Pilot Lenalidomide in Adult Diamond-Blackfan Anemia Patients w/ RBC Transfusion-Dependent Anemia

A Pilot Study of Lenalidomide in Adult Diamond-Blackfan Anemia Patients With Red Blood Cell Transfusion-Dependent Anemia

This is a single-center, single arm, open-label study of oral lenalidomide monotherapy administered to red blood cell (RBC) transfusion dependent adult subjects with Diamond-Blackfan Anemia (DBA).

Primary Objective: To evaluate the erythroid response rate as measured by rate of red blood cell transfusion independence [MDS International Working Group (IWG) 2000 Criteria will be applied].

Secondary Objective: 1)To evaluate the tolerability and safety profile of lenalidomide in patients with DBA and other inherited marrow failure syndromes 2) To correlate response to lenalidomide with biologic surrogates of DBA including ribosomal protein mutation status, ex vivo erythroid colony growth, and microarray gene expression

Study Overview

• Status: Terminated
• Conditions: Leukemia; Anemia; Myelodysplastic Syndromes (MDS); Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: Lenalidomide

Detailed Description

This pilot study will utilize an intra-patient dose escalation design. Cycles are 28 days in length. Subjects will receive lenalidomide 2.5 mg weekly during days 1 to 21 of cycle 1 (dose level 1). If patients do not experience any grade > 3 hematologic or non-hematologic toxicity, the dose will be increased to 2.5 mg twice weekly on days 1 to 21 of cycle 2 (dose level 2). If patients do not experience any grade > 3 hematologic or non-hematologic toxicity, the dose will be increased to 5 mg twice weekly on days 1 to 21 of cycle 3 (dose level 3). If patients do not experience any grade >3 hematologic or non-hematologic toxicity, the dose will be increased to 5 mg thrice weekly on days 1 to 21 of cycle 4 (dose level 4). Patients who experience grade >3 hematologic or non-hematologic toxicity at dose level 1 will be discontinued from study. Patients who experience grade > 3 hematologic or non-hematologic toxicity at dose level 2, 3, or 4 will have the lenalidomide held and dose reduced according to protocol dose interruption/modification algorithms (section 5.5.3). If at least a minor erythroid response is not achieved at the end of 8 cycles of treatment, patients will be discontinued from study. If a minor or major erythroid response is achieved after completion of 8 cycles of treatment, patients can continue study drug on a maintenance phase until loss of erythroid response (return to baseline hemoglobin or transfusion requirement) or unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

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

INCLUSION CRITERIA

• Understand and voluntarily sign an informed consent form
• Diagnosis of DBA
• Age ≥ 18 years at the time of signing the informed consent form.
• Able to adhere to the study visit schedule and other protocol requirements.
• Red blood cell transfusion-dependent with a requirement of at least one unit of RBCs per month for the 2 months prior to study enrollment (eg, 2 units/8 weeks)
• If applicable, ongoing therapy with a stable or decreasing dose of prednisone ≤ 60 mg/d or corticosteroid equivalent, for which there has been no treatment-related improvement in RBC transfusion requirements for at least 2 months prior to study entry
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at study entry.

• Laboratory test results within these ranges:

  • Absolute neutrophil count (ANC) ≥ 1500/uL
  • Platelet (Plt) count ≥ 100,000/uL
  • Serum creatinine ≤ 2.0 mg/dL
  • Direct bilirubin ≤ 1.5 mg/dL
  • Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) ≤ 2.5 x ULN
  • Disease-free of prior malignancies for ≥ 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in-situ" of the cervix or breast
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of ≥ 50 milli-International Units (MIU)/mL within 10 to 14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy
• Able to take aspirin (81 to 325 mg) daily as prophylactic anticoagulation (patients intolerant to aspirin may use warfarin or low molecular weight heparin)

EXCLUSION CRITERIA

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
• Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide)
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
• Use of any other experimental drug or therapy (excluding steroids) specifically used for DBA within 28 days of baseline including metoclopramide, leucine, danazol, or other hormonal therapy
• Clinically significant anemia due to factors such as iron, B12, folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding.
• Known hypersensitivity to thalidomide
• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
• Any prior use of lenalidomide
• Concurrent use of other anti-cancer agents or treatments
• Known positive for HIV or infectious hepatitis, type A, B or C

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: Lenalidomide; Subjects will initially receive lenalidomide 2.5 mg, and may escalate up to 2.5 mg/wk up to 5 mg 3x/wk, depending toxicity and response.	Drug: Lenalidomide; 2.5 mg/wk up to 5 mg 3x/wk; Other Names: CC-5013; Revlimid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Red Blood Cell (RBC) Transfusion Independence	Red blood cell (RBC) transfusion independence is reported as the number of subjects who achieve a continuous absence of the intravenous infusion of any RBC transfusion during any consecutive "rolling" 56 days during the treatment period.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Red Blood Cell (RBC) Transfusions	The effect on red blood cell (RBC) transfusions was assessed as the number of participants that achieved a greater than 50% decrease in RBC transfusion requirements.	6 months
Hemoglobin Concentration	The effect on hemoglobin concentration was assessed as the change from baseline, measured in g/dL.	6 months
Neutrophil Response	The effect on neutrophil levels was assessed as the change in neutrophil count from baseline.	6 months
Platelet Response	The effect on platelet levels as assessed as the change in platelet count from baseline.	6 months
Duration of Response	The response duration was measured from the last of the consecutive 56 days during which the subject was free of red blood cells (RBC) transfusions to the date of the first RBC transfusion after the 56-day RBC-transfusion-free period.	6 months
Toxicity	Toxicity was assessed as the number of adverse events related to lenalidomide.	6 months

Collaborators and Investigators

• Sponsor: Jason Robert Gotlib
• Collaborators: Celgene Corporation
• Investigators: Principal Investigator: Jason Robert Gotlib, Stanford University

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: December 15, 2009
• First Submitted That Met QC Criteria: December 15, 2009
• First Posted (Estimate): December 17, 2009

Study Record Updates

• Last Update Posted (Actual): August 2, 2017
• Last Update Submitted That Met QC Criteria: June 27, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Precancerous Conditions; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Leukemia, Myeloid; Red-Cell Aplasia, Pure; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid, Acute; Preleukemia; Anemia; Anemia, Diamond-Blackfan; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide
• Other Study ID Numbers: IRB-16822; SU-12082009-4523 (Other Identifier: Stanford University); RV-0365 (Other Identifier: Celgene Corporation); HEMMDS0022 (Other Identifier: OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No