Lenalidomide in Older Patients With Acute Myeloid Leukemia Without Chromosome 5q Abnormalities
Phase II Trial of Lenalidomide in Older Patients (>/= 60 Years) With Untreated Acute Myeloid Leukemia Without Chromosome 5q Abnormalities
調査の概要
詳細な説明
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.
研究の種類
入学 (実際)
段階
- フェーズ2
連絡先と場所
研究場所
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Missouri
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St. Louis、Missouri、アメリカ、63110
- Washington University School of Medicine
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：非ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
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実験的：Cohort 1
Lenalidomide 50 mg/day oral for 14 days followed by 30 days of rest. Lenalidomide 50 mg/day oral for 21 days (this is Cycle 1 and Cycle 2). If no progressive disease (PD) then lenalidomide 10 mg/day oral for 28 days for 12 cycles. |
他の名前：
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実験的：Cohort 2
Cycle 1: Oral lenalidomide 50 mg/day x 28 days induction therapy. Treatment will then depend on the response to Cycle 1: if patients obtain a complete remission (CR) they will proceed to low dose lenalidomide therapy, if patients have a non-CR they will receive a second high dose cycle of lenalidomide 50 mg/day x 28 days (Cycle 2) Cycle 2 consists of lenalidomide 50mg/day x 28 days Further treatment will depend on the response to Cycle 2: if patients obtain a CR/partial remission (PR)/stable disease (SD) they will proceed to low dose lenalidomide therapy, if patients have PD they will be removed from the study. Low Dose Cycles: low dose lenalidomide therapy consisting of 10 mg daily for a 28 day cycle.be 1) For patients that achieve a CR, 2 cycles of low dose lenalidomide will be administered, and then patients observed off therapy. For patients with PR/SD, low dose lenalidomide will continue for a total of 6 cycles and then patients will be observed off therapy. |
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Complete Remission Rate (CRm + CRi + CRc)
時間枠：After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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CRm = Defined as morphologic leukemia-free state, including <5% blasts in BM aspirate with marrow spicules and a count of > 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC > 1000/uL, platelet count >100,000/uL. Patient must be independent of transfusions for a minimum of 1 week before each marrow assessment. There is no duration requirement for this designation. CRi = Defined as CR with the exception of neutropenia <1000/uL or thrombocytopenia <100,000/ul. Cytogenetic complete remission (CRc): Only patients with an identified cytogenetic abnormality may receive this designation. Defines as a morphologic complete remission plus reversion to a normal karyotype (no clonal abnormalities detected in a minimum of 20 mitotic cells). |
After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Safety and Tolerability (Removal From Study Due to Adverse Events)
時間枠：4 weeks after last dose of study drug [median duration of therapy was 65 days (range, 3-413 days)]
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Toxicity will be scored using CTCAE Version 3.0 for toxicity and adverse event reporting
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4 weeks after last dose of study drug [median duration of therapy was 65 days (range, 3-413 days)]
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Response Rate (RR)
時間枠：After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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RR = as patients obtaining any response (CRm + CRc +CRi + PR). CRm = Defined as morphologic leukemia-free state, including <5% blasts in BM aspirate with marrow spicules and a count of > 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC > 1000/uL, platelet count > 100,000/uL. Patient must be independent of transfusions for a minimum of 1 week before each marrow assessment. There is no duration requirement for this designation. CRc = Cytogenetic complete remission (CRc): Only patients with an identified cytogenetic abnormality may receive this designation. Defines as a morphologic complete remission plus reversion to a normal karyotype (no clonal abnormalities detected in a minimum of 20 mitotic cells). Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia <1000/uL or thrombocytopenia <100,000/ul. Partial remission (PR): Requires |
After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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Morphologic Leukemia Free State
時間枠：After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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Morphologic leukemia-free state: Defined as < 5% blasts on the BM aspirate with spicules and a count of > 200 nucleated cells and no blasts with Auer rods, and no persistent extramedullary disease.
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After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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Morphologic Complete Remission Rate (CRm)
時間枠：After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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CRm = Defined as morphologic leukemia-free state, including <5% blasts in BM aspirate with marrow spicules and a count of > 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC > 1000/uL, platelet count >100,000/uL.
Patient must be independent of transfusions for a minimum of 1 week before each marrow assessment.
There is no duration requirement for this designation.
