A Phase 2 interventional study of alvocidib and daunorubicin hydrochloride in Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Minimally Differentiated Myeloid Leukemia (M0) and Adult Acute Monoblastic Leukemia (M5a), sponsored by National Cancer Institute (NCI). Completed at 11 sites in United States. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2017-07-31.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
This randomized phase II trial is studying how alvocidib, cytarabine, and mitoxantrone hydrochloride work compared to cytarabine and daunorubicin hydrochloride in treating patients with newly diagnosed acute myeloid leukemia. Alvocidib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, mitoxantrone hydrochloride, and daunorubicin hydrochloride work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving alvocidib, cytarabine, and mitoxantrone hydrochloride is more effective than giving cytarabine and daunorubicin hydrochloride in treating patients with acute myeloid leukemia.
PRIMARY OBJECTIVES:
I. To compare the rate of complete remission (CR) after 1 course of induction therapy with the timed-sequential combination of alvocidib (flavopiridol), cytarabine (cytosine arabinoside [ara-C]), and mitoxantrone hydrochloride (FLAM) vs traditional "7+3" cytarabine and daunorubicin hydrochloride (ara-C + Daunorubicin) for adults (age 18 to 70) with newly diagnosed, previously untreated, intermediate-risk or poor-risk acute myelogenous leukemia (AML).
SECONDARY OBJECTIVES:
I. To evaluate and compare the toxicities of FLAM vs 7+3. II. To compare the 2-year disease-free survival (DFS) and overall survival (OS) in response to FLAM vs 7+3.
III. To detect and compare the presence of minimal-residual disease (MRD) remaining after FLAM vs 7+3.
IV. To determine the expression of ABC transport proteins multidrug resistance 1 (MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) on AML blasts pretreatment and correlate the expressions of one or both proteins with CR and DFS in response to FLAM vs 7+3.
OUTLINE: This is a multicenter study. Patients are stratified according to risk features: age (\< 50 vs >= 50), secondary AML (pre-existing myelodysplatic syndrome [MDS], myeloproliferative diseases [MPD], treatment-related [t]-AML, or severe multi-lineage dysplasia) and/or known adverse cytogenetics, and hyperleukocytosis (white blood cells [WBC] >= 50,000/mm\^3). Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive alvocidib intravenously (IV) over 1 hour on days 1-3, cytarabine IV over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Patients who achieve complete or partial response to the first course (completion of all doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days following blood count recovery, and/or undergo allogeneic bone marrow transplant.
ARM II: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients who have residual disease on day 14 may receive additional cytarabine for 5 days and daunorubicin hydrochloride for 2 days. Patients may undergo blood and bone marrow collection for correlative studies.
After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 5 years, and then annually thereafter.
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Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-3
Newly diagnosed AML, subtypes M0, 1, 2, 4-7 but excluding M3 (APL), including those with the following poor risk features:
Patients who have received hydroxyurea alone or have received non-cytotoxic therapies previously for myelodysplasia (MDS) or myeloproliferative disorder (MPD) (e.g., thalidomide or lenalidomide, interferon, cytokines, 5-azacytidine or decitabine, histone deacetylase inhibitors, low-dose cyclophosphamide [cytoxan], tyrosine kinase [TK] or dual TK/src inhibitors) will be eligible for this trial
Exclusion Criteria:
Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Patients who achieve complete or partial response to the first course (completion of all doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days following blood count recovery, and/or undergo allogeneic bone marrow transplant.
Drug: alvocidib · Drug: mitoxantrone hydrochloride · Drug: cytarabine
Patients receive cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV on days 1-3. Patients who have residual disease on day 14 may receive additional cytarabine for 5 days and daunorubicin hydrochloride for 2 days.
Drug: daunorubicin hydrochloride · Drug: cytarabine
Given IV
Also known as: FLAVO, flavopiridol, HMR 1275, L-868275
Given IV
Also known as: Cerubidin, Cerubidine, daunomycin hydrochloride, daunorubicin, RP-13057
Given IV
Also known as: CL 232315, DHAD, DHAQ
Given IV
Also known as: ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside
Complete Response Rate
Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/cu mm and a platelet count of 100,000/cu mm, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. These criteria are taken from Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453-474
Time frame: 3 years
Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.
