Phase 1/2 Safety and Efficacy of PLX3397 in Adults With Relapsed or Refractory Acute Myeloid Leukemia (AML)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Plexxikon
ClinicalTrials.gov Identifier:
NCT01349049
First received: May 4, 2011
Last updated: April 6, 2015
Last verified: April 2015
  Purpose

The purpose of this study is to evaluate the safety of study drug PLX3397 at 3 dose levels (800 mg/day, 1000 mg/day, and 1200 mg/day) and explore the efficacy in patients with relapsed or refractory acute myeloid leukemia (AML). Additional dose levels beyond 1200 mg/day may be considered based on safety and efficacy observations.


Condition Intervention Phase
Acute Myeloid Leukemia
Drug: PLX3397
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1/2 Safety and Efficacy Study of Orally Administered PLX3397 in Adults With Relapsed or Refractory FLT3-ITD Positive Acute Myeloid Leukemia (AML)

Resource links provided by NLM:


Further study details as provided by Plexxikon:

Primary Outcome Measures:
  • Safety-Subject incidence of adverse events [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    Subjects will take oral doses of PLX3397 twice a day. Physical examinations, vital signs, 12-lead electrocardiograms (ECG), adverse events, hematology and serum chemistry will be used to assess safety throughout the study. Adverse events will be monitored and reviewed for safety issues/abnormal changes in the above mentioned tests.

  • Complete Remission (CR) Rate including complete remission with incomplete blood count recovery (CRi) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Evaluated by bone marrow assessments at a minimum of once every month. Evaluated using the International Working Group Response Criteria (Cheson 2003) and a modified version of the International Working Group Response Criteria (Nybakken 2012).


Estimated Enrollment: 90
Study Start Date: November 2011
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PLX3397
Subjects will be dosed at the maximum tolerated dose.
Drug: PLX3397
Maximum Tolerated Dose of PLX3397 will be administered orally, twice daily.
Other Name: Plexxikon 3397
Experimental: oral dose of 800 mg/day of PLX3397
Level 0
Drug: PLX3397
The drug product is available in capsule form, to be taken orally.
Other Name: Plexxikon 3397
Experimental: oral dose of 1000 mg/day PLX3397
Level 1
Drug: PLX3397
The drug product is available in capsule form, to be taken orally.
Other Name: Plexxikon 3397
Experimental: oral dose of 1200 mg/day PLX3397
Level 2
Drug: PLX3397
The drug product is available in capsule form, to be taken orally.
Other Name: Plexxikon 3397
Experimental: oral dose of 1400 mg/day PLX3397
Level 3
Drug: PLX3397
The drug product is available in capsule form, to be taken orally.
Other Name: Plexxikon 3397
Experimental: oral dose of 2000 mg/day PLX3397
Level 4
Drug: PLX3397
The drug product is available in capsule form, to be taken orally.
Other Name: Plexxikon 3397
Experimental: oral dose of 3000 mg/day PLX3397
Level 5
Drug: PLX3397
The drug product is available in capsule form, to be taken orally.
Other Name: Plexxikon 3397
Experimental: oral dose of 4000 mg/day PLX3397
Level 6
Drug: PLX3397
The drug product is available in capsule form, to be taken orally.
Other Name: Plexxikon 3397
Experimental: oral dose of 5000 mg/day PLX3397
Level 7
Drug: PLX3397
The drug product is available in capsule form, to be taken orally.
Other Name: Plexxikon 3397

Detailed Description:

Protocol PLX108-05 is a Phase 1/2 open-label, sequential dose escalation (Part 1) followed by cohort expansion (Part 2) design at the recommended phase 2 dose established in Part 1 (i.e. 3,000 mg/day). Treatment with PLX3397 will consist of continuous oral administration in 28-day cycles until unacceptable or dose-limiting toxicity, disease progression or relapse, patient death, Investigator decision, or voluntary withdrawal.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female patients ≥18 years old.
  • Morphologically documented primary AML, prior-chemotherapy-related AML or AML secondary to an antecedent hematologic disorder (e.g., Myelodysplastic Syndrome) as defined by WHO criteria, confirmed by pathology review. For Cohort Expansion Phase (Part 2) only: Bone marrow involvement is required.
  • Have either relapsed or refractory AML, or who have newly diagnosed Flt3-ITD positive AML but either refuse or are considered by the Investigator not to be an appropriate candidate for standard chemotherapy.

    1. Relapsed disease is defined as the reappearance of leukemia cells in the bone marrow or peripheral blood or elsewhere in the body (other tissues/organs) after the attainment of a CR.
    2. Refractory disease is defined by the failure to obtain a complete remission (CR) with a HDAC-containing or a standard induction regimen. Patients who require two cycles of induction therapy to attain a first CR are not considered to have refractory disease.
  • Positive for Flt3-ITD activating mutations during Screening. Local laboratory results must be received prior to enrollment. Patients with a history of Flt3-ITD positive disease may be considered after discussion with the Medical Monitor.
  • ECOG performance status of 0, 1, or 2.
  • Adequate recovery (to at least Grade 1) from toxicity of prior therapy as follows:

