Clinical trial NCT00546897: Lenalidomide in Older Patients With Acute Myeloid Leukemia Without Chromosome 5q Abnormalities
Official title: Phase II Trial of Lenalidomide in Older Patients (>/= 60 Years) With Untreated Acute Myeloid Leukemia Without Chromosome 5q Abnormalities
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia, Myeloid, Acute
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2007-10-19
Enrollment: 48
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is designed to test the safety and efficacy of lenalidomide in older patients (age \> 60 years) with untreated acute myeloid leukemia without chromosomal abnormalities involving 5q.

Detailed description: The incidence of AML increases with age, and current treatment options for the older patient population with newly diagnosed AML (AML \>= 60) is limited, all with poor outcomes. AML \>= 60 patients are more likely to have poor-risk cytogenetics abnormalities, and many have a preceding myelodysplastic syndrome (MDS). Traditional induction chemotherapy approaches in AML with cytarabine and anthracyclines yield remissions in 45-60% of AML \>= 60, however the vast majority of these patients relapse with a median survival of about 9 months. These patients are rarely candidates for potentially curative allogeneic stem cell transplantation. Many untreated AML \>= 60 patients are not candidates for aggressive therapy, and those who do receive therapy have a significant induction mortality of 10-20%, and significant hematologic toxicity occurs in over 30%, with no change in overall survival compared with supportive care. AML \>= 60 patients with favorable risk cytogenetics have a modest improvement in prognosis, for example with a 5 year overall survival of \~20%, compared with 0% in other cytogenetic categories. Thus, all eligible patients with AML \>= 60 should be recommended a clinical trial, regardless of whether they would be offered generally ineffective traditional induction chemotherapy. More effective and less toxic therapies are needed for the treatment of AML in this older patient population, indeed the preferred first line therapy in the national cancer center network (NCCN) guidelines for AML is a clinical trial.

In trials of lenalidomide in patients with MDS the dose of lenalidomide has been reduced for myelotoxicity and/or thrombocytopenia. However, current paradigms for the therapy of acute myeloid leukemia are based on using high doses of myelosuppressive chemotherapy and supporting the patient through a 4-5 weeks period of neutropenia/thrombocytopenia in an attempt to eliminate the malignant clone. Based on its efficacy in the related myeloid disorder MDS, and the close relationship between MDS and AML in patients \> 60, this trial employs the same paradigm of myelosuppressive therapy using high dose lenalidomide instead of chemotherapy. Importantly, within the MDS trials using low doses of lenalidomide, responses were observed in 3/9 (33%) of patients with excess blasts (RAEB/RAEB-t), which are now classified as evolving into AML or AML. This suggests that the therapeutic effect of lenalidomide occurs in the setting of a large percentage of blasts, such as AML, although the dose and schedule of lenalidomide administration is different. The response of AML \>= 60 patients to the proposed high dose lenalidomide regimen is unknown. Following high dose lenalidomide, in those patients that have a response, we propose using a lower dose maintenance strategy similar to the FDA approved dosing for MDS. The maintenance phase will include standard dose reductions for unacceptable toxicities.

Eligibility criteria: Inclusion Criteria:

* AML, de novo, secondary to prior therapy, or transformed from MDS, as defined by the International Working Group (except acute promyelocytic leukemia (AML M3). Patients must not have abnormalities of chromosome 5q as assessed by routine cytogenetics or FISH. Diagnosis of AML by WHO criteria (≥20% blasts) is determined by CBC, bone marrow assessment, and immunophenotypic analysis performed within 2 weeks of study enrollment.
* Intermediate or poor-risk cytogenetics as defined by SWOG criteria
* Age ≥ 60 years at the time of signing the informed consent form.
* Understand and voluntarily sign an informed consent form.
* Able to adhere to the study visit schedule and other protocol requirements.
* No previous treatment for AML, however hydroxyurea, steroids, and leukopheresis are allowed
* ECOG performance status of ≤ 2 at study entry.
* Life expectancy \> 2 months
* Adequate organ function as defined by:
* Serum creatinine ≤ 1.5X institution upper limit of normal (ULN)
* Total bilirubin ≤ 2.0 mg/dL
* AST (SGOT) and ALT (SGPT) ≤ 5 x ULN
* Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO 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. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
* 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.

