Dose Escalation of OXi4503 as Single Agent and Combination With Cytarabine w/Subsequent Ph 2 Cohorts for AML and MDS

Study Overview
=================
Brief Summary
-----------------
Phase 1 will investigate maximum tolerated dose of OXi4503 as a single agent and in combination with intermediate-dose cytarabine in subjects with relapsed/refractory AML or MDS. Phase 2 will investigate overall response rate of OXi4503 in combination with intermediate-dose cytarabine in 1) subjects with MDS after failure of 1 prior hypomethylating agent (Arm A) and 2) subjects with relapsed and refractory AML after treatment failure of up to 1 prior chemotherapy regimen (Arm B).

Detailed Description
-----------------
Phase 1 dose escalation component will assess the safety, PK/PD, and preliminary efficacy of OXi4503 as a single agent in subjects with relapsed/refractory AML and MDS, and the safety and PK/PD of the combination of OXi4503 with intermediate-dose cytarabine in subjects with AML/MDS. Phase 2 will assess the preliminary efficacy of the OXi4503+cytarabine combination in 2 cohorts.

Official Title
-----------------
Ph 1b Dose Escalation Study of OXi4503 as a Single Agent and in Combination With Cytarabine With Subsequent Phase 2 Cohorts for Subjects With Relapsed/Refractory Acute AML and MDS

Conditions
-----------------
Acute Myelogenous Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: Phase 1 - OXi4503
* Drug: Phase 1 - OXi4503 + cytarabine
* Drug: Phase 2 - OXi4503 + cytarabine
* Drug: Phase 2 - OXi4503 + cytarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provide informed consent ≥ 18 years of age Phase 1 (dose escalation) subjects must have either: AML that has failed to achieve complete remission or morphologic complete remission or MDS - Marrow blasts must be > 5% and disease failed at least 1 prior hypomethylating agent Phase 2 (expansion) subjects must have either MDS or relapsed/refractory AML Eastern Cooperative Oncology Group performance status 0, 1, or 2 Total bilirubin ≤ 2 Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 2.5 times upper limit of normal (ULN) Serum creatinine < 2.5 times ULN Prothrombin time (PT)/international normalized ratio and (PTT) in normal range ± 25% Women of child-bearing potential Males with female partners of child-bearing potential must agree to use physician-approved contraceptive methods Exclusion Criteria: Acute promyelocytic leukemia Absolute peripheral blood myeloblast count greater than 20,000/mm3 Uncontrolled hypertension History of congenital long QT syndrome or torsades de pointes Pathologic bradycardia or heart block Prolonged baseline QTc Hiistory of ventricular arrhythmia Myocardial infarction and/or new ST elevation Any history of hemorrhagic stroke Symptomatic congestive heart failure Major hemorrhagic event within 28 days Suggestive central nervous system involvement with leukemia Any open wound Pregnant and nursing subjects are excluded Treatment with any anticancer therapy Treatment with colchicine is excluded. Psychiatric disorders that would interfere with consent

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: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2 AML<br>OXi4503 at MTD plus cytarabine 1g/m2/day | Drug: Phase 2 - OXi4503 + cytarabine<br>* Safety and efficacy of the combination of OXi4503 + cytarabine in subjects with AML<br>* Other names: combretastatin A1-diphosphate;|
| Experimental: Phase 2 MDS<br>OXi4503 at MTD plus cytarabine 1g/m2/day | Drug: Phase 2 - OXi4503 + cytarabine<br>* Safety and efficacy of the combination of OXi4503 + cytarabine in subjects with MDS<br>* Other names: combretastatin A1-diphosphate;|
| Experimental: OXi4503 dose escalation<br>MTD for OXi4503 will be determined | Drug: Phase 1 - OXi4503<br>* Determination of MTD of OXi4503<br>* Other names: combretastatin A1-diphosphate;|
| Experimental: OXi4503 + cytarabine dose escalation<br>MTD of the combination of OXi4503 + cytarbine will be determined | Drug: Phase 1 - OXi4503 + cytarabine<br>* Determination of MTD of the combination of OXi4503 + cytarabine<br>* Other names: combretastatin A1-diphosphate;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b:MTD of OXi4503 as a single agent and in combination with intermediate-dose cytarabine in subjects with relapsed/refractory AML or MDS |  | 1 year | 
| Phase 2: Overall response rate of OXi4503 in combination with intermediate-dose cytarabine in subjects with MDS after failure of 1 prior hypomethylating agent (Arm A), and subjects with relapsed and refractory AML after treatment failure of up |  | 2 years | 

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