Study of Idarubicin, Cytarabine, and Nivolumab in Patients With High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

NCT02464657 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 2014-0907NCI-2015-01258
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical research study is to find the highest tolerable dose of nivolumab that can be give in combination with idarubicin and cytarabine in patients with MDS and AML. The safety and effectiveness of this drug combination will also be studied. This is an investigational study. Nivolumab is not FDA-approved or commercially available. Idarubicin is FDA-approved and commercially available for the treatment of patients with AML. Cytarabine is FDA approved and commercially available for treatment of patient with AML. The use of these drugs in combination is investigational. The study doctor can explain how the drugs are designed to work. Up to 75 patients will take part in this study. All will be enrolled at MD Anderson.

Conditions

Leukemia; Acute Myeloid Leukemia; Myelodysplastic Syndrome

Keywords

Leukemia; Acute myeloid leukemia; AML; Myelodysplastic Syndrome; MDS; High-risk; Nivolumab; BMS-936558; Opdivo; Idarubicin; Idamycin; Cytarabine; Ara-C; Cytosar; DepoCyt; Cytosine Arabinosine Hydrochloride; Solu-Medrol; Methylprednisolone; Depo-Medrol; Medrol; Dexamethasone; Decadron

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) of Nivolumab

  MTD is highest dose level in which \<2 patients of 6 develop first cycle dose-limiting toxicity (DLT).

  28 days

Secondary Outcomes (3)

• Event-Free Survival (EFS)

  56 days

• Relapse Free Survival

  Up to 2 years and10 Months

• Overall Survival

  Up to 2 years and 10 Months

Study Arms (3)

Ph 1 Nivolumab (1mg) + Idarubicin + Cytarabine

EXPERIMENTAL

Phase I dose of Nivolumab 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.

Drug: Nivolumab; Drug: Idarubicin; Drug: Cytarabine; Drug: Solu-medrol; Drug: Dexamethasone

Ph 1 Nivolumab (3 mg) + Idarubicin + Cytarabine

EXPERIMENTAL

Phase I dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.

Drug: Nivolumab; Drug: Idarubicin; Drug: Cytarabine; Drug: Solu-medrol; Drug: Dexamethasone

Ph 2 Nivolumab (3 mg) + Idarubicin + Cytarabine

EXPERIMENTAL

Phase II dose of Nivolumab 3 mg/kg by vein on Day 24 of a 28 day cycle. Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle. Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle. Phase I and Phase II dose of Solumedrol 50 mg or Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.

Drug: Nivolumab; Drug: Idarubicin; Drug: Cytarabine; Drug: Solu-medrol; Drug: Dexamethasone

Interventions

Nivolumab DRUG

Phase I Starting Dose of Nivolumab: 1 mg/kg by vein on Day 24 of a 28 day cycle. Phase II Starting Dose of Nivolumab: Maximum tolerated dose from Phase I.

Also known as: BMS-936558, Opdivo

Ph 1 Nivolumab (1mg) + Idarubicin + Cytarabine; Ph 1 Nivolumab (3 mg) + Idarubicin + Cytarabine; Ph 2 Nivolumab (3 mg) + Idarubicin + Cytarabine

Idarubicin DRUG

Phase I and Phase II dose of Idarubicin 12 mg/m2 by vein daily for 3 on Days 1 - 3 of a 28 day cycle.

Also known as: Idamycin

Ph 1 Nivolumab (1mg) + Idarubicin + Cytarabine; Ph 1 Nivolumab (3 mg) + Idarubicin + Cytarabine; Ph 2 Nivolumab (3 mg) + Idarubicin + Cytarabine

Cytarabine DRUG

Phase I and Phase II dose of Cytarabine (Ara-C) 1.5 g/m2 by vein daily on Days 1 - 4 of a 28 day cycle.

Also known as: Ara-C, Cytosar, DepoCyt, Cytosine Arabinosine Hydrochloride

Ph 1 Nivolumab (1mg) + Idarubicin + Cytarabine; Ph 1 Nivolumab (3 mg) + Idarubicin + Cytarabine; Ph 2 Nivolumab (3 mg) + Idarubicin + Cytarabine

Solu-medrol DRUG

Phase I and Phase II dose of Solu-medrol 50 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.

Also known as: Methylprednisolone, Depo-Medrol, Medrol

Ph 1 Nivolumab (1mg) + Idarubicin + Cytarabine; Ph 1 Nivolumab (3 mg) + Idarubicin + Cytarabine; Ph 2 Nivolumab (3 mg) + Idarubicin + Cytarabine

Dexamethasone DRUG

Phase I and Phase II dose of Dexamethasone 10 mg by vein daily for 3 - 4 days with Ara-C on Days 1 - 4 of a 28 day cycle.

