Open-Label, Dose-Escalating, Clinical and Pharmacokinetic Phase I Study of Lurbinectedin (PM01183) in Patients with Advanced Acute Leukemia or Relapsed/refractory Myelodysplastic Syndrome
The goal of this clinical research study is to find the highest tolerable dose of lurbinectedin (PM01183) that can be given to patients with advanced acute leukemia.
Disease Group: Leukemia
Treatment Agent: PM01183
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Pharma Mar USA, Inc.
The objectives of this study are as follows: Primary objective: The primary objective of the study is to determine the MTD and the RD of lurbinectedin (PM01183) administered as 1-hour i.v. infusion on 3 consecutive days (Days 1-3) to patients with advanced acute leukemia or relapsed/refractory myelodysplastic syndrome (MDS) failing previous treatment with hypomethlating agents. Secondary objective: To assess the safety profile and tolerability of lurbinectedin in patients with advanced acute leukemia. To obtain preliminary information of the efficacy of lurbinectedin in patients with advanced acute leukemia or MDS. To characterize the PK of lurbinectedin in patients with advanced acute leukemia or MDS. To characterize the PGx profile in patients with advanced acute leukemia or MDS.
IRB Review and Approval Date: 05/17/2011
Recruitment Status: Not Accepting
Projected Accrual: 50
1) Voluntarily signed and dated written informed consent prior to any
specific study procedure
2) Age greater or equal to 18 years.
3) Patients must have a previous cytological or histological diagnosis of : -relapsed or primary refractory non-M3 AML by the World Health Organization (WHO) criteria (irrespective of the number of prior regimens), either de novo or secondary (ie., secondary to myelodysplastic syndromes (MDS), myeloproliferative neoplasms or pervious chemotherapy for another condition). -Untreated AML in patients greater or equal to 65 years of age, if patients are not candidates for standard induction chemotherapy or have poor risk AML (i.e., secondary AML or AML with adverse cytogenetics or complex karyotype). -Accelerated or blastic phase CML (with progressive disease despite treatment with BCR-ABL kinase inhibitors), or chronic myelomonocytic leukemia (CMML). -Relapsed or refractory ALL by WHO criteria. Relapsed or refractory MDS failing to previous treatment with hypomethlating agents (e.g., azacitidine or decitabine).
4) Recovery to grade less than or equal to 1 or to baseline from any AE derived from previous treatment (excluding alopecia of any grade and grade less than or equal to 2 non-painful peripheral neuropathy).
5) Patients must have the following laboratory values prior to the start of treatment: -total bilirubin less than or equal to 1.5 x upper limit of normal (ULN) range of values, unless due to elevated indirect bilirubin (e.g., Gilbert's syndrome or hemolysis). -aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN. -Alkaline phosphatase (AP) less than or equal to 2.5 x ULN. -Albumin grater than or equal to 2.5 g/dl. Calculated creatinine clearance (CrCl) greater or equal to 30ml/min (using Cockcroft and Gault's formula).-Creatine phosphokinase (CPK) less than or equal to 2.5 x ULN.
6) Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2.
7) Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan greater or equal to 45 percent.
8) Negative pregnancy test for women of childbearing potential.
9) All patients included in the PM1183-A-002-10 trial may be eligible for the Pharmacogenomic Study
10) Only those patients with available peripheral blood and BM samples that voluntarily sign the Informed Consent Form (ICF) for the Pharmacogenomic
11) (PGx) substudy will participate. Refusal to participate in the PGx substudy will not affect the patient's participation in the main trial.
1) Pregnant or lactating women; men and women of reproductive potential
who are not using effective contraception methods throughout the
treatment period and for six weeks after discontinuation of treatment.
Acceptable methods of contraceptive include complete abstinence,
intrauterine contraceptive device (IUD), oral contraceptive, subdermal
implant and double barrier (condom with a contraceptive sponge or
2) Uncontrolled disseminated intravascular coagulation (DIC).
3) Patients who plan to undergo allogeneic BM transplantation within four weeks.
4) Other relevant diseases or adverse clinical conditions: -History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year. -Symptomatic or unstable cardiac arrhythmias, and/or prolonged QT-QTc grade greater or equal to 2. -History of significant neurological or psychiatric disorders that may affect the patients compliance with the protocol assessments. -Active uncontrolled infection. -Myopathy or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 x ULN in two different determinations performed one week apart). -Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis). -Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in the study.
5) Hematopoietic allogeneic stem cell transplantation within the last four months and/or active graft versus host disease, or prior autologous transplantation within the last four weeks.
6) Patients known to be human immunodeficiency virus (HIV) positive.
7) Cytotoxic chemotherapy within the last two weeks; radiation therapy within the last two weeks; biologic agents, including hematopoietic growth factors, within the last week; biologic agents, including hematopoietic growth factors, within the last week; hydroxurea, imatinib, corticosteroids and arsenic trioxide should be discontinued at least 24 hours prior to first study drug administration.
8) Treatment with any investigational product in the less than or equal to 5 half-lives period prior to inclusion in the study, or 30 days after therapy (in case of unknown half-life), unless evidence of rapid proliferating disease and upon discussion with the Sponsor.
9) Known central nervous system (CNS) disease.
10) Known hypersensitivity to any of the components of the drug product (DP).
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