A Trial to Evaluate Two Schedules of MS275 in Combination With 5AC in Elderly Patients With Acute Myeloid Leukemia (AML)

NCT01305499 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: CASE291415-851
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 4

Brief Summary

This research is being done to help us learn how to best use new drugs which may be active against acute myeloid leukemia (AML). Two study drugs will be tested: 5AC (5-azacitidine) and entinostat. 5AC improves blood counts in 50 - 60% of patients with MDS and has also shown promise in AML. Entinostat has undergone early testing in patients with MDS and AML. It has decreased the blast count in some patients' blood and bone marrow and has improved the blood counts in some patients. The combinations of these two classes of drugs are well tolerated and appear to work well together in laboratory tests. A recent study at Johns Hopkins University administered 5AC and entinostat in an overlapping schedule to patients with myelodysplastic syndrome (MDS), Chronic myelomonocytic leukemia (CMMoL), and AML. The impressive results from this study have led to another phase II trial to further examine this drug combination versus 5AC alone in these patients. In this study, we want to see how the timing of when 5AC and entinostat are given affects the magnitude of the disease response.

Conditions

Acute Myeloid Leukemia

Keywords

AML

Outcome Measures

Primary Outcomes (2)

• To estimate the major response rate in patients with AML who are ≥ 60 years old and unable to tolerate or decline cytotoxic chemotherapy or patients who have relapsed despite one prior regimen.

  Up to 15 cycles (420 days)

• To estimate the overall response rate following treatment in patients with AML ≥ 60 years old who are unable to tolerate or decline cytotoxic chemotherapy or those who have relapsed despite one prior regimen.

  Up to 15 cycles (420 days)

Secondary Outcomes (5)

• To identify changes in gene promoter methylation and gene expression in response to combination therapy and compare the dynamics and kinetics of these alterations in promoter methylation and gene re-expression in the two different dosing schedules.

  Up to 15 cycles (420 days)

• To evaluate the effect of entinostat on the induction of hyperacetylation of histones from peripheral blood and/or bone marrow samples.

  Up to 15 cycles (420 days)

• To evaluate changes in DNA damage in response to combination therapy using gammaH2AX determination by western blotting.

  Up to 15 cycles (420 days)

• To evaluate the pharmacodynamics of 5AC and entinostat when given at either dosing schedule and to evaluate these in relation to pharmacokinetic and clinical outcomes.

  Up to 15 cycles (420 days)

• To evaluate duration of response.

  Up to 15 cycles (420 days)

Study Arms (2)

A: 5AC days 1-10 / entinostat days 3, 10

EXPERIMENTAL

Arm A will be given an overlapping schedule of drugs with 5AC given at 50mg/m2 subcutaneously daily for 10 days on days 1 - 10 of a 28 day cycle and entinostat given at a flat dose of 8 mg orally on days 3 and 10.

Drug: Entinostat days 3, 10; Drug: 5AC

B: 5AC days 1-10 / entinostat days 10,17

EXPERIMENTAL

In Arm B the agents will be administered sequentially with 5AC given at 50mg/m2 subcutaneously daily for 10 days on days 1 - 10 of a 28 day cycle followed by entinostat at a 8 mg flat dose on days 10 and 17.

Drug: 5AC; Drug: Entinostat days 10,17

Interventions

Entinostat days 3, 10 DRUG

Given orally on days 3, 10

Also known as: MS275

A: 5AC days 1-10 / entinostat days 3, 10

5AC DRUG

Also known as: 5-azacitidine

A: 5AC days 1-10 / entinostat days 3, 10; B: 5AC days 1-10 / entinostat days 10,17

Entinostat days 10,17 DRUG

Given orally on days 10, 17

Also known as: MS275

B: 5AC days 1-10 / entinostat days 10,17

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• One of the following:
• Untreated AML in (de novo or treatment related) patients in the following categories:
• Medical conditions that compromise the ability to give cytotoxic chemotherapy as the primary modality.
• Patients who decline cytotoxic chemotherapy.
• Patients with AML who have relapsed despite one prior regimen
• ECOG performance status 0, 1, or 2
• Patients must not have untreated active infections at the time of study entry.
• Normal organ function as defined below:
• Creatinine \< 2 mg/dl.
• Total serum bilirubin within institutional limits unless due to hemolysis, Gilbert's syndrome, or ineffective erythropoiesis.
• AST(SGOT)/ALT(SGPT) ≤2.5 X institutional upper limit of normal.
• Life expectancy of at least three months.
• Patients must be informed of the investigational nature of the treatment, results that might be expected, and potential toxicities. They must be able to understand and give informed written consent according to federal and institutional guidelines.
• Declined or ineligible for potentially curative options such as allogeneic stem cell transplant.
• No chemotherapy or study drugs for \>3 weeks prior to starting study.

You may not qualify if:

• Any of the Following:
• Treatment for acute myeloid leukemia (AML), including hematopoietic growth factors, \< 3 weeks prior to study registration. Exception: Hydroxyurea may be administered to patients with WBC \> 30,000/µL
• Diagnosis of acute promyelocytic leukemia (APL)
• Radiotherapy \< 4 weeks prior to study registration
• Failure to recover (to \< grade 1) from all adverse events associated with prior therapy.
• Valproic acid \< 2 weeks prior to study registration.
• Hypersensitivity to azacytidine, deoxyazacytidine, mannitol, entinostat or components of the entinostat tablet
• Any advanced malignant hepatic tumor(s)
• Prior therapy with demethylating agents for leukemia treatment within the last four months.
• Clinical evidence of CNS or pulmonary leukostasis, disseminated intravascular coagulation, or central nervous system leukemia.
• Serious or uncontrolled medical conditions.
• Concurrent use of any other investigational agents.
• Known HIV-positive patients.
• Pregnancy or breast feeding
• Male and female patients who are fertile who do not agree to use an effective barrier methods of birth control (i.e. abstinence) to avoid pregnancy during the study and for a minimum of 30 days after study treatment.

Sponsors & Collaborators

• Hetty Carraway: lead

Study Sites (4)

Yale School of Medicine

New Haven, Connecticut, 06520, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44195, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Hetty Carraway, MD

  Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, MBA

Study Record Dates

• First Submitted: February 25, 2011
• First Posted: February 28, 2011
• Study Start: July 1, 2011
• Primary Completion: September 30, 2021
• Study Completion: September 30, 2024
• Last Updated: May 28, 2024

Record last verified: 2024-05

Locations

US (4)