Time frame: Up to 14 days after completion of study treatment
Disease-free Survival
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated. Disease-free survival Overall survival was defined from date of randomization to death or last known follow-up. Event free survival was defined as date of randomization to the first occurrence of persistent AML after 1 cycle of induction, relapse or death. Patients were censored for event free survival if they had received non-protocol therapy or a stem cell transplant.
Time frame: Time from randomization until death from any cause or relapse or recurrence, assessed up to 2 years
Overall Survival
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
Time frame: 4 years
Number of Patients With Minimal Residual Disease
Comparisons of the treatments with respect to MRD will be based on the number of patients with MRD at day 14 after the start of treatment.
Time frame: From study start to 14 days after the start of treatment
Progression-free Survival
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
Time frame: 4 years
| Milestone | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) |
|---|---|---|
| Started | 114 | 58 |
| Completed | 109 | 56 |
| Not completed | 5 | 2 |
Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/cu mm and a platelet count of 100,000/cu mm, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. These criteria are taken from Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453-474
| participants | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) |
|---|---|---|
| Complete Response Rate | 76 | 24 |
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.
| Number of events | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) |
|---|---|---|
| Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade | 156 | 77 |
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated. Disease-free survival Overall survival was defined from date of randomization to death or last known follow-up. Event free survival was defined as date of randomization to the first occurrence of persistent AML after 1 cycle of induction, relapse or death. Patients were censored for event free survival if they had received non-protocol therapy or a stem cell transplant.
| years | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) |
|---|---|---|
| Disease-free Survival | 1.46 (1.06 to 2.11) | 1.85 (1.35 to 3.33) |
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
| years | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) |
|---|---|---|
| Overall Survival | 1.46 (0.09 to 2.12) | 1.850 (1.35 to 3.33) |
Comparisons of the treatments with respect to MRD will be based on the number of patients with MRD at day 14 after the start of treatment.
| Participants | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) |
|---|---|---|
| Number of Patients With Minimal Residual Disease | 26 | 24 |
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
| years | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) |
|---|---|---|
| Progression-free Survival | 0.81 (0.42 to 0.98) | 0.28 (0.11 to 1.11) |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | — | 53/114 (46.5%) | 32/114 (28.1%) |
| Arm II (Cytarabine, Daunorubicin Hydrochloride) | — | 21/58 (36.2%) | 21/58 (36.2%) |
| Event | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) |
|---|---|---|
| left ventricular systolic dysfunctionCardiac disorders | 5/114 | 0/58 |
| tumor lysis syndromeMetabolism and nutrition disorders | 4/114 | 1/58 |
| atrial fibrillationCardiac disorders | 1/114 | 2/58 |
| cytokine release syndromeImmune system disorders | 3/114 | 2/58 |
| hypophosphatemiaMetabolism and nutrition disorders | 2/114 | 2/58 |
| acute kidney injuryRenal and urinary disorders | 2/114 | 2/58 |
| Disseminated Intravascular CoagulationBlood and lymphatic system disorders | 2/114 | 1/58 |
| heart failureCardiac disorders | 2/114 | 0/58 |
| myocardial infarctionCardiac disorders | 2/114 | 0/58 |
| feverGeneral disorders | 2/114 | 0/58 |
| Event | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) |
|---|---|---|
| Febril eNeutropeniaBlood and lymphatic system disorders | 5/114 | 7/58 |
| mucositisGastrointestinal disorders | 1/114 | 3/58 |
| Tumor Lysis SyndromeMetabolism and nutrition disorders | 1/114 | 3/58 |
| SepsisInfections and infestations | 4/114 | 1/58 |
| Alanine aminotransferase increasedInvestigations | 4/114 | 0/58 |
| DiarrheaGastrointestinal disorders | 4/114 | 0/58 |
| Rash maculo-papularSkin and subcutaneous tissue disorders | 1/114 | 2/58 |
| Aspartate aminotransferase increasedInvestigations | 3/114 | 1/58 |
| Blood bilirubin increasedInvestigations | 3/114 | 0/58 |
| BacteremiaInfections and infestations | 2/114 | 0/58 |
| Age, Categorical(Participants) | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 79 | 43 | 122 |
| >=65 years | 35 | 15 | 50 |
| Sex: Female, Male(Participants) | Arm I (Alvocidib, Cytarabine, Mitoxantrone Hydrochloride) | Arm II (Cytarabine, Daunorubicin Hydrochloride) | Total |
|---|---|---|---|
| Female | 53 | 27 | 80 |
| Male | 61 | 31 | 92 |
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