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

NCT01349049 | Completed Phase 1 Results

• 1 other identifier: PLX108-05
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 9

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Keywords

AML; relapsed; refractory

Outcome Measures

Primary Outcomes (2)

• Summary of Best Modified Criteria Response Results, Bridged-to-Transplant (BTT) Participants, and Composite Remission Rates in Patients on Treatment With PLX3397 (Dose Expansion, Part 2).

  Complete remission (CR): Has bone marrow regenerating normal cells, achieve a morphologic leukemia-free state, Complete remission with incomplete platelet recovery (CRp): CR except for incomplete platelet recovery, Complete remission with incomplete recovery (CRi): CR except for incomplete hematological recovery with residual neutropenia, Partial response (PR): bone marrow generates normal hematopoietic cells, evidence of peripheral recovery with no or a few regenerating circulating blasts. Decrease of ≥50% of blasts in bone marrow aspirate, total marrow blasts between 5% -25%, Non-response (NR) were assessed using modified International Working Group (IWG) response criteria for AML. Successfully (BTT) patients and successfully BTT patients (CR, CRp, or CRi) are also reported. Successfully BTT is defined as any patient who discontinued PLX3397 treatment specifically for the purpose of undergoing a hematopoietic stem cell transplant and who subsequently received the planned transplant.

  1 year post dose

• Summary of Time-to-Event Endpoints in Patients on Treatment With PLX3397 (Dose Expansion, Part 2)

  Median survival estimates were based on the Kaplan-Meier method. In the event disease progression/relapse or death was not documented prior to study termination, endpoints were censored at the date of last evaluable tumor assessment. Duration of remission, duration of complete remission, and disease-free survival, initial response was based on the modified response criteria. Duration of complete remission was defined as the number of days from the date of initial CR, CRp, or CRi response to the date of first documented disease relapse or death, whichever occurred first. Disease-free survival was defined as the number of days from the date of initial CR, CRp, or CRi to the date of documented disease relapse or death from any cause, whichever occurred first.

  1 year post dose

Secondary Outcomes (6)

• Number of Participants With On-treatment Best Modified Criteria Response Results of Partial Remission (PR) During Treatment With PLX3397 (Dose Expansion, Part 2)

  1 year post dose

• Number of Participants With On-treatment Best Classic Criteria Response Results During Treatment With PLX3397 (Dose Expansion, Part 2)

  1 year post dose

• Number of Participants Reporting an Incidence of Adverse Events During Treatment With PLX3397 (Part 1, Dose Escalation and Part 2, Dose Expansion)

  1 year post dose

• Number of Participants Reporting an Incidence of Treatment-Related Treatment Emergent Adverse Events During Treatment With PLX3397 (Dose Escalation, Part 1 and Dose Expansion, Part 2)

  1 year post dose

• Number of Participants Reporting a Treatment Emergent Adverse Events With a CTCAE Grade ≥3 During Treatment With PLX3397 (Dose Escalation, Part 1 and Dose Expansion, Part 2)

  1 year post dose

Other Outcomes (1)

• A Summary of Time From Initial Dosing to First and Best Response, Modified Response Criteria in Patient Treated With PLX3397 (Dose Expansion, Part 2)

  1 year post dose

Study Arms (9)

oral dose of 3000 mg/day PLX3397 (RP2D)

EXPERIMENTAL

Subjects will be dosed at the recommended Phase 2 dose (RP2D)

Drug: PLX3397

oral dose of 800 mg/day of PLX3397

EXPERIMENTAL

Level 0

Drug: PLX3397

oral dose of 1000 mg/day PLX3397

EXPERIMENTAL

Level 1

Drug: PLX3397

oral dose of 1200 mg/day PLX3397

EXPERIMENTAL

Level 2

Drug: PLX3397

oral dose of 1400 mg/day PLX3397

EXPERIMENTAL

Level 3

Drug: PLX3397

oral dose of 2000 mg/day PLX3397

EXPERIMENTAL

Level 4

Drug: PLX3397

oral dose of 3000 mg/day PLX3397

EXPERIMENTAL

Level 5

Drug: PLX3397

oral dose of 4000 mg/day PLX3397

EXPERIMENTAL

Level 6

Drug: PLX3397

oral dose of 5000 mg/day PLX3397

EXPERIMENTAL

Level 7

Drug: PLX3397

Interventions

PLX3397 DRUG

Maximum Tolerated Dose of PLX3397 will be administered orally, twice daily.

Also known as: Plexxikon 3397

oral dose of 3000 mg/day PLX3397 (RP2D)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients ≥18 years old.
• Morphologically documented primary Acute Myeloid Leukemia (AML), prior-chemotherapy-related AML or AML secondary to an antecedent hematologic disorder (e.g., Myelodysplastic Syndrome) as defined by World Health Organization 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.
• 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.
• Refractory disease is defined by the failure to obtain a complete remission (CR) with a High-Dose Cytarabine (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.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Adequate recovery (to at least Grade 1) from toxicity of prior therapy as follows:
• ≥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.
• ≥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
• Adequate renal function, defined as Creatinine Clearance \>60 mL/min or serum creatinine of ≤ 1.3 mg/dL (115 μM).
• Adequate hepatic function, defined as Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤3.0X Upper limit of normal (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.

You may not qualify if:

• Diagnosis of acute promyelocytic leukemia
• Diagnosis of chronic myelogenous leukemia in blast crisis
• Presence of central nervous system (CNS) involvement of leukemia. Patients with a history of CNS involvement may be considered after discussion with the Medical Monitor
• Patients eligible for Hematopoietic Stem Cell Transplantation (HSCT) at the time of screening. However, patients who meet one or both of the following criteria may be eligible for study participation:
• 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.
• 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.
• 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, QT interval, Frederica's formula (QTcF) \>450 msec for males; QTcF \>470 msec for females
• Patients with a history of D835 mutations

Sponsors & Collaborators

• Daiichi Sankyo: lead
• Plexxikon: collaborator

Study Sites (9)

UCSF Helen Diller Family Family Comprehensive Cancer Center

San Francisco, California, 94143, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21231, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10022, United States

Location

New York Presby Hospital, Weill Medical College at Cornell University

New York, New York, 10065, United States

Location

University of Pennsylvania, Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

Related Publications (1)

• Smith CC, Levis MJ, Frankfurt O, Pagel JM, Roboz GJ, Stone RM, Wang ES, Severson PL, West BL, Le MH, Kayser S, Lam B, Hsu HH, Zhang C, Bollag G, Perl AE. A phase 1/2 study of the oral FLT3 inhibitor pexidartinib in relapsed/refractory FLT3-ITD-mutant acute myeloid leukemia. Blood Adv. 2020 Apr 28;4(8):1711-1721. doi: 10.1182/bloodadvances.2020001449.

  PMID: 32330242 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Recurrence

Interventions

pexidartinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Medical Director
• Organization: Daiichi Sankyo Inc.

CTRinfo@dsi.com

908-992-6400

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 4, 2011
• First Posted: May 6, 2011
• Study Start: November 21, 2011
• Primary Completion: January 20, 2015
• Study Completion: January 9, 2018
• Last Updated: March 2, 2020
• Results First Posted: November 21, 2019

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.

Locations

US (9)