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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II Study of Pyrimethamine, a STAT3 Inhibitor, for the Treatment of Relapsed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia

Intervention / Treatment
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* Drug: pyrimethamine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DL1: Pyrimethamine 12.5 mg<br>Pyrimethamine single daily oral 12.5 mg dose. | Drug: pyrimethamine<br>* Taken orally once a day<br>* Other names: daraprim;|
| Experimental: DL2: Pyrimethamine 25 mg<br>Pyrimethamine single daily oral 25 mg dose. | Drug: pyrimethamine<br>* Taken orally once a day<br>* Other names: daraprim;|
| Experimental: DL3: Pyrimethamine 50 mg<br>Pyrimethamine single daily oral 50 mg dose. | Drug: pyrimethamine<br>* Taken orally once a day<br>* Other names: daraprim;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose (MTD) | maximum tolerated dose and recommended Phase 2 dose pyrimethamine | 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. | 
| Phase II: Overall Response Rate (ORR) | 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. | Within 10 days of the completion of the cycle required for response evaluation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Grade 3 or Higher Treatment-Related Toxicity | 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. | 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. | 
| Median Progression Free Survival (PFS) | 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, SLL, relapsed, pyrimethamine