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Pyrimethamine for the Treatment of Relapsed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01066663
Recruitment Status : Recruiting
First Posted : February 10, 2010
Last Update Posted : January 6, 2020
Brigham and Women's Hospital
Beth Israel Deaconess Medical Center
Lymphoma Research Foundation
Information provided by (Responsible Party):
Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute

Brief Summary:
In this research study we will start by looking for the highest dose of pyrimethamine that can be given safely to CLL patients without severe or unmanageable side effects. This dose will then be used for a larger Phase II study to assess the efficacy of pyrimethamine for the treatment of CLL/SLL. Pyrimethamine is an antibiotic that is used for the treatment of certain infections. Previous research studies have shown that pyrimethamine may target a protein in tumor cells, called STAT3, which may be important for the growth of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) cells. Pyrimethamine can kill CLL/SLL cells in the laboratory, and we are therefore undertaking this study to assess whether pyrimethamine will result in clinical benefit or tumor responses in CLL in patients.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Small Lymphocytic Leukemia Drug: pyrimethamine Phase 1 Phase 2

Detailed Description:
  • Participants will be required to enroll in DFCI Protocol 99-224, the CLL Research Consortium Tissue Bank, and DFCI Protocol 01-206, Tissue and Data Collection for Research Studies in Patients with Hematologic Malignancies, Bone Marrow Disorders, and Normal Donors, or may have blood banked for future use.
  • Each treatment cycle lasts 28 days during which time participants will take pyrimethamine orally once per day. Since we are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects, not everyone who participates will receive the same dose of study drug.
  • The following tests and procedures will be performed at specific time points during participation in the study: Physical exam, vital signs, blood tests and bone marrow biopsy. The participant's tumor will be assessed by CT scans of the chest, abdomen and pelvis prior to the start of the study and at the end of the 1st, 3rd and 6th months.
  • Participants can continue to receive pyrimethamine as long as they do not have side effects and their disease does not worsen.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Pyrimethamine, a STAT3 Inhibitor, for the Treatment of Relapsed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Actual Study Start Date : March 2010
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2024

Arm Intervention/treatment
Experimental: Pyrimethamine
Single daily oral 50 mg dose.
Drug: pyrimethamine
Taken orally once a day
Other Name: daraprim

Primary Outcome Measures :
  1. Phase I: To determine the maximum tolerated dose and recommended Phase 2 dose of pyrimethamine in relapsed CLL/SLL [ Time Frame: 1 year ]
  2. Phase II: To determine the overall response rate of pyrimethamine in relapsed CLL/SLL. [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. To assess the toxicity profile of pyrimethamine in relapsed CLL/SLL, both acutely and over prolonged daily dosing. [ Time Frame: 2 years ]
  2. To determine pyrimethamine levels in vivo with prolonged dosing. [ Time Frame: 2 years ]
  3. To determine the progression-free survival following pyrimethamine for the treatment of relapsed CLL/SLL [ Time Frame: 2 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Diagnosed with CLL/SLL based on the standard histologic and immunophenotypic criteria described in the WHO classification of lymphoid malignancies, including immunophenotypic confirmation that the tumor cells co-express B cell antigens CD19/20 and CD5. Mantle cell lymphoma should be excluded based on positive staining of the tumor cells for CD23, or the absence of staining of the tumor cells for cyclin D1 or the absence of t(11;14). This diagnosis should be confirmed at a Dana-Farber/Harvard Cancer Center institution within approximately one month after the subject is registered.
  • Measurable disease, defined as lymphocytosis > 5,000/uL, or at least one palpable or CT measurable lesion > approximately 1.5cm, or bone marrow involvement > approximately 30%
  • Relapsed after at least one prior purine analogue-containing regimen, or at least two non-purine analogue containing regimens
  • 18 years of age or older
  • Life expectancy of greater than 3 months
  • ECOG performance status of 0, 1 or 2
  • Normal organ function as outlined in the protocol
  • Require treatment based on IWCLL 2008 criteria
  • Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation.

Exclusion Criteria:

  • 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.
  • May not be receiving any other study agents
  • Known CNS involvement with CLL
  • History of allergic reactions or sensitivity to pyrimethamine
  • Patients taking folic acid are eligible if the folic acid is discontinued prior to pyrimethamine administration and not taken for the duration of time enrolled on this study
  • Prior allogeneic SCT is an exclusion only if the subject has active graft vs. host disease or requires immunosuppression other than a constant stable dose of glucocorticoids
  • Uncontrolled intercurrent illness
  • Pregnant or breastfeeding women
  • HIV-positive individuals on combination antiretroviral therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01066663

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Contact: Jennifer Brown, MD, PhD 617-632-4165
Contact: Kalin Goldstone, MD, PhD 617-582-8713 Kalin_Goldstone@DFCI.HARVARD.EDU

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United States, Massachusetts
Beth Israel Deaconess Medical Center Completed
Boston, Massachusetts, United States, 02115
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Principal Investigator: Jennifer Brown, MD, PhD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Beth Israel Deaconess Medical Center
Lymphoma Research Foundation
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Principal Investigator: Jennifer Brown, MD, PhD Dana-Farber Cancer Institute

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Responsible Party: Jennifer R. Brown, MD, PhD, Assistant Professor of Medicine, Dana-Farber Cancer Institute Identifier: NCT01066663    
Other Study ID Numbers: 09-421
First Posted: February 10, 2010    Key Record Dates
Last Update Posted: January 6, 2020
Last Verified: January 2020
Keywords provided by Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute:
Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action