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

• ClinicalTrials.gov Identifier: NCT01066663
• Recruitment Status: Completed
• First Posted: February 10, 2010
• Results First Posted: December 1, 2022
• Last Update Posted: February 22, 2023
• Sponsor: Dana-Farber Cancer Institute
• Collaborators: 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

Study Description

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential 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
• Actual Primary Completion Date: February 2022
• Actual Study Completion Date: January 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: DL1: Pyrimethamine 12.5 mg; Pyrimethamine single daily oral 12.5 mg dose.	Drug: pyrimethamine; Taken orally once a day; Other Name: daraprim
Experimental: DL2: Pyrimethamine 25 mg; Pyrimethamine single daily oral 25 mg dose.	Drug: pyrimethamine; Taken orally once a day; Other Name: daraprim
Experimental: DL3: Pyrimethamine 50 mg; Pyrimethamine single daily oral 50 mg dose.	Drug: pyrimethamine; Taken orally once a day; Other Name: daraprim

Outcome Measures

Primary Outcome Measures :

1. Phase I: Maximum Tolerated Dose (MTD) [ Time Frame: Disease were evaluated weekly in 1st 28 days, and every 2 weeks in 2nd cycle then monthly. Median treatment duration is 1.07 months with range 0.23-9.99 months. ]
   maximum tolerated dose and recommended Phase 2 dose pyrimethamine
2. Phase II: Overall Response Rate (ORR) [ Time Frame: Within 10 days of the completion of the cycle required for response evaluation ]
   The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

Secondary Outcome Measures :

1. Incidence of Grade 3 or Higher Treatment-Related Toxicity [ Time Frame: Disease were evaluated weekly in 1st 28 days, and every 2 weeks in 2nd cycle then monthly. Median treatment duration is 1.07 months with range 0.23-9.99 months. ]
   All grade 3 or higher adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAE as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 3 or higher AE of any type during the time of observation.
2. Median Progression Free Survival (PFS) [ Time Frame: Disease were evaluated weekly in 1st 28 days, and every 2 weeks in 2nd cycle then monthly, and every 3-6 months during the follow-up. ]
   Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02115

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Dana-Farber Cancer Institute

Brigham and Women's Hospital

Beth Israel Deaconess Medical Center

Lymphoma Research Foundation

Investigators

• Principal Investigator: Jennifer Brown, MD, PhD; Dana-Farber Cancer Institute

  Study Documents (Full-Text)

Documents provided by Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute:

Study Protocol and Statistical Analysis Plan  [PDF] May 10, 2016

More Information

• Responsible Party: Jennifer R. Brown, MD, PhD, Assistant Professor of Medicine, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01066663
• Other Study ID Numbers: 09-421
• First Posted: February 10, 2010
• Results First Posted: December 1, 2022
• Last Update Posted: February 22, 2023
• Last Verified: January 2023

Keywords provided by Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute:

CLL; SLL; relapsed; pyrimethamine

Additional relevant MeSH terms:

Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Disease Attributes; Pathologic Processes; Pyrimethamine; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Folic Acid Antagonists; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action