RAD001(Everolimus) in Treating Patients With Myelodysplastic Syndromes

A Phase 2 Trial of RAD001(Everolimus) in Low and Intermediate-1 Risk Myelodysplastic Syndrome

RATIONALE: RAD001(Everolimus) may stop the growth of cancer cells by blocking some of the enzymes needed for their growth and by blocking blood flow to the cancer.

PURPOSE: This phase II trial is studying how well RAD001(everolimus) works in treating patients with myelodysplastic syndromes.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: everolimus; Other: laboratory biomarker analysis; Procedure: Bone marrow aspirate/biopsy

Detailed Description

OBJECTIVES:

Primary

• Determine the clinical activity (improvement in erythroid response and/or improvement in other cytopenias, bone marrow morphology/cytogenetics) of RAD001(everolimus) in patients with low or intermediate-1 risk myelodysplastic syndromes.
• Assess the toxicity of this drug in these patients.

Secondary

• Examine laboratory correlates (S6K1 levels, angiogenesis pre- and post-treatment) and determine how these correlates correspond to dosing and clinical activity of RAD001(everolimus).
• Evaluate the presence of HLA-DR15 and cytotoxic T-cell populations in patients pre- and post-treatment and correlate this with response to treatment.
• Examine the incidence of the null GSTT-1 phenotype in myelodysplastic syndromes patients and correlate this with response to RAD001(everolimus).

OUTLINE: Patients receive oral RAD001(everolimus) once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or relapse.

Blood samples are collected periodically during study. Samples are analyzed for S6K1 activity, effector T cells by flow cytometry, GSTT-1 by PCR, and HLA-DR15 levels.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Low or intermediate-1 risk myelodysplastic syndromes by International Prognostic Scoring System (IPSS) criteria

  • IPSS score < 1.5
• Requiring transfusion of 2 units of red blood cells at least once a month (four weeks prior to accrual on study)

• High levels of endogenous epoetin alfa (i.e., > 200 mU/mL)

  • Unlikely to respond to epoetin alfa, or has a documented clinical non-response to epoetin alfa (at a dose of ≥ 40,000 U weekly) or darbepoetin alfa (at a dose > 200 mcg every other week) (i.e., < 2 g/dL increase in hemoglobin and no decrease in transfusion requirements after at least 4 weeks of treatment)
• No chronic myelomonocytic leukemia

PATIENT CHARACTERISTICS:

• ECOG Performance Status of 0-2
• Liver enzymes (AST and ALT) and total bilirubin ≤ 2 times upper limit of normal
• Serum creatinine ≤ 2 times upper limits of normal
• No clinically significant anemia due to iron, B12, or folate deficiencies; autoimmune or hereditary hemolysis; or gastrointestinal bleeding
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other serious or poorly controlled medical condition that could be exacerbated by or complicate compliance with study therapy

PRIOR CONCURRENT THERAPY:

• At least 4 weeks since prior treatment (including growth factors)
• No chronic use (> 2 weeks) of physiologic doses of a corticosteroid agent (dose equivalent to > 10 mg/day of prednisone) within 28 days of the first day of study drug
• No concurrent use of another investigational agent
• No concurrent therapy with any cytotoxic drugs, steroids, or growth factors

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: RAD001 (everolimus); RAD001 (everolimus) at 10mg/day with Bone marrow aspirate/biopsy and other laboratory biomarker analysis

Drug: everolimus; Patients will receive monotherapy with RAD001(everolimus)for 21 days within the 28 day cycle.; Other Names: RAD001; Other: laboratory biomarker analysis; Laboratory correlates (cytotoxic t cell populations, S6K1 levels, GSTT-1 mutations, and the presence or absence of HLA-DR15) will be assessed to see if any of these correlates correspond to response.; Procedure: Bone marrow aspirate/biopsy; Bone marrow aspirate and biopsy with cytogenetics should be obtained within 4 weeks prior to starting drug and at week 33. A bone marrow aspirate and biopsy should also be obtained for patients going off study prior to week 33 (including cytogenetics). The percentage of blasts on the aspirate should be used to determine the IPSS score.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Either a Major or Minor Erythroid Response (Hemoglobin Change From Baseline Measure)	Major erythroid response: (1) For patients with a baseline hemoglobin less than 11 g/dL, a major erythroid response is defined as a > 2 g/dL increase in hemoglobin from baseline; or (2) 100% decrease in red blood cell transfusion requirements. Minor erythroid response: (1) For patients with baseline hemoglobin less than 11 g/dL, a minor erythroid response is defined as an increase in hemoglobin greater than 1 g/dL but less than 2 g/dL from baseline; or (2) > 50% decrease in red blood cell transfusion requirements.	2 years of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Dose- and Non-dose-limiting Toxicities	Number of Dose- and Non-dose-limiting Toxicities at the end of cycle 1 associated with RAD001 (see AE/SAE section for details).	at end of one cycle (28 days)
Number of Participants With Bone Marrow Morphology and Cytogenetics Pre- and Post-therapy	Number of Participants with change in bone marrow morphology and cytogenetics	at 2 years of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Laboratory Correlates (Cytotoxic T-cell Populations, S6K1 Levels, GSTT-1 Mutations, and Presence or Absence of HLA-DR15)	T-cell populations in patients pre- and post-treatment	at 2 years of treatment

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Anjali Advani, MD, Cleveland Clinic Taussig Cancer Center, Case Comprehensive Cancer Center

Publications and helpful links

General Publications

• Advani AS, Mahfouz RZ, Maciejewski J, Rybicki L, Sekeres M, Tripp B, Kalaycio M, Bates J, Saunthararajah Y. Ribosomal S6 kinase and AKT phosphorylation as pharmacodynamic biomarkers in patients with myelodysplastic syndrome treated with RAD001. Clin Lymphoma Myeloma Leuk. 2014 Apr;14(2):172-177.e1. doi: 10.1016/j.clml.2013.10.001. Epub 2013 Nov 11.

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (Actual): February 1, 2009
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: December 16, 2008
• First Submitted That Met QC Criteria: December 16, 2008
• First Posted (Estimate): December 17, 2008

Study Record Updates

• Last Update Posted (Actual): March 7, 2019
• Last Update Submitted That Met QC Criteria: February 25, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: CASE1905 (Other Identifier: Case Comprehensive Cancer Center); P30CA043703 (U.S. NIH Grant/Contract); CASE-CCF-8514 (Other Identifier: Cleveland Clinic IRB)