A Phase I Dose Finding and Proof-of-concept Study of the Histone Deacetylase Inhibitor Panobinostat (LBH589) in Combination With Standard Dose Cytarabine and Daunorubicin for Older Patients With Untreated Acute Myeloid Leukemia or Advanced Myelodysplastic Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 29
- 试验地点
- 1
- 主要终点
- The maximum tolerated dose (MTD) for the combination of panobinostat with standard-dose cytarabine and daunorubicin (7+3) for untreated AML and advanced MDS in the elderly.
研究概览
简要总结
The purpose of this study is to see if Panobinostat is safe to give to patients and to determine the best dose to give in combination with standard cytarabine and daunorubicin chemotherapy.
详细描述
In the United States, the incidence of acute myeloid leukemia (AML) is approximately 3.5 cases per 100,000 persons per year. Approximately 13,000 people were diagnosed with AML in 2009 and 9,000 died of the disease, making AML the 6th leading cause of cancer death. Over the past three decades, AML survival has improved for younger patients with 5-year survival rates of greater than 60% for adults under the age of 45 years likely owing to improvements in induction and consolidation chemotherapy, allogeneic hematopoietic stem cell transplant (HSCT) and supportive care. Post-remission therapy with high-dose cytarabine-based regimens after cytarabine and anthracycline based induction has improved disease free and overall survival at the expense of increased treatment related mortality limiting its use in many older patients and those with significant comorbidities. Although allogeneic HSCT remains the standard of care for patients with poor risk AML or relapsed disease, advanced age, comorbidities and donor availability preclude this option for a large number of patients making improvement in the tolerability and efficacy of induction therapy an important goal.
Over half of newly diagnosed AML patients are over 65 years of age with a third over the age of 75 years. Unlike younger patients, the prognosis of elderly patients with AML is still dismal with five-year survival rates of less than 10% for patients over the age of 65 years. For the last thirty years, induction therapy with standard dose cytarabine with an anthracycline has remained the standard of care for elderly patients with AML. In the elderly, complete response rates to induction chemotherapy are lower than younger patients at 40 to 60% with median survival approaching 12 months. New strategies using novel agents to increase the sensitivity of malignant myeloid precursors to standard induction chemotherapy may improve complete response and relapse rates without increasing treatment related mortality.
Myelodysplastic syndromes (MDS)
The myelodysplastic syndromes are neoplasms of hematopoietic progenitor cells characterized by ineffective hematopoiesis and increased risk of transformation to AML. Clinically, patients develop symptoms related to with cytopenias, typically progressive anemia with or without thrombocytopenia or neutropenia that is unrelated to a defined reversible cause such as nutritional deficiency. Histologically, MDS is suggested by the presence of dysplasia in >10% of cells in one or more myeloid lineage on bone marrow evaluation. Characteristic cytogenetic abnormalities also aid in making the diagnosis of MDS.
