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Trial record 1 of 1 for:    Phase 2 LCL-161 in Patients With Primary Myelofibrosis
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LCL161 in Treating Patients With Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocytosis Myelofibrosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02098161
Recruitment Status : Active, not recruiting
First Posted : March 27, 2014
Last Update Posted : April 1, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Novartis Pharmaceuticals
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE March 21, 2014
First Posted Date  ICMJE March 27, 2014
Last Update Posted Date April 1, 2020
Actual Study Start Date  ICMJE December 18, 2014
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 22, 2019)
Objective response rate (ORR) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 24, 2014)
Objective Response (OR) of LCL-161 [ Time Frame: After 3, 28 day cycles ]
Objective response (OR), defined as CR (complete remission) + PR (partial remission) + CI (clinical improvement) for myelofibrosis (MF) patients after 3 cycles of treatment. Categorized according to the International Working Group (IWG) consensus criteria for myelofibrosis .
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2019)
  • Incidence of grade 3-4 clinically relevant non-hematologic toxicity or a serious adverse event that is at least possibly drug related [ Time Frame: 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 [ Time Frame: 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 Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2014)
Time to response [ Time Frame: Day 1 of third, 28 day cycle ]
Time to response defined as time from study registration to the first date at which the subject's objective status was classified as a response (CR or PR). In subjects who do not achieve a response, time to response censored at the subject's last evaluation date. The distribution for each of these event-time variables (duration of response and time to response) estimated by Kaplan-Meier curves.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE LCL161 in Treating Patients With Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocytosis Myelofibrosis
Official Title  ICMJE 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)
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).
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the efficacy of LCL161 as therapy for primary myelofibrosis (PMF), post-polycythemia vera (PV) myelofibrosis (MF) and post-essential thrombocytosis (ET) MF.

II. 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:

I. To determine the safety of LCL161 as therapy for PMF, post-PV MF and post-ET MF.

II. 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:

I. 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Primary Myelofibrosis
  • Secondary Myelofibrosis
Intervention  ICMJE
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Questionnaire Administration
    Ancillary studies
  • Drug: Smac Mimetic LCL161
    Given PO
    Other Name: LCL161
Study Arms  ICMJE 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.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
  • Drug: Smac Mimetic LCL161
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: December 12, 2019)
50
Original Estimated Enrollment  ICMJE
 (submitted: March 24, 2014)
40
Estimated Study Completion Date  ICMJE December 31, 2020
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02098161
Other Study ID Numbers  ICMJE 2013-0612
NCI-2014-01241 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CLCL161AUS02T
2013-0612 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Novartis Pharmaceuticals
Investigators  ICMJE
Principal Investigator: Naveen Pemmaraju M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP