Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia
Conditions
Keywords
CLL, SLL, relapsed, pyrimethamine
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.
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.
Interventions
DRUGpyrimethamine
Taken orally once a day
Sponsors
Brigham and Women's Hospital
Beth Israel Deaconess Medical Center
Lymphoma Research Foundation
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Maximum Tolerated Dose (MTD) | 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 |
| Phase II: Overall Response Rate (ORR) | 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
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Grade 3 or Higher Treatment-Related Toxicity | 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. |
| Median Progression Free Survival (PFS) | 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. |
Countries
United States
Participant flow
Recruitment details
from May 2010 to April 2012
Participants by arm
| Arm | Count |
|---|---|
| DL1: Pyrimethamine 12.5 mg Pyrimethamine single daily oral 12.5 mg dose. | 3 |
| DL2: Pyrimethamine 25 mg Pyrimethamine single daily oral 25 mg dose. | 3 |
| DL3: Pyrimethamine 50 mg Pyrimethamine single daily oral 50 mg dose. | 10 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | DL1: Pyrimethamine 12.5 mg | DL2: Pyrimethamine 25 mg | DL3: Pyrimethamine 50 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 53 years | 54 years | 60 years | 56 years |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 3 Participants | 9 Participants | 14 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 10 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 10 / 10 |
| serious Total, serious adverse events | 1 / 3 | 2 / 3 | 6 / 10 |
Outcome results
Primary
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.
Time frame: Within 10 days of the completion of the cycle required for response evaluation
Population: The phase 2 study were not done and data not collected
Primary
Phase I: Maximum Tolerated Dose (MTD)
maximum tolerated dose and recommended Phase 2 dose pyrimethamine
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pyrimethamine Phase 1 (Dose-escalation) | Phase I: Maximum Tolerated Dose (MTD) | NA mg |
Secondary
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pyrimethamine Phase 1 (Dose-escalation) | Incidence of Grade 3 or Higher Treatment-Related Toxicity | 1 number of new cases per 1000 person year |
| DL2: Pyrimethamine 25 mg | Incidence of Grade 3 or Higher Treatment-Related Toxicity | 5 number of new cases per 1000 person year |
| DL3: Pyrimethamine 50 mg | Incidence of Grade 3 or Higher Treatment-Related Toxicity | 8 number of new cases per 1000 person year |
Secondary
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.
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pyrimethamine Phase 1 (Dose-escalation) | Median Progression Free Survival (PFS) | 1.116 months |
| DL2: Pyrimethamine 25 mg | Median Progression Free Survival (PFS) | 3.677 months |
| DL3: Pyrimethamine 50 mg | Median Progression Free Survival (PFS) | 0.969 months |