Exclusion Criteria:

* Received prior treatment for AML
* Favorable risk cytogenetic abnormalities as defined by SWOG criteria (http://www.bloodjournal.org/cgi/content/abstract/96/13/4075) that include: inv(16)/t(16;16)/del(16q), t(15;17) with/without secondary aberrations, t(8;21) lacking del(9q) or complex karyotype (16). Prior to enrollment, FISH, molecular studies or routine cytogenetics must be completed to rule out these cytogenetic abnormalities.
* Known CNS leukemia
* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
* 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 within 30 days of enrollment.
* Known hypersensitivity to thalidomide.

Primary outcomes:
measure: Complete Remission Rate (CRm + CRi + CRc)
timeFrame: After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
Secondary outcomes:
measure: Safety and Tolerability (Removal From Study Due to Adverse Events)
timeFrame: 4 weeks after last dose of study drug [median duration of therapy was 65 days (range, 3-413 days)]
measure: Response Rate (RR)
timeFrame: After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
measure: Morphologic Leukemia Free State
timeFrame: After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
measure: Morphologic Complete Remission Rate (CRm)
timeFrame: After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
measure: Cytogenetics CR Rate (CRc)
timeFrame: After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
measure: CR With Complete Blood Counts (CRi) Rate
timeFrame: After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
measure: Partial Remission Rate (PR)
timeFrame: After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
measure: Overall Survival (OS)
timeFrame: 2 years
measure: Event Free Survival (EFS)
timeFrame: 2 years
measure: Progression-free Survival
timeFrame: 2 years
measure: Relapse Free Survival (RFS) for Complete Responders
timeFrame: 2 years
measure: Duration of CR for Complete Responders
timeFrame: 2 years
measure: Changes in NK Cell Number and Function
timeFrame: Baseline, during therapy, and posttherapy
measure: Gene Expression Profiles of Bone Marrow and Peripheral Blood
timeFrame: Pre and post treatment
measure: Plasma Proteins Via Proteomics
timeFrame: Pre and post treatment
Other outcomes:
Locations:
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Ravi Vij, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. doi: 10.1056/NEJMoa041668.
citation: List, AF, G Dewald, J Bennett, et al. 2005. Hematologic and Cytogenetic (CTG) Response to Lenalidomide (CC-5013) in Patients with Transfusion-Dependent (TD) Myelodysplastic Syndrome (MDS) and Chromosome 5q31.1 Deletion: Results of the Multicenter MDS-003 Study. In ASCO, Orlando, FL.
citation: Bansal D, Vij K, Chang GS, Miller CA, DiPersio JF, Vij R, Heath SE, Westervelt P, Welch JS, Fehniger TA. Lenalidomide results in a durable complete remission in acute myeloid leukemia accompanied by persistence of somatic mutations and a T-cell infiltrate in the bone marrow. Haematologica. 2018 Jun;103(6):e270-e273. doi: 10.3324/haematol.2017.184168. Epub 2018 Mar 22. No abstract available.
citation: Fehniger TA, Uy GL, Trinkaus K, Nelson AD, Demland J, Abboud CN, Cashen AF, Stockerl-Goldstein KE, Westervelt P, DiPersio JF, Vij R. A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia. Blood. 2011 Feb 10;117(6):1828-33. doi: 10.1182/blood-2010-07-297143. Epub 2010 Nov 4.
citation: Fehniger TA, Byrd JC, Marcucci G, Abboud CN, Kefauver C, Payton JE, Vij R, Blum W. Single-agent lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated trisomy 13. Blood. 2009 Jan 29;113(5):1002-5. doi: 10.1182/blood-2008-04-152678. Epub 2008 Sep 29.