Open Label Phase 2 Single agent study of LCL-161 in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), or Post-Essential Thrombocytosis Myelofibrosis (Post-ET MF)
To goal of this clinical research study is to learn if LCL161 can help to control myelofibrosis. The safety of this drug will also be studied.
Disease Group: Leukemia
Treatment Agent: LCL-161
Treatment Location: Only at MDACC
Primary Objectives To determine the efficacy of LCL161 as therapy for primary myelofibrosis (PMF), post-polycythemia veria (PV) myelofibrosis (MF) and post-essential thrombocytosis (ET) MF . To determine the objective response which is defined as CR (complete remission) + PR (partial remission) + CI (clinical improvement) after three cycles of treatment. It will be categorized according to the International Working Group (IWG) consensus criteria for myelofibrosis . Secondary Objectives To determine the safety of LCL161 as therapy for PMF, post-PV MF and post-ET MF. To determine time to response and response duration To assess changes in symptom burden as assessed by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF TSS) and M. D. Anderson Symptom Inventory (MDASI) questionnaires. Exploratory Objectives Samples will be collected during the course of the study to assess the mechanisms of action of LCL161 in patients with MF. These studies will include the analysis of cIAP1, XIAP, and PARP protein levels which will be determined by western blot (actin as loading control) and will be measured at baseline and at beginning of each cycle for first 3 cycles and at end of study.
IRB Review and Approval Date: 12/18/2014
Recruitment Status: Open
Projected Accrual: N/A
1) Patients must provide written informed consent.
2) Age 18 years or older.
3) Willing and able to comply with scheduled visits, treatment plan and laboratory tests
4) Patient is able to swallow and retain oral medication
5) Must be diagnosed with treatment requiring PMF or post ET/PV MF with intermediate-1, intermediate -2 or high risk disease according to the IWG prognostic scoring system, or if with low risk disease then with symptomatic splenomegaly that is >/=5 cm below left costal margin by physical exam.
6) Patients who are not candidates for, intolerant, or relapsed/refractory to Ruxolitinib
7) ECOG performance status 0-2
8) Required baseline laboratory status: Absolute neutrophil count (ANC) >/= 0.5 x 109/L (1500/mm3); Serum direct bilirubin </= 2.0 x ULN (upper limit of normal); AST (SGOT) and ALT (SGPT) </= 2.5 x ULN, except for patients with MF involvement of the liver who must have AST and ALT </= 5 x ULN; Serum creatinine </= 1.5 x ULN
9) Treatment-related toxicities from prior therapies must have resolved to Grade </= 1
10) At least 2 weeks from prior MF-directed treatment (till the start of study drug)
1) Any concurrent severe and/or uncontrolled medical conditions that
could increase the patient’s risk for toxicity while in the study or
that could confound discrimination between disease- and study
2) Impaired cardiac function or clinically significant cardiac diseases, including any of the following: History or presence of ventricular tachyarrhythmia; Presence of unstable atrial fibrillation (ventricular response > 100 bpm). Patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria. Clinically significant resting bradycardia (< 50 bpm). Angina pectoris or acute myocardial infarction </= 3 months prior to starting study drug. Other clinically significant heart disease (e.g., symptomatic congestive heart failure; uncontrolled arrhythmia or hypertension; history of labile hypertension or poor compliance with an antihypertensive regimen).
3) Patients who are currently receiving chronic (>14 days) treatment with corticosteroids at a dose >/= 10 mg of prednisone (or its glucocorticoid equivalent) per day, or any other chronic immunosuppressive treatment that cannot be discontinued prior to starting study drug
4) Patients who are currently receiving treatment with agents that are metabolized solely through CYP3A4/5 and have a narrow therapeutic index or are strong CYP2C8 inhibitors; or are receiving treatment with agents that carry a risk for QT prolongation and are CYP3A substrates.
5) Patients with impairment of GI function or GI disease that may significantly alter the absorption of LCL161 as per physicians opinion
6) Pregnant or breast feeding (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive beta-HCG laboratory test.
7) Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 90 days after study treatment. Highly effective contraception methods include: Total abstinence or Male partner or female sterilization or Combination of any two of the following (a+b or a+c, or b+c): a. Use of oral, injected or implanted hormonal methods of contraception, b. Placement of an intrauterine device (IUD) or intrauterine system (IUS), c. Barrier methods of contraception: condom for male partner or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
8) Continued from #7 above: Note: Postmenopausal women are allowed to participate in this study. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of asomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, a woman is considered to be of not child bearing potential only when her reproductive status has been confirmed by follow-up hormone level assessment.
9) Sexually active males must use a condom during intercourse while taking the drug and for 3 months after stopping study drug and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid
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