    1. ≥2 weeks for cytotoxic therapy (except hydroxyurea, which is permitted at doses of ≤5g/day during the first 2 weeks of Cycle 1) prior to C1D1.
    2. ≥4 half-lives for non-cytotoxic therapy prior to C1D1. Patients must have a wash-out period from their last chemotherapy of either ≥2 weeks OR at least 4 half-lives prior to C1D1. For patients whose most recent anti-tumor treatment regimen consisted of a multi-agent cocktail, the patient must have a wash-out period of at least 4 half-lives of the agent with the longest half-life.
  • Adequate hepatic and renal function

    1. Adequate renal function, defined as Creatinine Clearance >60 mL/min or serum creatinine of ≤ 1.3 mg/dL (115 μM).
    2. Adequate hepatic function, defined as AST and ALT ≤3.0X ULN and serum direct bilirubin ≤1.5X ULN. Exceptions may be made for patients with elevated liver transaminases secondary to AML after discussion with the Medical Monitor
  • Life expectancy of at least 1 month
  • Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements and for 3 months after last dose.
  • Women of child-bearing potential must have a negative pregnancy test within 7 days of initiation of dosing and must agree to use two acceptable methods of birth control while on study drug and for 3 months after the last dose. Women of non-childbearing potential may be included if they meet at least one of the following criteria:

    1. Surgically sterile
    2. Have been postmenopausal for ≥1 year
    3. Have FSH levels indicative of postmenopausal state (i.e., 30-120 IU/L) documented within 21 days of C1D1.

Sexually active men must also agree to use an acceptable method of birth control while on study drug and for at least 3 months after the last dose

Exclusion Criteria:

  • Diagnosis of acute promyelocytic leukemia
  • Diagnosis of chronic myelogenous leukemia in blast crisis
  • Presence of CNS involvement of leukemia. Patients with a history of CNS involvement may be considered after discussion with the Medical Monitor
  • Patients eligible for HSCT at the time of screening. However, patients who meet one or both of the following criteria may be eligible for study participation:

    1. Patients who are eligible for HSCT but with non-optimal AML disease control (i.e., blasts > 5%) may be enrolled into this study as a bridge-to-transplant.
    2. Patients with relapsed disease following a prior HSCT may be enrolled into this study as an alternative to a second HSCT or as a bridge-to-transplant regimen.
  • For both Parts 1 and 2, receipt of HSCT within 60 days of the first dose of PLX3397 is an exclusion criterion. Patients on immunosuppressive therapy post HSCT, or with clinically significant graft-versus-host disease are excluded from Part 1. (Use of topical steroids for ongoing skin GVHD is permitted). Patients for Part 1 must have a wash-out period of ≥2 weeks or at least 4 half-lives from their last systemic immunosuppressive treatment for GVHD. Patients for Part 2 may be receiving systemic immunosuppressive treatment for management of GVHD at the time of screening and enrollment
  • Investigational drug use within 28 days of the first dose of PLX3397
  • For Cohort Expansion Phase (Part 2) only: Patients who are positive for the D835 mutation at Screening are excluded.
  • A concurrent active cancer that requires non-surgical therapy (e.g., chemotherapy, radiation, adjuvant therapy). Prior history of other cancer is allowed, as long as there is no active disease within 1 year of the first dose of PLX3397.
  • Refractory nausea and vomiting, malabsorption, biliary shunt significant bowel resection, GVHD affecting the gut, or any other condition that would preclude adequate absorption
  • Patients with serious illnesses, uncontrolled infection, medical conditions, or other medical history including abnormal laboratory results, which in the investigator's opinion would be likely to interfere with a patient's participation in the study, or with the interpretation of the results
  • Women of child-bearing potential who are pregnant or breast feeding
  • At Screening, QTcF >450 msec for males; QTcF >470 msec for females
  • Patients with a history of D835 mutations
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01349049

Locations
United States, California
UCSF Helen Diller Family Family Comprehensive Cancer Center
San Francisco, California, United States, 94143
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10022
New York Presby Hospital, Weill Medical College at Cornell University
New York, New York, United States, 10065
United States, Pennsylvania
University of Pennsylvania, Abramson Cancer Center
Philadelphia, Pennsylvania, United States, 19104
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Plexxikon
Investigators
Principal Investigator: Olga Frankfurt, MD Robert H. Lurie Comprehensive Cancer Center of Northwestern University - Chicago, IL
Principal Investigator: Mark Levis, MD, PhD Johns Hopkins University
Principal Investigator: John Pagel, MD, PhD Fred Hutchinson Cancer Research Center - Seattle, WA
Principal Investigator: Alexander Perl, MD Hospital of the University of Pennsylvania - Philadelphia, PA
Principal Investigator: Gail Roboz, MD Weill Cornell Medical College/New York Presbyterian Hospital - New York, NY
Principal Investigator: Catherine Smith, MD University of California Medical Center - San Francisco, CA
Principal Investigator: Richard Stone, MD Dana-Farber Cancer Institute - Boston, MA
Principal Investigator: Eunice Wang, MD Roswell Park Cancer Institute - Buffalo, NY
  More Information

No publications provided

Responsible Party: Plexxikon
ClinicalTrials.gov Identifier: NCT01349049     History of Changes
Other Study ID Numbers: PLX108-05
Study First Received: May 4, 2011
Last Updated: April 6, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Plexxikon:
AML
relapsed
refractory

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on May 27, 2015