Clinical Trials /

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

NCT02098161

Description:

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).

Related Conditions:
  • Myelofibrosis Transformation in Essential Thrombocythemia
  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Primary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: LCL161 in Treating Patients With Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocytosis Myelofibrosis
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: 2013-0612
  • SECONDARY ID: NCI-2014-01241
  • SECONDARY ID: CLCL161AUS02T
  • SECONDARY ID: 2013-0612
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02098161

Conditions

  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Primary Myelofibrosis
  • Secondary Myelofibrosis

Interventions

DrugSynonymsArms
Smac Mimetic LCL161LCL161Treatment (SMAC mimetic LCL161)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (SMAC mimetic LCL161)ExperimentalPatients 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.
  • Smac Mimetic LCL161

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:After 84 days (3 courses) of treatment
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:The distribution for duration of response will be estimated by Kaplan-Meier curves.
Measure: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
Safety Issue:
Description:The distribution for time to response will be estimated by Kaplan-Meier curves.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 12, 2019