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

Study Overview
=================
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.

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.

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)

Conditions
-----------------
Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: PLX3397
* Drug: PLX3397


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. 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: Surgically sterile Have been postmenopausal for ≥1 year Have Follicle Stimulating Hormone (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 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. 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 Graft vs. host disease [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 Graft vs. host disease. 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, QT interval, Frederica's formula (QTcF) >450 msec for males; QTcF >470 msec for females Patients with a history of D835 mutations

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: oral dose of 3000 mg/day PLX3397 (RP2D)<br>Subjects will be dosed at the recommended Phase 2 dose (RP2D) | Drug: PLX3397<br>* Maximum Tolerated Dose of PLX3397 will be administered orally, twice daily.<br>* Other names: Plexxikon 3397;|
| Experimental: oral dose of 800 mg/day of PLX3397<br>Level 0 | Drug: PLX3397<br>* The drug product is available in capsule form, to be taken orally.<br>* Other names: Plexxikon 3397;|
| Experimental: oral dose of 1000 mg/day PLX3397<br>Level 1 | Drug: PLX3397<br>* The drug product is available in capsule form, to be taken orally.<br>* Other names: Plexxikon 3397;|
| Experimental: oral dose of 1200 mg/day PLX3397<br>Level 2 | Drug: PLX3397<br>* The drug product is available in capsule form, to be taken orally.<br>* Other names: Plexxikon 3397;|
| Experimental: oral dose of 1400 mg/day PLX3397<br>Level 3 | Drug: PLX3397<br>* The drug product is available in capsule form, to be taken orally.<br>* Other names: Plexxikon 3397;|
| Experimental: oral dose of 2000 mg/day PLX3397<br>Level 4 | Drug: PLX3397<br>* The drug product is available in capsule form, to be taken orally.<br>* Other names: Plexxikon 3397;|
| Experimental: oral dose of 3000 mg/day PLX3397<br>Level 5 | Drug: PLX3397<br>* The drug product is available in capsule form, to be taken orally.<br>* Other names: Plexxikon 3397;|
| Experimental: oral dose of 4000 mg/day PLX3397<br>Level 6 | Drug: PLX3397<br>* The drug product is available in capsule form, to be taken orally.<br>* Other names: Plexxikon 3397;|
| Experimental: oral dose of 5000 mg/day PLX3397<br>Level 7 | Drug: PLX3397<br>* The drug product is available in capsule form, to be taken orally.<br>* Other names: Plexxikon 3397;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With On-treatment Best Modified Criteria Response Results of Partial Remission (PR) During Treatment With PLX3397 (Dose Expansion, Part 2) | Modified International Working Group Response Criteria for Acute Myeloid Leukemia defines Partial Remission (PR) as the following: Partial Remission (PR): Patients must have bone marrow regenerating normal hematopoietic cells with evidence of peripheral recovery with no (or only a few regenerating) circulating blasts and with a decrease of at least 50% in the percentage of blasts in the bone marrow aspirate with the total marrow blasts between 5% and 25%. In addition, patients do not need to be Red Blood Cell (RBC) or platelet transfusion independent. | 1 year post dose | 
| Number of Participants With On-treatment Best Classic Criteria Response Results During Treatment With PLX3397 (Dose Expansion, Part 2) | Complete Remission (CR): Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0 x 109/L (1000/μL); platelet count >100 x 109/L (100000/μL); red cell transfusion independent CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia (<1.0 x 109/L) or thrombocytopenia Partial Remission (PR): All hematologic criteria of CR; decrease of bone marrow blast percentage to 5-25%; decrease of pretreatment bone marrow blast percentage by at least 50%. | 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) | Data reported are Treatment-Related Treatment Emergent Adverse Events that are ≥15% Occurrence in all patients. | 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) | Data reported are Treatment Emergent Adverse Events with a CTCAE Grade ≥3 During Treatment that are ≥10% Occurrence in all patients. | 1 year post dose | 
| Number of Participants With Clinically Significant Abnormal Chemistry and Hematology Values Reported as Adverse Events (AE) During Treatment With PLX3397 (Dose Escalation, Part 1 and Dose Expansion, Part 2) |  | 1 year post dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AML, relapsed, refractory