LCL161 in Treating Patients With Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocytosis Myelofibrosis

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT02098161

Collaborator

National Cancer Institute (NCI) (NIH), Novartis Pharmaceuticals (Industry)

Enrollment

Location

Arm

Actual Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies how well second mitochondrial-derived activator of caspases (SMAC) mimetic LCL161 (LCL161) works in treating patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytosis myelofibrosis. SMAC mimetic LCL161 may help control the growth of abnormal cells by promoting apoptosis (programmed cell death).

Condition or Disease	Intervention/Treatment	Phase
Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase Primary Myelofibrosis Secondary Myelofibrosis	Other: Laboratory Biomarker Analysis Other: Questionnaire Administration Drug: Smac Mimetic LCL161	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

To determine the efficacy of LCL161 as therapy for primary myelofibrosis (PMF), post-polycythemia vera (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.

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. III. To assess changes in symptom burden as assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) and M.D. Anderson Symptom Inventory (MDASI) questionnaires.

EXPLORATORY OBJECTIVE:

To assess the mechanisms of action of LCL161 in patients with MF; these studies will include the analysis of baculoviral IAP repeat containing 2 (cIAP1), X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase (XIAP), and poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (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.

OUTLINE:

Patients receive SMAC mimetic LCL161 orally (PO) on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Study Design

Study Type:

Interventional

Actual Enrollment :

53 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Dec 18, 2014

Actual Primary Completion Date :

May 19, 2022

Actual Study Completion Date :

May 19, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (SMAC mimetic LCL161) Patients receive SMAC mimetic LCL161 PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis Correlative studies Other: Questionnaire Administration Ancillary studies Drug: Smac Mimetic LCL161 Given PO Other Names: LCL161

Arm

Intervention/Treatment

Experimental: Treatment (SMAC mimetic LCL161)

Patients receive SMAC mimetic LCL161 PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis

Correlative studies

Other: Questionnaire Administration

Ancillary studies

Drug: Smac Mimetic LCL161

Given PO

Other Names:

LCL161

Outcome Measures

Primary Outcome Measures

Objective response rate (ORR) [After 84 days (3 courses) of treatment]
Will be defined as complete remission (CR), partial remission (PR), or clinical improvement (CI) after 3 courses of treatment according to International Working Group (IWG) consensus criteria for myelofibrosis. The Optimum two-stage design proposed by Simon will be implemented. ORR will be estimated along with the Bayesian 95% credible interval.

Secondary Outcome Measures

Incidence of grade 3-4 clinically relevant non-hematologic toxicity or a serious adverse event that is at least possibly drug related [Up to 30 days post-treatment]
Will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Safety data will be summarized by category, severity and frequency. The proportion of patients with adverse events will be estimated, along with the Bayesian 95% credible interval.
Duration of response [Date at which the subject's objective status is first noted to the date of progression (no longer meeting criteria for any type of response), assessed up to 30 days post-treatment]
The distribution for duration of response will be estimated by Kaplan-Meier curves.
Time to response [Time from study registration to the first date at which the subject's objective status was classified as a response, assessed up to 30 days post-treatment]
The distribution for time to response will be estimated by Kaplan-Meier curves.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must provide written informed consent
Willing and able to comply with scheduled visits, treatment plan and laboratory tests
Patient is able to swallow and retain oral medication
Must be diagnosed with treatment requiring PMF or post ET/PV MF with intermediate-1, intermediate -2 or high risk disease according to the International Working Group (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
Patients who are not candidates for, intolerant, or relapsed/refractory to ruxolitinib
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Absolute neutrophil count (ANC) >= 0.5 x 10^{9/L (1500/mm}3)
Serum direct bilirubin =< 2.0 x ULN (upper limit of normal)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [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
Treatment-related toxicities from prior therapies must have resolved to grade =< 1
At least 2 weeks from prior MF-directed treatment (till the start of study drug)

Exclusion Criteria:

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 treatment-related toxicities
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 beats per minute [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)
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
Patients who are currently receiving treatment with agents that are metabolized solely through cytochrome P450 family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) and have a narrow therapeutic index or are strong cytochrome P450 family 3, subfamily C, polypeptide 8 (CYP2C8) inhibitors; or are receiving treatment with agents that carry a risk for QT prolongation and are CYP3A substrates
Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of LCL161 as per physicians opinion
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-human chorionic gonadotropin (HCG) laboratory test
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
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 vasomotor 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
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