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After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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Cytogenetics CR Rate (CRc)
時間枠：After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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Cytogenetic complete remission (CRc): Only patients with an identified cytogenetic abnormality may receive this designation.
Defines as a morphologic complete remission plus reversion to a normal karyotype (no clonal abnormalities detected in a minimum of 20 mitotic cells).
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After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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CR With Complete Blood Counts (CRi) Rate
時間枠：After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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CRi = Defined as CR with the exception of neutropenia <1000/uL or thrombocytopenia <100,000/ul.
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After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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Partial Remission Rate (PR)
時間枠：After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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Partial remission (PR): Requires that the criteria for complete remission be met with the following exceptions: decrease of >50% in the percentage of blasts to 5-25% in the BM aspirate.
A value of < 5% blasts in BM with Auer rods is also considered a partial remission.
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After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2)
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Overall Survival (OS)
時間枠：2 years
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Overall survival: Defined as the date of first dose of study drug to the date of death from any cause.
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2 years
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Event Free Survival (EFS)
時間枠：2 years
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Event free survival: Defined as the interval from the date of first dose of study drug to date of treatment failure, recurrence, or death due to any cause.
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2 years
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Progression-free Survival
時間枠：2 years
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Progression-free survival (PFS) denotes the chances of staying free of disease progression for a group of individuals suffering from a cancer after a particular treatment.
It is the percentage of individuals in the group whose disease is likely to remain stable (and not show signs of progression) after a specified duration of time.
Progression-free survival rates are an indication of how effective a particular treatment is.
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2 years
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Relapse Free Survival (RFS) for Complete Responders
時間枠：2 years
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This is determined only for patients achieving a complete remission.
Defined as the interval from the date of first documentation of a leukemia free state to date of recurrence or death due to any cause.
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2 years
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Duration of CR for Complete Responders
時間枠：2 years
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Duration of remission: Defined as the interval from the date complete remission is documented to the date of recurrence
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2 years
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Changes in NK Cell Number and Function
時間枠：Baseline, during therapy, and posttherapy
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Peripheral blood mononuclear cells (PBMC) will be viably cryopreserved from patients at baseline (pre-therapy, newly diagnosed AML), during lenalidomide therapy, and posttherapy.
Following sample collection, PBMC will be thawed, and flow cytometry will be performed to assess NK cell number (CD56+CD3-), subsets, and phenotype utilizing the Siteman Cancer Center Flow Cytometry / Cell Sorting Core.
In addition, NK cell function will be assessed in flow based killing assays using PBMC (containing NK cells) as effectors and NK sensitive cell lines (K562) and/or autologous leukemic blasts as target cells.
Thus, analyzing these parameters in patients before, during, and after therapy will provide a comprehensive evaluation of the ability of lenalidomide to modulate NK cells in patients in vivo.
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Baseline, during therapy, and posttherapy
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Gene Expression Profiles of Bone Marrow and Peripheral Blood
時間枠：Pre and post treatment
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RNA will be made from total bone marrow cells for labeling and evaluations by RNA profiling.
Cellular RNA and corresponding biotinylated cRNA targets will be prepared and hybridized with Affymetrix GeneChip® microarrays within the Multiplexed Gene Analysis SCC Core (Dr.
Mark Watson, Director).
Microarray data (and eventually corresponding gene sequence data) will be integrated an analyzed with state-of-the-art software packages.
The pre- and post-treatment RNA profiling studies will be used as a discovery tool.
Patterns of gene expression before and after lenalidomide therapy will be compared within each patient's sample to identify genes with altered expression after lenalidomide therapy.
In addition, supervised algorithms will be sued to identify genes that can potentially predict clinical outcome and response to lenalidomide therapy.
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Pre and post treatment
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Plasma Proteins Via Proteomics
時間枠：Pre and post treatment
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Proteomic analysis will be performed within the Siteman Cancer Center proteomics core on pre- and post-treatment plasma samples.
This pilot proteomic study will identify candidate proteins of interest with altered expression after treatment with lenalidomide.
This approach will provide an unbiased method to assess global changes in serum proteins following lenalidomide therapy.
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Pre and post treatment
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協力者と研究者
出版物と役立つリンク
一般刊行物
- 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.
- 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.
- 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.
- 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.
- 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.
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (見積もり)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
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レナリドミドの臨床試験
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University of Alabama at BirminghamJanssen Scientific Affairs, LLC; Amgen完了