Phase II Trial of Alisertib With Induction Chemotherapy in High-risk AML

NCT02560025 | Completed Phase 2 Results DMC

• 1 other identifier: 15-334
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 2

Brief Summary

This research study is studying a targeted therapy (a form of treatment that uses drugs or other substances to identify and attack specific types of cancer cells with less harm to normal cells) as a possible treatment for high-risk acute myeloid leukemia. The names of the study interventions involved in this study are:

• Alisertib / MLN8237
• Cytarabine / Cytosine Arabinoside
• Idarubicin / Idarubicin hydrochloride
• Daunorubicin (Can be used in place of idarubicin)

Conditions

Acute Myeloid Leukemia

Keywords

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Number of Participants That Achieved Complete Remission

  The number of participants that achieved a best overall response of complete remission while on study. Complete remission (CR): Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/μL and a platelet count of 100,000/μL, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, existing extramedullary disease. If possible, at least one bone marrow biopsy should be performed to confirm CR.

  From the start of treatment until the end of study treatment, up to approximately 10 months

• Number of Participants That Achieved Complete Remission With Incomplete Blood Count Recovery (CRi)

  The number of participants that achieved a best overall response of CRi while on study. Complete Remission with Incomplete Blood Count Recovery (CRi): Same as for CR but without achievement of ANC at least 1000/uL (CRi) and/or platelet count of 100,000/uL (CRp).

  From the start of treatment until the end of study treatment, up to approximately 10 months

Secondary Outcomes (4)

• 1 Year Overall Survival Rate

  1 Year

• Median Relapse Free Survival

  From the time of treatment response until death or disease progression (up to about one year)

• Median Duration of Remission

  From the time of first remission to disease progression or death, median duration of 12.8 months

• Number of Participants With Serious Adverse Events

  From the start of treatment until 30 days after the last dose of a study drug is received, up to approximately 11 months

Study Arms (1)

Alisertib / MLN8237

EXPERIMENTAL

Participants will initially receive 7+3 induction chemotherapy, consisting of cytarabine and concurrent idarubicin (or daunorubicin if appropriate). Oral alisertib, at 30mg twice daily, will begin on day 8, and will continue for 7 days. During induction, patients with residual disease at day 14 may have re-induction with "5+2" chemotherapy, but will not receive additional dosing of alisertib at that time. Following count recovery after induction, if patients proceed to consolidative cycles of therapy with cytarabine, they will receive alisertib at day 6 following conclusion of cytarabine administration. Upon count recovery following consolidation, alisertib will be resumed for 7 days, followed by 14 days off, and will be continued as 21-day cycles of maintenance, for up to 12 cycles.

Drug: Alisertib; Drug: Cytarabine; Drug: Idarubicin; Drug: Daunorubicin

Interventions

Alisertib DRUG

Also known as: MLN8237

Alisertib / MLN8237

Cytarabine DRUG

Also known as: Cytosine Arabinoside

Alisertib / MLN8237

Idarubicin DRUG

Also known as: Idarubicin hydrochloride

Alisertib / MLN8237

Daunorubicin DRUG

Can be used in place of idarubicin

Also known as: Cerubidine®

Alisertib / MLN8237

Eligibility Criteria

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

You may qualify if:

