Sirolimus and Cyclosporine for Treatment-Resistant Aplastic Anemia

A Phase I/II Trial of Sirolimus (Rapamune) and Cyclosporine in Patients With Refractory Aplastic Anemia

Aplastic anemia is a rare autoimmune disorder in which the bone marrow production of blood cells is greatly decreased or absent. Symptoms include fatigue, weakness, tiny reddish-purple marks on the skin, abnormal bruising, and bleeding from the gums, nose, or intestine. While some cases of aplastic anemia are caused by medications, toxic exposures, or inherited genes, most often the cause remains unknown. The purpose of this study is to determine the safety and efficacy of combining two drugs, sirolimus and cyclosporine, for treating individuals with aplastic anemia that has not responded to other treatments.

Study Overview

• Status: Unknown
• Conditions: Anemia, Aplastic
• Intervention / Treatment: Drug: Sirolimus; Drug: Cyclosporine

Detailed Description

The most successful treatment for aplastic anemia is bone marrow transplantation. However, few patients are eligible for this procedure. For others, treatment usually consists of immunosuppressive agents, such as antithymocyte globulin (ATG) and cyclosporine. Unfortunately, even with immunosuppressive therapy, relapse is common. New combinations of medications may offer alternative and more effective treatment options. Sirolimus and cyclosporine are two drugs routinely used to suppress the immune system and prevent rejection in patients who have received organ transplants. While cyclosporine has been proven effective for treating aplastic anemia, sirolimus has not been tested for this disease. This study will evaluate the safety and efficacy of sirolimus in combination with cyclosporine for treating individuals with aplastic anemia that has not responded to other treatments.

This study will last at least 6 months. Participants will first be screened to verify diagnosis of aplastic anemia. The screening will include a physical examination, blood test, bone marrow biopsy from the pelvic bone, and review of medications and medical history. Individuals who are eligible will then start the first treatment period. Participants will receive two medications: cyclosporine will be taken twice a day and sirolimus will be taken once a day. Depending on side effects, the doses of either drug may be temporarily stopped or lowered. On Day 1, blood will be drawn and females will undergo a pregnancy test. Subsequent study visits will occur weekly for the first month, every 2 weeks for 2 months, and then once a month for the remainder of the study. Each visit will include a physical examination, vital sign assessment, and review of side effects and medications. Blood tests will be performed weekly for the first 3 weeks, and then every 2 weeks.

After 6 months of treatment, if a participant has shown improvements in disease status without major side effects, the treatment will continue. Over time the doses may be lowered. If a participant has not improved while on the study medication, treatment will stop at 6 months. Whenever treatment is discontinued, the participant will again undergo a physical examination, blood tests, and bone marrow biopsy.

• Study Type: Interventional
• Enrollment (Anticipated): 52
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Lynn Tihopu; Phone Number: 310-794-0738
• Study Contact Backup: Name: Meenal Chalukya; Phone Number: 310-825-8091

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • UCLA Center for Health Sciences
      • Contact: Ronald Paquette, MD; Phone Number: 310-206-5755; Email: paquette@ucla.edu
  • Florida
    • Tampa, Florida, United States, 33606
      • Recruiting
      • Lee Moffitt Cancer Center
      • Contact: Alan List, MD
      • Principal Investigator: Hussain Saba, MD
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Taussig Cancer Center, Cleveland Clinic Foundation
      • Contact: Jaroslaw P. Maciejewski, MD
      • Principal Investigator: Jaroslaw P. Maciejewski, MD
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Recruiting
      • Penn State University Cancer Center
      • Contact: Thomas Loughran, MD
      • Principal Investigator: Thomas Loughran, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of moderate or severe aplastic anemia with bone marrow cellularity of less than 25%

• Falls within one of the following descriptions at the time of the original diagnosis:

