Lymphoma, Precancerous/Nonmalignant Condition
Conditions
Keywords
recurrent adult T-cell leukemia/lymphoma, stage I adult T-cell leukemia/lymphoma, stage II adult T-cell leukemia/lymphoma, stage III adult T-cell leukemia/lymphoma, stage IV adult T-cell leukemia/lymphoma, HTLV-1 infection
Brief summary
RATIONALE: Human T-cell lymphotropic virus type 1 (HTLV-1) can cause cancer. Zidovudine is an antiviral drug that acts against the human T-cell lymphotropic virus type 1. Giving zidovudine, interferon alfa-2b, and PEG-interferon alfa-2b together may stimulate the immune system and slow down or keep the cancer cell from growing. PURPOSE: This clinical trial is studying how well giving zidovudine together with interferon alfa-2b and PEG-interferon alfa-2b works in treating patients with human T-cell lymphotropic virus type 1-associated adult T-cell leukemia/lymphoma.
Detailed description
OUTLINE: This is a multicenter study. * Induction therapy: Patients receive zidovudine IV twice daily on days 1-14, and recombinant interferon alfa-2b IV twice daily on days 3-14. Patients achieving clinical complete response (CR) proceed to part 1 maintenance therapy; patients achieving partial response (PR) receive another 7 days of zidovudine and recombinant interferon alfa-2b and then proceed to part 1 maintenance therapy. * Part 1 maintenance therapy: Patients receive oral zidovudine twice daily and PEG-interferon alfa-2b subcutaneously (SC) once weekly, beginning on day 14 or 21 and continue to day 60. Patients are evaluated after completion of part 1 maintenance therapy and proceed to part 2 maintenance therapy. * Part 2 maintenance therapy: Patients achieving CR with undetectable clonal disease proceed to group A; patients achieving CR with minimal residual disease (by PCR) or PR proceed to group B. * Group A: Patients receive oral zidovudine twice daily and PEG-interferon alfa-2b SC once weekly. Treatment continues in the absence of disease progression or unacceptable toxicity. * Group B: Patients receive oral zidovudine twice daily and PEG-interferon alfa-2b SC once weekly for 12 weeks and undergo reevaluation. Patients in continued CR with minimal residual disease or stable PR receive oral valproic acid twice daily, PEG-interferon alfa-2b SC once weekly, and oral zidovudine twice daily for 6 months. At that point (month 9) patients with no detectable clonal disease continue their previous treatment, while patients with minimal residual disease receive PEG-interferon alfa-2b SC and oral zidovudine twice daily in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline, days 1 and 2, and months 3, 6, and 12 for protein, genomic DNA, and RNA analysis. Baseline molecular characteristics of the tumor and tumor response to treatment is assessed. After completion of study treatment, patients are followed every 3 months for 1 year.
Interventions
BIOLOGICALPEG-interferon alfa-2b
Administered subcutaneously.
BIOLOGICALInterferon alfa-2b
Administered intravenously.
DRUGValproic Acid
Administered orally.
DRUGZidovudine
Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).
Sponsors
National Cancer Institute (NCI)
University of Miami
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
* Any stage, histologically or cytological documented adult T-cell leukemia/lymphoma (ATLL), leukemic types only (smoldering, chronic or acute). See Appendix I for definitions of the clinical subtypes. * Patients who have received prior treatment, including zidovudine and/or IFN, are eligible, provided that zidovudine/IFN therapy did not result in progressive disease. * Documented HTLV-I infection: documentation may be serologic assay (ELISA, Western blot) and confirmed to be HTLV-I rather than HTLV-2 by differential Western blot (e.g., Genelabs Diagnostics HTLV Blot 2.4) or PCR. * Measurable or evaluable disease. * Age 18 or older. * Karnofsky performance status ≥ 50%. * Patients must have adequate end organ and bone marrow function as defined below: * Absolute neutrophil count ≥ 1,000 cells/mm3 and platelets ≥ 50,000 cells/mm3 unless cytopenias are secondary to ATLL. * Adequate hepatic function: (transaminase ≤ 7 times the upper limit of normal, total bilirubin \< 2.0), unless secondary to hepatic infiltration with lymphoma. If the elevated bilirubin is felt to be secondary to Indinavir or Atazavinir therapy (anti-HIV medications), patients will be allowed to enroll on protocol if the total bilirubin is ≤ 3.5 mg/dl provided that the direct bilirubin is normal. * Creatinine \< 2.0 unless due to lymphomatous infiltration. * Patients who are HIV+ are also eligible. * Females with childbearing potential must have a negative serum pregnancy test within 72 hours of entering into the study. Males and females must agree to use adequate birth control if conception is possible during the study. Women must avoid pregnancy and men avoid fathering children while in the study. * Able to give consent. * Patients already receiving erythropoietin or granulocyte-colony stimulating factor (G-CSF) are eligible.
