Acute Myelogenous LeukemiaPhase 1/2NCT01037556
PR104 in Treating Patients With Refractory/Relapsed Acute Leukemia
A Phase 1/2 study testing PR104 in people with Acute Myelogenous Leukemia and Acute Lymphocytic Leukemia, run by Proacta, Incorporated at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia
- What is being tested?
- PR104
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 2 sitesUnited States
- Study dates
- Jan 2010to Dec 2012
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Show all 13Show fewer
- 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.
Who cannot join
- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
MD Anderson Cancer Center
Houston, Texas, 77030
Seattle Cancer Care Alliance
Seattle, Washington, 98109
About this study
Official title: Phase I/II Study of PR104 in Subjects With Refractory/Relapsed Acute Leukemia Using Adaptive Dose Selection
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.
Read more
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
Read the 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.
- Being tested
- PR104
- Keywords
- AML, Acute Myeloid Leukemia, Acute Myelogenous Leukemia, Refractory AML, Relapsed AML, Refractory Acute Myeloid Leukemia, Relapsed Acute Myeloid Leukemia, Refractory Acute Myelogenous Leukemia, Relapsed Acute Myelogenous Leukemia, ALL, Acute Lymphocytic Leukemia, Relapsed Acute Lymphocytic Leukemia, Refractory Acute Lymphocytic Leukemia, Relapsed ALL, Refractory ALL
- Medical subject headings
- Leukemia, Myeloid, Acute, Precursor Cell Lymphoblastic Leukemia-Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PR104Drug
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.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1: PR104 | Experimental | Not described Receives: Drug: PR104 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 42 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Dec 2009 (estimated)
- Study startJan 2010
- Primary completionDec 2012 (estimated)
- Study completionDec 2012 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute Myelogenous LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Proacta, Incorporated
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01037556
- Sponsor's protocol ID
- PR104-2004
- Status last verified
- Aug 2012
- First submitted
- 21 Dec 2009
- Last updated
- 31 Aug 2012
- Results posted
- No
- Data monitoring committee
- No
Publications
Konopleva M, Thall PF, Yi CA, Borthakur G, Coveler A, Bueso-Ramos C, Benito J, Konoplev S, Gu Y, Ravandi F, Jabbour E, Faderl S, Thomas D, Cortes J, Kadia T, Kornblau S, Daver N, Pemmaraju N, Nguyen HQ, Feliu J, Lu H, Wei C, Wilson WR, Melink TJ, Gutheil JC, Andreeff M, Estey EH, Kantarjian H. Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia. Haematologica. 2015 Jul;100(7):927-34. doi: 10.3324/haematol.2014.118455. Epub 2015 Feb 14.
PubMed 25682597
Study at a glance
From the registry record, last updated by the sponsor on 31 Aug 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Study of PR104 in Subjects With Refractory/Relapsed Acute Leukemia Using Adaptive Dose Selection
- ClinicalTrials.gov ID
- NCT01037556
- Acronym / sponsor ID
- PR104-2004
- Keywords
- AML, Acute Myeloid Leukemia, Acute Myelogenous Leukemia, Refractory AML, Relapsed AML, Refractory Acute Myeloid Leukemia, Relapsed Acute Myeloid Leukemia, Refractory Acute Myelogenous Leukemia
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Proacta, IncorporatedIndustry (pharma, biotech, devices)
- Study start
- Jan 2010
- Primary completion
- Dec 2012 (estimated)
- Study completion
- Dec 2012 (estimated)
- First posted
- 23 Dec 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Arm 1: PR104 | Experimental | Drug: PR104 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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).
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PR104Nine 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. | Drug | Arm 1: PR104 |
Primary outcome
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).
Time frame: 42 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Aug 2012.
- Derived from this study: PubMed 25682597Konopleva M, Thall PF, Yi CA, Borthakur G, Coveler A, Bueso-Ramos C, Benito J, Konoplev S, Gu Y, Ravandi F, Jabbour E, Faderl S, Thomas D, Cortes J, Kadia T, Kornblau S, Daver N, Pemmaraju N, Nguyen HQ, Feliu J, Lu H, Wei C, Wilson WR, Melink TJ, Gutheil JC, Andreeff M, Estey EH, Kantarjian H. Phase I/II study of the hypoxia-activated prodrug PR104 in refractory/relapsed acute myeloid leukemia and acute lymphoblastic leukemia. Haematologica. 2015 Jul;100(7):927-34. doi: 10.3324/haematol.2014.118455. Epub 2015 Feb 14.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing PR104 in people with Acute Myelogenous Leukemia and Acute Lymphocytic Leukemia, run by Proacta, Incorporated at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 31 Aug 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). (time frame: 42 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01037556, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Aug 2012.