Leukemia
Conditions
Keywords
B-cell chronic lymphocytic leukemia, stage 0 chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia
Brief summary
RATIONALE: Green tea extract contains ingredients that may slow the growth of certain cancers. PURPOSE: This phase I/II trial is studying the side effects and best dose of green tea extract and to see how well it works in treating patients with stage 0, stage I, or stage II chronic lymphocytic leukemia (CLL).
Detailed description
OBJECTIVES: Phase I * Determine the maximally tolerated dose of green tea extract (Polyphenon E) in patients with previously untreated stage 0-II chronic lymphocytic leukemia. * Describe the dose-limiting toxicity of green tea extract (Polyphenon E). Phase II * Evaluate the response rate and response duration of patients with previously untreated, asymptomatic Rai stage 0-II chronic lymphocytic leukemia treated with green tea extract (Polyphenon E) for 6 months at the MTD. * Further characterize toxicity. OUTLINE: This is a phase I, dose-escalation study of green tea extract (Polyphenon E) followed by a phase II study. * Phase I: Patients receive oral green tea extract (Polyphenon E) once or twice daily for 4 weeks. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of green tea extract (Polyphenon E) until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. * Phase II: Patients receive green tea extract (Polyphenon E) as in the phase I portion of the study at the MTD. After completion of study treatment, patients are followed periodically for up to 5 years. PROJECTED ACCRUAL: A total of 73 patients will be accrued for this study.
Interventions
BIOLOGICALPolyphenon E
Phase I Dose Escalation:. 400 mg orally twice a day to 2000 mg orally twice a day Phase II: 2000 mg orally twice a day
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Confirmed diagnosis of chronic lymphocytic leukemia (CLL) * Stage 0, I, or II disease * Previously untreated disease * Splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL * Absolute lymphocyte count \> 10,000/mm\^3 * Lymphocytosis must consist of small to moderate size lymphocytes, with ≤ 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically * Phenotypically characterized B-CLL defined by all of the following criteria: * A population of leukemic cells that co-expresses the B-cell antigen CD23 as well as CD5 in the absence of other T-cell markers (CD3, CD2, etc.) * Dim surface immunoglobulin expression * Exclusively κ or λ light chains * Mantle cell lymphoma must be excluded by demonstrating the absence of the t(11:14) by FISH testing * Patients who require chemotherapy for treatment of CLL, based on any of the following criteria, are excluded: * CLL-related symptoms requiring treatment, including any of the following: * Unintentional weight loss ≥ 10% body weight within the previous 6 months * Extreme fatigue * Fevers \> 100.5°F for 2 weeks without evidence of infection * Night sweats without evidence of infection * Evidence of progressive marrow failure due to CLL involvement of bone marrow as manifested by the development of worsening anemia (hemoglobin \< 11 g/dl) and/or thrombocytopenia (platelet count \< 100,000/mm\^3) * Thrombocytopenia due to immune phenomena (ITP) is permitted as long as platelet count is ≥ 100,000/mm\^3and the patient is not on active pharmacologic therapy * Massive (i.e. \> 6 cm below left costal margin) or progressive splenomegaly * Massive nodes or clusters (i.e., \> 10 cm in longest diameter) or progressive adenopathy * Progressive lymphocytosis with an increase of \> 50% over 2 month period, or an anticipated lymphocyte doubling time of \< 6 months PATIENT CHARACTERISTICS: * Platelet count ≥ 100,000/µL * ANC ≥ 1500/µL * Hemoglobin ≥ 11 g/dL * Total or direct bilirubin ≤ 1.5 x upper limit of normal (ULN) * AST (SGOT) and ALT (SGPT) ≤ 2 x ULN * Creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 40 mL/min * May have a history of autoimmune hemolytic anemia (AIHA) and positive Coombs test provided there has not been active hemolysis requiring transfusion or steroid treatment ≤ 10 weeks prior to registration * ECOG performance status 0, 1, or 2 * Life expectancy of ≥ 6 months * No uncontrolled infection * No myocardial infarction within the past 