The incidence of MDS in the U.S. has been estimated at 3.4 cases per 100,000 people per year with the incidence increasing 10 fold in people over the age of 70. Risk factors for the development of MDS include advanced age, male sex, and prior exposure to DNA-damaging chemotherapy or radiation therapy, typically for treatment of other malignancies. As a group, patients with advanced MDS and those with MDS progressing to AML have treatment resistant disease with low response rates and short durations of response after induction therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Untreated histologically confirmed acute myeloid leukemia OR advanced myelodysplastic syndrome (INT-2 or High risk) not previously treated with anthracycline-based chemotherapy OR a therapy-related myeloid neoplasm
- •Male or female aged ≥ 60 years
- •ECOG performance status 0-2
- •Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
- •Absence of major metabolic, renal and hepatic impairment as defined by the following laboratory parameters: AST and ALT ≤ 2.5 x ULN Serum bilirubin ≤ 1.5 x ULN Albumin > 3.0 g/dl Serum potassium ≥ LLN Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN Serum magnesium ≥ LLN
- •Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
- •Prior treatment of myelodysplastic syndrome or myeloproliferative neoplasm acceptable
排除标准
- •Acute promyelocytic leukemia (FAB M3 AML)
- •Known central nervous system involvement by leukemia
- •Isolated myeloid sarcoma not meeting bone marrow criteria for AML or MDS
- •Cumulative anthracycline exposure greater than 200 mg/m2 doxorubicin isotoxic equivalents (See Appendix A6 for conversions)
- •Prior HDAC inhibitor, DAC inhibitor, Hsp90 inhibitor or valproic acid for the treatment of cancer
- •Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
- •Prior allogeneic hematopoietic stem cell transplant
- •Prior solid organ transplant
- •Active bleeding diathesis or current treatment with therapeutic doses of sodium warfarin (Coumadin®) or other vitamin K active agents (Note: mini-dose of Coumadin® (e.g., 1 mg/day) or anti-coagulants given to maintain intravenous line patency, as well as unfractionated or low molecular weight heparin therapy are permitted)
- •Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
- •History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial arrhythmia are eligible but should be discussed with Novartis prior to enrollment) Any history of ventricular fibrillation or torsade de pointes Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 bpm Screening ECG with a QTcF > 450 msec Right bundle branch block + left anterior hemiblock (bifascicular block) Patients with myocardial infarction or unstable angina ≤ 6 months prior to starting study drug Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction <50% by MUGA scan or by transthoracic echocardiogram Other clinically significant heart disease (e.g. uncontrolled hypertension, or history of labile hypertension)
- •Impairment of GI function or GI disease that may significantly alter the absorption of panobinostat.
- •Patients with active diarrhea > CTCAE grade 2
- •Known HIV infection
- •Known active Hepatitis B or Hepatitis C virus infection
- •Other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values that could in the opinion of the investigator cause unacceptable safety risks or compromise compliance with the protocol.
- •Active second malignancy except localized prostate cancer, basal cell carcinoma of the skin and carcinoma in situ of the skin or cervix
- •Patients who are unwilling to stop the use of herbal remedies while on the Treatment Phase of the study
- •Concomitant use of drugs with a risk of prolonging the QT interval and/or causing torsades de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug. Concomitant use of strong CYP3A4 inhibitors.
- •Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (which ever is longer) and who have not recovered from side effects of those therapies.
- •Patients who have received either immunotherapy within < 8 weeks; chemotherapy within < 4 weeks; or radiation therapy to > 30% of marrow-bearing bone within < 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies.
- •Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
- •Treatment with investigational agent within 30 days prior to enrollment
- •Male patients whose sexual partners are women of childbearing potential not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom.
- •Unwilling to accept blood product transfusions
- •Unable to swallow pills
- •Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff.
研究组 & 干预措施
Panobinostat
干预措施: Panobinostat (Drug)
Panobinostat
干预措施: Cytarabine (Drug)
Panobinostat
干预措施: Daunorubicin (Drug)
结局指标
主要结局
The maximum tolerated dose (MTD) for the combination of panobinostat with standard-dose cytarabine and daunorubicin (7+3) for untreated AML and advanced MDS in the elderly.
时间窗: Start of induction therapy until 21 days after the last dose of induction or second induction therapy or until count recovery in patients without residual disease, whichever is longer
The recommended Phase II dose for the combination of panobinostat with standard-dose cytarabine and daunorubicin (7+3) for untreated AML and advanced MDS in the elderly.
时间窗: Start of induction therapy until 21 days after the last dose of induction or second induction therapy or until count recovery in patients without residual disease, whichever is longer
次要结局
- Response rate (OR, CR, CRi) for AML using Revised Recommendations of the International Working Group(18 days after the start of induction therapy or 37 days after the second induction therapy or when white blood cell count recovers, whichever is first.)
- Response rate (OR, CR, CRi) for AMS using International Working Group response criteria in myelodysplasia(18 days after the start of induction therapy or 37 days after the second induction therapy or when white blood cell count recovers, whichever is first.)
- Overall Survival(The time to death from any cause from the day 1 of induction therapy.)
- Relapse-free survival(The time to relapse or death from any cause from the date of confirmed morphologic CR.)