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

Condition(s) targeted: Chronic Lymphocytic Leukemia; Small Lymphocytic Leukemia

Intervention: pyrimethamine (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Dana-Farber Cancer Institute

Official(s) and/or principal investigator(s):
Jennifer Brown, MD, PhD, Principal Investigator, Affiliation: Dana-Farber Cancer Institute

Overall contact:
Jennifer Brown, MD, PhD, Phone: 617-632-6692

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.

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

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Phase I: To determine the maximum tolerated dose and recommended Phase 2 dose of pyrimethamine in relapsed CLL/SLL

Phase II: To determine the overall response rate of pyrimethamine in relapsed CLL/SLL.

Secondary outcome:

To assess the toxicity profile of pyrimethamine in relapsed CLL/SLL, both acutely and over prolonged daily dosing.

To determine pyrimethamine levels in vivo with prolonged dosing.

To determine the progression-free survival following pyrimethamine for the treatment of relapsed CLL/SLL

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Jennifer Brown, MD, PhD, Phone: 617-632-6692

Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, United States; Recruiting
Robin Joyce, MD, Principal Investigator

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States; Recruiting
Jennifer Brown, MD, PhD, Principal Investigator

Starting date: March 2010
Last updated: December 12, 2014