6 weeks * No New York Heart Association class III or IV congestive heart failure * Not pregnant or nursing * Negative pregnancy test * Must employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device \[IUD\], or abstinence, etc.) prior to study entry and for the duration of study participation * No other severe medical or psychiatric illness * No active hemolysis requiring transfusion or other pharmacologic therapy PRIOR CONCURRENT THERAPY: * At least 8 weeks since prior and no other concurrent over the counter green tea or green tea extract * No prior daily use of over the counter green tea products for medicinal purposes for \> 4 weeks (phase II only) * No other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-FDA-approved indication and in the context of a research investigation) * No concurrent combination anti-retroviral therapy for HIV positive patients * No concurrent oral steroid preparations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Confirmed Response [Complete Response (CR) and Partial Response (PR)] on 2 Consecutive Evaluations at Least 4 Weeks Apart | 6 months | National Cancer Institute working group criteria (NCIWG) was used to assess response. * CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy * PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, \>100000/μL platelets, \>11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions |
| Number of Participants With Biological Response (Bio-R) on 2 Consecutive Evaluations at Least 4 Weeks Apart | 6 months | Bio-R: A reduction in the absolute lymphocyte count (ALC) of more than 20% from the pretreatment level for at least 2 months or a \>= 30% reduction in all palpable lymphadenopathy without meeting the NCIWG criteria for PR was required |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Confirmed Complete Response (CR) | 6 months | A confirmed complete response is a CR which is reported on 2 consecutive cycles at least 4 weeks apart. CR is defined in Primary Outcome Measure #1. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 24 Month Treatment Free Survival Rate | 24 months (from registration) | Percentage of participants who were alive and treatment (for progressive CLL) free at 24 months. The 24 month treatment free survival, with 95% CI, was estimated using the Kaplan-Meier method. |
Countries
United States
Participant flow
Recruitment details
A total of 73 participants were enrolled at the Mayo Clinic from August 2005 - October 2009.
Pre-assignment details
Thirty-six (36) and 37 patients recruited to the phase I and phase II portions, respectively. Three phase I patients were replaced and one patient was ineligible for evaluation. Per study design, the 36 eligible phase II participants along with the 6 phase I participants treated at the phase II dose level were evaluated (n=42).
Participants by arm
| Arm | Count |
|---|---|
| Phase I Polyphenon E Dose ranging from 400 to 1,800 mg orally twice daily for 6 months | 27 |
| Phase II Polyphenon E 2000mg twice daily for 6 months | 42 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 9 |
| Overall Study | Disease progression | 0 | 3 |
Baseline characteristics
| Characteristic | Phase I Polyphenon E | Phase II Polyphenon E | Total |
|---|---|---|---|
| Age Continuous | 62 years | 60 years | 60 years |
| CD38 Status Negative (<30%) | 23 participants | 35 participants | 58 participants |
| CD38 Status Positive (>=30%) | 4 participants | 7 participants | 11 participants |
| Dose Level of Polyphenon E 1000 mg | 3 participants | 0 participants | 3 participants |
| Dose Level of Polyphenon E 1200 mg | 6 participants | 0 participants | 6 participants |
| Dose Level of Polyphenon E 1400 mg | 3 participants | 0 participants | 3 participants |
| Dose Level of Polyphenon E 1600 mg | 3 participants | 0 participants | 3 participants |
| Dose Level of Polyphenon E 1800 mg | 3 participants | 0 participants | 3 participants |
| Dose Level of Polyphenon E 2000 mg | 0 participants | 42 participants | 42 participants |
| Dose Level of Polyphenon E 400 mg | 3 participants | 0 participants | 3 participants |
| Dose Level of Polyphenon E 800 mg | 6 participants | 0 participants | 6 participants |
| Fluorescence In Situ Hybridization (FISH) Abnormalities deletion (11q23) | 0 participants | 1 participants | 1 participants |