Also known as: Decadron

Ph 1 Nivolumab (1mg) + Idarubicin + Cytarabine; Ph 1 Nivolumab (3 mg) + Idarubicin + Cytarabine; Ph 2 Nivolumab (3 mg) + Idarubicin + Cytarabine

Eligibility Criteria

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

You may qualify if:

• Diagnosis of 1) AML (WHO classification definition of \>/= 20% blasts), or 2) high risk MDS (defined as the presence of 10% blasts).
• Patients aged 18 to 60 years are eligible. Patients older than 60 who are deemed fit to receive intensive chemotherapy by the treating physician are eligible after discussion with the PI.
• In the Phase I portion, patients with relapsed or refractory AML/MDS are also eligible, as per the treating physician's discretion.
• For the Phase II portion of the study, patients must be chemo-naive, i.e. not have received any prior chemotherapy (except hydrea or one dose of ara-C \</= 2g) for AML or MDS. They could have received hypomethylator agents, transfusions, hematopoietic growth factors or vitamins. Temporary prior measures such as apheresis or hydrea or one dose of ara-C \</= 2g in order to safely control hyperleucocytosis prior to enrollment.
• Serum biochemical values with the following limits unless considered due to leukemia: ---Creatinine \</= 1.5 mg/dl --- total bilirubin \</= 1.5 mg/dL, unless increase is due to hemolysis or congenital disorder --- transaminases (SG PT) \</= 2.5 x upper limit of normal (ULN).
• Ability to take oral medication.
• Ability to understand and provide signed informed consent.
• Baseline test of ejection fraction must be \>/= 50%.
• Performance status \< 3, unless directly related to disease process as determined by the Principal Investigator.

You may not qualify if:

• Subjects with APL.
• Any coexisting medical condition that in the judgment of the treating physician is likely to interfere with study procedures or results.
• Nursing women, women of childbearing potential with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (such as birth control pills, IUD, diaphragm, abstinence, or condoms by their partner) over the entire course of the study. --- Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. --- Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab. --- Women must not be breastfeeding.
• Continued:Men who are sexually active with WOCBP must use acceptable birth control methods. Acceptable birth control methods include: oral or injectable hormonal birth control, intrauterine devices(IUDS), and double barrier methods (for example a condom in combination with spermicide). Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception.
• Cardiac disease: Congestive heart failure \> class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
• History of cardiac ventricular arrhythmias requiring anti-arrhythmic therapy within past 3 months.
• Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
• Pulmonary hemorrhage/bleeding event \> CTCAE Grade 2 within 4 weeks of first dose of study drug.
• Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.
• Active clinically serious and uncontrolled infection \> CTCAE Grade 2 uncontrolled with antibiotics.
• Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Patients should be excluded if they are known to be positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
• Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• History of allergy to study drug components.
• Prior immune checkpoint targeting drugs (e.g., anti PD1, and PDL1, anti-kir, anti CD137...etc)

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Ravandi F, Assi R, Daver N, Benton CB, Kadia T, Thompson PA, Borthakur G, Alvarado Y, Jabbour EJ, Konopleva M, Takahashi K, Kornblau S, DiNardo CD, Estrov Z, Flores W, Basu S, Allison J, Sharma P, Pierce S, Pike A, Cortes JE, Garcia-Manero G, Kantarjian HM. Idarubicin, cytarabine, and nivolumab in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a single-arm, phase 2 study. Lancet Haematol. 2019 Sep;6(9):e480-e488. doi: 10.1016/S2352-3026(19)30114-0. Epub 2019 Aug 7.

  PMID: 31400961 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Leukemia; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Nivolumab; Idarubicin; Cytarabine; Methylprednisolone Hemisuccinate; Methylprednisolone; Methylprednisolone Acetate; Dexamethasone; Calcium Dobesilate

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Dr. Farhad Ravandi-Kashani, MD/Professor
• Organization: The University of Texas MD Anderson Cancer Center

fravandi@mdanderson.org

(713)745-0394

Study Officials

• Farhad Ravandi-Kashani, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 3, 2015
• First Posted: June 8, 2015
• Study Start: July 1, 2015
• Primary Completion: May 7, 2020
• Study Completion: May 7, 2020
• Last Updated: October 7, 2021
• Results First Posted: October 7, 2021

Record last verified: 2021-09

Locations

US (1)