  1. For severe aplastic anemia, fulfills any two of the following three criteria: absolute neutrophil count less than 500/uL; absolute reticulocyte count less than 60,000/uL; and platelet count less than 20,000/uL
  2. For moderate aplastic anemia, fulfills any two of the following three criteria: absolute neutrophil count less than 1200/ul; hemoglobin less than 8 g/dL with corrected reticulocyte count less than 1%; and platelet count less than 60,000/uL (Note: Participants who have progressed from moderate to severe aplastic anemia prior to study entry will be classified as having severe aplastic anemia)
• Diagnosis of refractory aplastic anemia, as defined by a failure to achieve at least a partial response to ATG within 6 months of treatment. Individuals who had a prior response to ATG but who have relapsed and not responded to salvage ATG are eligible. Individuals with relapsed disease who are not candidates for salvage ATG because they experienced a serious or life-threatening complication prior to ATG are also eligible.
• A Karnofsky performance status of at least 60%
• Adequate organ function, as defined by creatine levels less than 1.5 times the upper limit normal (ULN), and liver function tests (AST, bilirubin) less than 2 times the ULN
• Women of childbearing age must be willing to use effective contraception throughout the study

Exclusion Criteria:

• Received ATG treatment less than 6 months prior to study entry
• Candidate for related allogeneic stem cell transplantation
• Active uncontrolled infection
• History of myelodysplastic syndrome or bone marrow cytogenetic abnormalities
• History of Fanconi's anemia or other congenital form of aplastic anemia
• Treatment with an investigational agent within 1 month of study entry
• HIV infection
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: 1; Participants will be treated with sirolimus and cyclosporine. In phase I, each dose cohort will initially enroll three patients. If no dose-limiting toxicity (DLT) is observed by Day 28 in any patient of a cohort, then 3 patients will be treated with the next highest sirolimus dose. If 1 out of 3 patients in any cohort experiences a DLT, then 3 more patients will be enrolled in that cohort. If no more patients have a DLT by Day 28, then sirolimus dose escalation will proceed. If one or more patients experience a DLT then that dose level will be considered to be the maximum tolerated sirolimus dose, and Phase II patients will be treated at the next lowest level. Cyclosporine will be given as a twice daily oral dose.

Drug: Sirolimus; Oral loading dose followed by a once daily dose: Cohort 1: Loading Dose - 1.2 mg; Daily Dose - 0.4 mg; Cohort 2: % Dose Increase - 100%; Loading Dose - 2.4 mg; Daily Dose - 0.8 mg; Cohort 3: % Dose Increase - 67%; Loading Dose - 3.9 mg; Daily Dose - 1.3 mg; Cohort 4: % Dose Increase - 50%; Loading Dose - 6.0 mg; Daily Dose - 2.0 mg; Drug: Cyclosporine; Dose of 5 mg/kg divided as a twice daily oral dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability of sirolimus and cyclosporine in each stratum of participants	Measured at Month 6

Secondary Outcome Measures

Outcome Measure	Time Frame
Response rate	Measured at Months 3 and 6
Duration of hematologic response	Measured at Month 6
Rate of clonal disease evolution	Measured at Month 6
Survival	Measured at Month 6

Collaborators and Investigators

• Sponsor: Office of Rare Diseases (ORD)
• Collaborators: Rare Diseases Clinical Research Network

Publications and helpful links

General Publications

• Maciejewski JP, Risitano AM. Aplastic anemia: management of adult patients. Hematology Am Soc Hematol Educ Program. 2005:110-7. doi: 10.1182/asheducation-2005.1.110.
• Young NS. Immunosuppressive treatment of acquired aplastic anemia and immune-mediated bone marrow failure syndromes. Int J Hematol. 2002 Feb;75(2):129-40. doi: 10.1007/BF02982017.
• Brodsky RA, Chen AR, Brodsky I, Jones RJ. High-dose cyclophosphamide as salvage therapy for severe aplastic anemia. Exp Hematol. 2004 May;32(5):435-40. doi: 10.1016/j.exphem.2004.02.002.
• Paquette RL. Diagnosis and management of aplastic anemia and myelodysplastic syndrome. Oncology (Williston Park). 2002 Sep;16(9 Suppl 10):153-61.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (ANTICIPATED): July 1, 2009
• Study Completion (ANTICIPATED): December 1, 2009

Study Registration Dates

• First Submitted: April 28, 2006
• First Submitted That Met QC Criteria: April 28, 2006
• First Posted (ESTIMATE): April 27, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): October 7, 2008
• Last Update Submitted That Met QC Criteria: October 6, 2008
• Last Verified: October 1, 2008

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Bone Marrow Failure Disorders; Anemia; Anemia, Aplastic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Calcineurin Inhibitors; Sirolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: RDCRN 5403; U54RR019397-01 (NIH); BMF 5403