| Fluorescence In Situ Hybridization (FISH) Abnormalities deletion (13q14.2) | 17 participants | 27 participants | 44 participants |
| Fluorescence In Situ Hybridization (FISH) Abnormalities Normal | 6 participants | 10 participants | 16 participants |
| Fluorescence In Situ Hybridization (FISH) Abnormalities Trisomy 12 | 4 participants | 4 participants | 8 participants |
| Immunoglobulin Variable Heavy Chain (IGVH) Mutation Status Mutated (>2%) | 18 participants | 27 participants | 45 participants |
| Immunoglobulin Variable Heavy Chain (IGVH) Mutation Status Unavailable | 2 participants | 9 participants | 11 participants |
| Immunoglobulin Variable Heavy Chain (IGVH) Mutation Status Unmutated (<=2%) | 7 participants | 6 participants | 13 participants |
| Rai Stage Stage 0 | 15 participants | 13 participants | 28 participants |
| Rai Stage Stage I | 8 participants | 24 participants | 32 participants |
| Rai Stage Stage II | 4 participants | 5 participants | 9 participants |
| Region of Enrollment United States | 27 participants | 42 participants | 69 participants |
| Sex: Female, Male Female | 9 Participants | 12 Participants | 21 Participants |
| Sex: Female, Male Male | 18 Participants | 30 Participants | 48 Participants |
| ZAP-70 Status Negative (<20%) | 21 participants | 30 participants | 51 participants |
| ZAP-70 Status Positive (>=20%) | 6 participants | 12 participants | 18 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 40 / 42 |
| serious Total, serious adverse events | 0 / 42 |
Outcome results
Primary
Number of Participants With a Confirmed Response [Complete Response (CR) and Partial Response (PR)] on 2 Consecutive Evaluations at Least 4 Weeks Apart
National Cancer Institute working group criteria (NCIWG) was used to assess response. * CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy * PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, \>100000/μL platelets, \>11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions
Time frame: 6 months
Population: Phase II participants who satisfied all eligibility criteria, signed the consent form and started therapy were evaluated for this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II Polyphenon E | Number of Participants With a Confirmed Response [Complete Response (CR) and Partial Response (PR)] on 2 Consecutive Evaluations at Least 4 Weeks Apart | 1 participants |
Primary
Number of Participants With Biological Response (Bio-R) on 2 Consecutive Evaluations at Least 4 Weeks Apart
Bio-R: A reduction in the absolute lymphocyte count (ALC) of more than 20% from the pretreatment level for at least 2 months or a \>= 30% reduction in all palpable lymphadenopathy without meeting the NCIWG criteria for PR was required
Time frame: 6 months
Population: Phase II participants who satisfied all eligibility criteria, signed the consent form and started therapy were evaluated for this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II Polyphenon E | Number of Participants With Biological Response (Bio-R) on 2 Consecutive Evaluations at Least 4 Weeks Apart | 28 participants |
Secondary
Number of Participants With a Confirmed Complete Response (CR)
A confirmed complete response is a CR which is reported on 2 consecutive cycles at least 4 weeks apart. CR is defined in Primary Outcome Measure #1.
Time frame: 6 months
Population: Phase II participants who satisfied all eligibility criteria, signed the consent form and started therapy were evaluated for this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II Polyphenon E | Number of Participants With a Confirmed Complete Response (CR) | 0 participants |
Other Pre-specified
24 Month Treatment Free Survival Rate
Percentage of participants who were alive and treatment (for progressive CLL) free at 24 months. The 24 month treatment free survival, with 95% CI, was estimated using the Kaplan-Meier method.
Time frame: 24 months (from registration)
Population: Phase II participants who satisfied all eligibility criteria, signed the consent form and started therapy were evaluated for this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II Polyphenon E | 24 Month Treatment Free Survival Rate | 79 percentage of participants |