclear
medicine gated blood pool examination is preferred; a two-dimensional (2-D)
echocardiogram (ECHO) scan is acceptable if a calculated ejection fraction is
obtained and follow-up measurement of the cardiac ejection fraction will also be
performed by echocardiography; measurement of cardiac ejection fraction should be
within two weeks prior to receiving treatment

- NOTE: when a multi gated acquisition scan (MUGA) or echocardiogram cannot be
obtained due to weekend or holiday, then patients may be enrolled provided there
is no history of significant cardiovascular disease and a measurement of cardiac
ejection fraction will be performed within 5 days of study enrollment

- Patients with suspected central nervous system (CNS) involvement should undergo
lumbar puncture; those with documented CNS involvement will be excluded

- Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if
adequate number of circulating blasts (>10^9/l) from peripheral blood; this must be
done via E3903

- NOTE: SWOG/CTSU institutions: E3903 is not open at the CTSU; therefore, baseline
submissions must be submitted on E2906

- Patients who have received previous treatment for antecedent hematological disorders
(AHD) with 5-azacitidine, decitabine, or low dose cytarabine will be excluded

- Patients with known human immunodeficiency virus (HIV) infection are excluded

- HLA typing should be performed at registration, if possible

- Diagnostic bone marrow and peripheral blood specimens must be submitted for
immunophenotyping and selected molecular testing; this must be done via E2906

- NOTE: SWOG/CTSU institutions: E3903 is not open at the CTSU; therefore, baseline
submissions must be submitted on E2906

- CONSOLIDATION CRITERIA:

- NOTE: All patients achieving CR or complete remission with incomplete blood count
recovery (CRi) will receive consolidation when fit

- NOTE: Patients proceeding to transplant are allowed up to one cycle of consolidation
treatment

- Consolidation cycle 1 must commence within sixty days of the bone marrow aspirate and
biopsy that confirmed the presence of a CR or CRi

- Patients must have achieved a CR or CRi (or morphologic leukemia-free state for those
patients proceeding to Arm G transplant)

- Patients who have achieved a CR or CRi must have maintained peripheral blood evidence
of a CR or CRi

- Patients must have an ECOG performance status of 0-2

- Patients must have resolved any serious infectious complications related to induction

- NOTE: Patients with an HLA-matched donor and proceeding to transplant will be
allowed up to one cycle of consolidation treatment

- Any significant medical complications related to induction must have resolved

- Patients must have a creatinine and AST =< grade 1

- MAINTENANCE CRITERIA:

- Maintenance should commence within 60 days of recovery of peripheral blood counts
after consolidation cycle 2; patients must begin consolidation cycle 2 within 60 days
of recovery to be eligible for further therapy

- Patients must have maintained peripheral blood evidence of a remission and must have
a CR or CRi, confirmed on restaging bone marrow (BM) aspirate and biopsy and
cytogenetic analysis

- Patients must have an ECOG performance status of 0 -2

- Patients must have resolved any serious infectious complications related to
consolidation cycle 2

- Any significant medical complications related to consolidation cycle 2 must have
resolved

- Total serum bilirubin =< 1.5 x ULN

- NOTE: if total bilirubin is 2-3 mg/dL, but direct bilirubin is normal, then the
patient will be considered eligible

- Serum creatinine =< grade 1

- The absolute neutrophil count (ANC) must be > 1000 mm^3 prior to starting every cycle
of treatment with decitabine; decitabine may be delayed for up to 4 weeks between
cycles (i.e. may be administered as infrequently as every (q) 8 weeks) while waiting
for counts to recover

- The platelet count must be > 75,000 mm^3 prior to starting every cycle of treatment
with decitabine; decitabine may be delayed for up to 4 weeks between cycles (i.e. may
be administered as infrequently as every (q) 8 weeks) while waiting for counts to
recover

- ALLOGENEIC TRANSPLANTATION:

- Patients must be > 30 days and < 90 days from the start of induction or re-induction
chemotherapy, or > 30 days and < 90 days of recovery from consolidation cycle 1 (if
received), and must have achieved a response to induction therapy (CR, CRi, or
"morphologic disease-free state", documented > 27 days after start of most-recent
chemotherapy)

- Patients must have recovered from the effects of induction, re-induction, or
consolidation chemotherapy (all toxicities =< grade I with the exception of
reversible electrolyte abnormalities), and have no ongoing active infection requiring
treatment

- Patients must have a total serum bilirubin =< 1.5 x ULN (grade =< 1) and a serum
creatinine =< grade 1

- An eligible HLA-identical donor (either related or unrelated) should be available; in
sibling donors, low resolution HLA typing (A,B,DR) will be considered sufficient; in
the case of unrelated donors, high-resolution class I and II typing (A, B, C, DRB1
and DQ) should be matched at all 10 loci; donors must be willing and able to undergo
peripheral blood progenitor mobilization

- HLA-identical sibling (6/6): the donor must be determined to be an HLA-identical
sibling (6/6) by serologic typing for class (A, B) and low resolution molecular
typing for class II (DRB1)

- Matched unrelated donor (10/10): high resolution molecular typing at the
following loci is required: HLA-A, -B, -C, -DRBL, and -DQB1

- NOTE: for matched donors - will allow select 1 antigen mismatched sibling donors
and unrelated donors in accordance with site institutional standard, as long as
matched at HLA-A, HLA-B, HLA-C, and DRB1, and with advanced discussion/approval
by the Study Chair and the bone marrow transplant (BMT) co-chair

- Patients must be considered reliable enough to comply with the medication regimen and
follow-up, and have social support necessary to allow this compliance

- Patients must have a cardiac ejection fraction of >= 40%, or within institutional
normal limits; a nuclear medicine gated blood pool examination is preferred; a 2-D
ECHO scan is acceptable if a calculated ejection fraction is obtained and follow-up
measurement of the cardiac ejection fraction will also be performed by
echocardiography; measurement of cardiac ejection fraction should be within two weeks
prior to allogeneic transplantation

- Diffusion capacity of carbon monoxide (DLCO) > 40% with no symptomatic pulmonary
disease

- No known hypersensitivity to Escherichia (E.) coli-derived products

- No human immunodeficiency virus (HIV) infection; patients with immune dysfunction are
at a significantly higher risk of toxicities from intensive immunosuppressive
therapies

- Creatinine =< grade 1

- Bilirubin =< grade 1

- If bilirubin is 2-3 mg/dL, but direct bilirubin is normal then patient will be
considered eligible

- AST =< grade 1

Gender: Both
Steward Physician(s)
  • James Foran
Facilities
  • St. Elizabeth's Medical Center - Recruiting
Trial Interventions
Drug
  • clofarabine
  • daunorubicin hydrochloride
  • cytarabine
  • decitabine
Other
  • clinical observation
  • laboratory biomarker analysis
  • questionnaire administration
Procedure
  • quality-of-life assessment
For more information about this trial, contact

Uma Narayanasami

Phone: (617) 789-2903


Physician Researcher

Investigator Name:

  • James Foran

Other Information

Sponsor: Eastern Cooperative Oncology Group
Phase: Phase 3
Trial ID: NCT02085408
Volunteers:  Not Accepting Healthy Volunteers

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