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

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• Status: Withdrawn
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Pyrimethamine

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: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicity (DLT)	Determination of DLT to be made at the completion of each cohort.	Day 28
Maximum tolerated dose (MTD)	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)	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

• Sponsor: Montefiore Medical Center
• Collaborators: Albert Einstein College of Medicine
• Investigators: Principal Investigator: Aditi Shastri, MD, Montefiore Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 11, 2019
• Primary Completion (ACTUAL): June 29, 2021
• Study Completion (ACTUAL): June 29, 2021

Study Registration Dates

• First Submitted: November 30, 2016
• First Submitted That Met QC Criteria: February 15, 2017
• First Posted (ACTUAL): February 20, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 22, 2021
• Last Update Submitted That Met QC Criteria: September 15, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Relapsed; Refractory; Myelodysplastic Syndromes (MDS); Pyrimethamine
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Pyrimethamine
• Other Study ID 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