PR104 in Treating Patients With Refractory/Relapsed Acute Leukemia

Sponsor

Proacta, Incorporated (Industry)

Overall Status

Unknown status

CT.gov ID

NCT01037556

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The current understanding of PR104 justifies the evaluation of PR104 in subjects with relapsed/refractory AML and ALL. These include:

Hypoxia. Leukemic bone marrow is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M.
Myelotoxicity as the primary toxicity at MTD. In prior clinical studies in subjects with solid tumors PR104 has demonstrated myelotoxicity as the primary toxicity. This observation suggests that PR104 will exert a similar effect on leukemic cells.
AKR1C3. AML has been reported to exhibit high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic leukemic cells.
Preclinical data. PR104 has demonstrated impressive activity in an initial study using primary human ALL in a mouse model.

The initial dose finding phase of the study will provide estimates of the activity and toxicity of PR104 in subjects with refractory/relapsed AML, and determine the optimal individualized dose to give each subject based on his/her covariates (prior CR duration, prior number of salvage therapies, age). Once a potentially beneficial dose has been determined, an expanded cohort of subjects with AML or ALL will receive PR104 at a uniform dose. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity and acceptable safety in AML to warrant future phase II or phase III studies in this indication.

Primary objectives

Determine the toxicities and recommended dose of PR104 when administered IV to subjects with relapsed/refractory AML and ALL.

Secondary objectives

Evaluate the pharmacokinetics (PK) of PR104 and a series of PR104 metabolites
Evaluate any anti-tumor effects of PR104
Evaluate the expression of AKR1C3 in bone marrow and leukemic cells
Evaluate potential biomarkers of hypoxia

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia Acute Lymphocytic Leukemia	Drug: PR104	Phase 1/Phase 2

Detailed Description

A single arm study defining the recommended dose of PR104 for each subpopulation in this patient population.

Following informed consent, subjects will undergo baseline evaluation with a history, physical exams, blood work, and disease assessment. Subjects will be assigned a dose of PR104 based on a Bayesian model maintained at the Statistical department at MD Anderson Cancer Center. The model will be updated with both toxicity and efficacy data as it is generated for each subject. New subjects will receive the currently predicted best dose for their respective subset based on prior treatment, age and duration of prior response.

PR104 will be administered initially as induction therapy for up to 3 cycles. Response will be assessed around day 42 (+/- 2 days) of the study. Subjects who obtain a CR or CRp will receive consolidation therapy for up to 4 additional cycles.

Subjects will be evaluated each week during the induction phase of the study. During the consolidation phase of the study, subjects will be evaluated on Day 1 of each cycle and as clinically indicated. Subjects with clinically significant progression will be removed from study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I/II Study of PR104 in Subjects With Refractory/Relapsed Acute Leukemia Using Adaptive Dose Selection

Study Start Date :

Jan 1, 2010

Anticipated Primary Completion Date :

Dec 1, 2012

Anticipated Study Completion Date :

Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: PR104	Drug: PR104 Nine pre-defined dose levels for specific subsets of subjects will be administered by IV (in the vein). PR104 will be administered initially as induction therapy followed by administration as consolidation therapy, as is typical of established treatment regimens in AML.

Arm

Intervention/Treatment

Experimental: Arm 1: PR104

Drug: PR104

Nine pre-defined dose levels for specific subsets of subjects will be administered by IV (in the vein). PR104 will be administered initially as induction therapy followed by administration as consolidation therapy, as is typical of established treatment regimens in AML.

Outcome Measures

Primary Outcome Measures

Determine the optimal individualized dose to give each refractory/relapsed AML subject based on his/her covariates (prior CR duration, prior number of salvage therapies, age). [42 days]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed informed consent
Age 18 years or more
Histologically diagnosed acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) by WHO classification
Refractory or relapsed disease (requiring at least 5% leukemic blasts in the bone marrow, regardless of the presence of other features such as new or recurrent dysplastic changes or extramedullary disease) according to the following definitions:

AML Relapsed (defined as ≥5% leukemic blasts in the bone marrow) after receiving up to 2 prior induction regimens, (i.e., first or second relapse); Refractory (defined as ≥5% leukemic blasts in the bone marrow) to not more than 1 prior induction regimen (defined as failure to achieve a CR or CRp following induction therapy), (i.e., up to 1 induction failure).

ALL Relapsed/refractory (defined as ≥5% leukemic blasts in the bone marrow) after receiving 1 or more prior induction regimens, (i.e., any number of relapses)

ECOG performance status of 0-2
At least 2 weeks from administration of prior anti-leukemia therapy unless subject has progressed while receiving targeted therapy on a continuous dosing schedule
No remaining clinically significant toxicities from prior chemotherapy of grade 2 or greater
Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must be willing to use an acceptable contraceptive method (abstinence, oral contraceptive or double barrier device) for the duration of the study and for 30 days following the last dose of study drug, and must have a negative urine or serum pregnancy test within 2 weeks prior to beginning treatment on this trial
Sexually active men must be willing to use an acceptable contraceptive method for the duration of time on study and for 30 days following the last dose of study drug
Clinical laboratory values within the following ranges unless considered due to leukemic organ involvement: Serum creatinine 2.0 mg/dl; Total bilirubin 1.5x the upper limit of normal unless considered due to Gilbert's syndrome; Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) 3x the upper limit of normal
Willingness to provide at least one pre-PR104 leukemia sample (e.g., bone marrow or peripheral blood) for analysis of AKR1C3.

Exclusion Criteria:

Pregnant and nursing subjects
Uncontrolled intercurrent illness including, but not limited to uncontrolled infection, symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Active heart disease including myocardial infarction within previous 3 months, symptomatic coronary artery disease, arrhythmias not controlled by medication, or uncontrolled congestive heart failure
Another active concomitant malignancy likely to effect any of the primary or secondary outcome measures in the current study
Subjects receiving any other standard or investigational treatment for their hematologic malignancy (other than hydroxyurea). Subjects with CNS leukemia are eligible and may receive concurrent standard intrathecal chemotherapy.