Pyrimethamine for Intermediate/High-risk Myelodysplastic Syndromes (MDS)

September 15, 2021 updated by: Montefiore Medical Center

A Phase 1 Study of Pyrimethamine, a STAT3 Inhibitor, for the Treatment of Intermediate/ High-risk Myelodysplastic Syndromes (MDS) That Has Relapsed or is Refractory to Azanucleosides

This is a phase I study designed to assess the maximum tolerated dose (MTD) of pyrimethamine and provide the recommended Phase 2 dose (RP2D) for the treatment of intermediate/high-risk MDS that is refractory to or relapsed after treatment with azanucleosides.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Withdrawn

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The objective of this study is to determine the safety, dose tolerance, pharmacokinetics and pharmacodynamics of pyrimethamine in intermediate / high-risk / relapsed or azanucleoside-refractory MDS within the confines of a phase I study.

Pyrimethamine self-administered by participants orally once per day in morning with food. Phase 1 study will start at dose of 50 mg once per day. (NOTE: For participants at dose level of 50mg, the dose reduction, if needed is 25 mg.)

Intra-patient dose escalation is permitted (not beyond the highest dose allowed) if Complete Remission/Response (CR) is not reached in week 1 of Cycle 3 and there is no significant toxicity. (NOTE: In this study, the term "intra-patient" indicates within each participant and not between different participants; i.e., dose escalation will be done within each individual participant.) The decision to escalate intra-patient doses will be based on safety and dose tolerance assessments made at the end of one treatment cycle (28 days of continuous drug administration) for all 6 participants. Dose-limiting toxicity (DLT) is defined as the occurrence of two consecutive grade 2 or 3 serious adverse events (SAEs) not recovered within 24 hours at a given dose. MTD will be defined as the dose where no DLT is observed among three consecutive participants, or no more than one DLT among six participants. Participants will be treated initially for one 28-day cycle followed by a toxicity evaluation - Toxicity and adverse effect assessments will be made on Day 1 and Day 28 of every cycle of therapy.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • Bronx, New York, United States, 10467
        • Montefiore Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Participants at or above the age of 18 years
  • Diagnosis of MDS confirmed within 6 months, by review of patient chart, prior to study entry according to WHO (World Health Organization) criteria or FAB (French-American-British) classification
  • MDS classified as intermediate-1, intermediate-2 or high risk as per the International Prognostic Scoring System-Revised (IPSS-R) score with a confirmed diagnosis of MDS with cytogenetic abnormalities at diagnosis and bone marrow blast percentage between 10 and 30 percent (for patients with cytogenetic failure or dry tap)

  • Potential participants must meet ONE of the following:

    • Progression (according to 2006 International Working Group (IWG) criteria) at any time after initiation of azacitidine or decitabine treatment during the past 3 years; OR
    • Failure to achieve complete or partial response or hematological improvement (according to 2006 IWG) after at least four cycles of azacitidine or decitabine administered during the past 3 years OR
    • Relapse after initial complete or partial response or hematological improvement (according to 2006 IWG criteria) observed after at least four cycles of azacitidine or decitabine administered during the past 3 years OR
    • Intolerance to azacitidine or decitabine defined by drug-related more than or equal to Grade 3 liver or renal toxicity leading to treatment discontinuation during the past 3 years
  • Off all other treatments for MDS for at least 3 weeks. Filgrastim (G-CSF) and erythropoietin are allowed before and during the study as clinically indicated
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
  • Willing to adhere to the prohibitions and restrictions specified in this protocol
  • Patient (or patient's legally authorized representative) must signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study
  • Adequate organ and marrow function as defined in the protocol.
  • Women of child-bearing potential and men with partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy.

Exclusion Criteria:

  • Current or anticipated use of other investigational agents
  • Participants who have had chemotherapy or radiotherapy within 3 weeks prior to entering the study or those who have not recovered from clinically significant adverse events due to agents administered more than 3 weeks earlier.
  • History of allergic reactions or sensitivity to pyrimethamine
  • Patients with a history of folic acid deficiency, currently on folic acid replacement therapy or a previous history of megaloblastic anemia thought related to folic acid deficiency
  • Current use or anticipated need for treatment with any medications or substances that are inhibitors or inducers of CYP2C9.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant or nursing women

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Pyrimethamine Treatment (Intra-patient)
50mg/100mg/150mg once daily on days 1-28 of each 28-day cycle. Administered using intra-patient dose escalation, starting at 50 mg and up to 150 mg.
Drug: Pyrimethamine
Pyrimethamine will be administered 50mg/100mg/150mg once daily on days 1-28 of each 28-day cycle. Administered using intra-patient dose escalation, starting at 50 mg and up to 150 mg.
Other Names:
  • Daraprim

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Dose-limiting toxicity (DLT)
Time Frame: Day 28
Determination of DLT to be made at the completion of each cohort.
Day 28
Maximum tolerated dose (MTD)
Time Frame: up to 28 days
The dose where no DLT is observed among 3 consecutive participants, or no more than one DLT among 6 participants.
up to 28 days
Recommended Phase II Dose (RPTD, RP2D)
Time Frame: 12 months
Pyrimethamine will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicity information from all participants.
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Montefiore Medical Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Albert Einstein College of Medicine

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Aditi Shastri, MD, Montefiore Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 11, 2019

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 29, 2021

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 29, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 30, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 15, 2017

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 20, 2017

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 22, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 15, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2019-10346

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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