• Participants must have pathologically confirmed, newly diagnosed high-risk acute myeloid leukemia, as defined by at least one of the following criteria
• Age greater than or equal to 65 years
• Poor risk karyotype, as per Leukemianet criteria
• Antecedent or underlying myelodysplastic syndrome or myeloproliferative neoplasm
• AML with MDS-related changes
• Adults, age 18 years or older at the time of diagnosis, eligible for standard induction chemotherapy according to their treating physician.
• ECOG performance status 0-2 (Karnofsky ≥60%, see Appendix A)
• Left ventricular ejection fraction \> 50% as measured by echocardiogram or MUGA scan
• Must not have received systemic antineoplastic therapy including radiation therapy within 14 days of the study enrollment, except hydroxyurea or 6-mercaptopurine for the purposes of cytoreduction. Patients may also have received all-trans retinoic acid (ATRA) if there is an early suspicion of acute promyelocytic leukemia (APL, M3-AML), although if confirmed to have APL these patients will be excluded from the study.
• Adequate renal function as defined by: calculated creatinine clearance ≥40 mL/min (Cockcroft-Gualt Formula)
• Direct bilirubin \< 2.0 x upper limit of normal (ULN), SGOT (AST) and SGPT (ALT)\< 2.5 x ULN. AST and/or ALT may be up to 5X ULN if thought to be secondary to leukemia.
• The effects of alisertib on the developing human fetus are unknown. For this reason and because other chemotherapeutic agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation, and 6 months after completion of therapy.
• Subject must be able to take oral medication and to maintain a fast as required for 2 hours before and 1 hour after alisertib administration.
• Ability to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• Patients will be excluded from this study if they do not otherwise fulfill criteria mentioned in bullet 3.1.1, and are found to harbor "intermediate" or "favorable" risk cytogenetics 41:
• In such patients, a sample to evaluate patient cytogenetics will be sent at the time of diagnosis per standard clinical care and the absence of favorable or intermediate-risk cytogenetics must be confirmed by Day 8. If the cytogenetic analysis reveals that the patient harbors non-poor risk cytogenetics, or if the cytogenetic results are not received prior to Day 8, the participant will be removed from the study.
• Patients with acute bilineal/biphenotypic leukemia
• Participants who have had chemotherapy or radiotherapy within 14 days prior to entering the study, except for hydroxyurea or 6-MP as noted.
• Participants who are receiving or have received any other investigational agents within 14 days of enrollment.
• Chemo-, hormono-, radio- or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug
• Persistence of clinically relevant therapy related toxicity from previous anti-cancer therapy
• Prior allogeneic bone marrow or organ transplantation
• Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
• Current clinical central nervous system (CNS) symptoms deemed by the investigator to be related to leukemic CNS involvement (no lumbar puncture required, clinical assessment per investigator's judgment is sufficient).
• If applicable, patient with ≥Grade 2 peripheral neuropathy within 14 days before enrollment
• Prior treatment with alisertib
• Known history of hepatitis C infection or suspected currently active hepatitis C infection. Known or suspected history of hepatitis B infection will be excluded when any of the following conditions are met:
• Received hematopoietic stem cell transplantation (either allogenic or autologous), or
• Received any rituximab-containing treatment regimen in the last 12 months before entering the study, or

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Takeda: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Brunner AM, Blonquist TM, DeAngelo DJ, McMasters M, Fell G, Hermance NM, Winer ES, Lindsley RC, Hobbs GS, Amrein PC, Hock HR, Steensma DP, Garcia JS, Luskin MR, Stone RM, Ballen KK, Rosenblatt J, Avigan D, Nahas MR, Mendez LM, McAfee SL, Moran JA, Bergeron M, Foster J, Bertoli C, Manning AL, McGregor KL, Fishman KM, Kuo FC, Baltay MT, Macrae M, Burke M, Behnan T, Wey MC, Som TT, Ramos AY, Rae J, Lombardi Story J, Nelson N, Logan E, Connolly C, Neuberg DS, Chen YB, Graubert TA, Fathi AT. Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial. Lancet Haematol. 2020 Feb;7(2):e122-e133. doi: 10.1016/S2352-3026(19)30203-0. Epub 2019 Dec 11.

  PMID: 31837959 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

MLN 8237; Cytarabine; Idarubicin; Daunorubicin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Results Point of Contact

• Title: Amir Fathi, MD
• Organization: Massachusetts General Hospital

AFATHI@mgh.harvard.edu

617-724-1124

Study Officials

• Amir Fathi, MD

  Massachusetts General Hospital

  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: Principal Investigator

Study Record Dates

• First Submitted: September 23, 2015
• First Posted: September 25, 2015
• Study Start: December 1, 2015
• Primary Completion: October 1, 2017
• Study Completion: December 1, 2018
• Last Updated: May 5, 2020
• Results First Posted: October 11, 2018

Record last verified: 2020-04

Locations

US (2)