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

NCT03057990 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: 2019-10346
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Myelodysplastic Syndromes

Keywords

Pyrimethamine; Myelodysplastic Syndromes (MDS); Refractory; Relapsed

Outcome Measures

Primary Outcomes (3)

• 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

Study Arms (1)

Pyrimethamine Treatment (Intra-patient)

EXPERIMENTAL

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

Interventions

Pyrimethamine DRUG

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.

Also known as: Daraprim

Pyrimethamine Treatment (Intra-patient)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Montefiore Medical Center: lead
• Albert Einstein College of Medicine: collaborator

Study Sites (1)

Montefiore Medical Center

The Bronx, New York, 10467, United States

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Recurrence

Interventions

Pyrimethamine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Aditi Shastri, MD

  Montefiore Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 30, 2016
• First Posted: February 20, 2017
• Study Start: September 11, 2019
• Primary Completion: June 29, 2021
• Study Completion: June 29, 2021
• Last Updated: September 22, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)