Exclusion criteria
* Concurrent active malignancies, with the exception of in situ carcinoma of the cervix, non-metastatic, non-melanomatous skin cancer, or Kaposi's sarcoma not requiring systemic chemotherapy. * Grade 3 or 4 cardiac failure and/or ejection fraction \< 50%. * Psychological, familial, sociological or geographical conditions that do not permit treatment and/or medical follow-up required to comply with the study protocol. * Patients may not be receiving any other investigational agents. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant or breast-feeding women. * Hypersensitivity to interferon alpha-2b, peginterferon alpha-2b, zidovudine or any component of the formulation * Autoimmune or viral hepatitis or decompensated liver disease unless due to lymphoma.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Presence of Minimal Residual Disease at 3 and 6 Months of Maintained Remission and at 1 Year Post Initiation of Therapy | 3, 6 and 12 months. | Number of participants achieving complete response (CR) with minimal residual disease at 3, 6 and 12 months post-initiation of protocol therapy. Treatment response was assessed according to the International Consensus Review's adult T-cell leukemia/lymphoma (ATLL) consensus report by Tsukasaki et al published in the Journal of Clinical Oncology (JCO) in 2009. For imaging, Cheson criteria was used to assess response: * Complete response (CR): Disappearance of all clinical, microscopic, and radiographic evidence of disease. All lymph nodes regressed to normal size (≤ 1.5 cm), and previously involved nodes that were 1.1 to 1.5 cm decreased to ≤ 1.0 cm. In addition, abnormally elevated peripheral blood absolute lymphocyte count (ALC) \< 4 x 10\^9 /L. * Partial response (PR): ≥ 50% reduction in measurable disease and abnormal lymphocyte count in peripheral blood. * CR or PR had to persist for a period of at least 4 weeks. |
| Number of Participants Exhibiting NF-kB Inhibition Upon Treatment With AZT in Vivo | During 48 hours of first AZT therapy | Number of patients exhibiting NF-kb inhibition upon treatment with AZT in vivo. Investigation of whether AZT functions as an inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in vivo by analyzing serially collected leukemic samples during the first 48 hours of treatment with AZT only. The investigators will report the number of participants exhibiting NF-kB inhibition upon treatment with AZT in vivo and correlate with response using two-sample t-test. |
| The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission | 3, 6 and 12 months. | Number of participants achieving a molecular remission after starting valproic acid as evidenced by disappearance of T-cell clonality as measured by gene rearrangement studies using multiplex PCR |
| Number of Patients Achieving Clinical Response to Protocol Therapy Who Lack IRF-4 and/or c-Rel Expression. | Up to 12 months post-initiation of protocol therapy | Number of patients achieving clinical response (complete response (CR) + partial response (PR)) who lack interferon regulatory factor 4 (IRF-4) or c-Rel biomarker expression. Treatment response was assessed according to the International Consensus Review's adult T-cell leukemia/lymphoma (ATLL) consensus report by Tsukasaki et al published in the Journal of Clinical Oncology (JCO) in 2009. For imaging, Cheson criteria was used to assess response: * Complete response (CR): Disappearance of all clinical, microscopic, and radiographic evidence of disease. All lymph nodes regressed to normal size (≤ 1.5 cm), and previously involved nodes that were 1.1 to 1.5 cm decreased to ≤ 1.0 cm. In addition, abnormally elevated peripheral blood absolute lymphocyte count (ALC) \< 4 x 10\^9 /L. * Partial response (PR): ≥ 50% reduction in measurable disease and abnormal lymphocyte count in peripheral blood. * CR or PR had to persist for a period of at least 4 weeks. |
| Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | At time of relapse or disease progression, assessed up to 12 months | Expressions of c-Rel, IRF-4 or other molecular events (p53, p16 mutations) including expansion of novel clones obtained at time of relapse will be compared to baseline data using paired t-test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From date of treatment initiation until date of death, assessed up to 5 years | Overall survival (OS) is the elapsed time from the date of initiation of study treatment until date of death from any cause. In the absence of death, the follow-up was censored at date of last contact. |
| Failure-free Survival (FFS) | From date of treatment initiation until date of documented disease progression, relapse after response, or death from any cause, assessed up to 5 years | Failure-free survival is the elapsed time from the date of initiation of study treatment until date of documented disease progression, relapse after response, or death from any cause. For patients alive and free of relapse or progression, follow-up time was censored at the last documented date of failure-free status. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Induction + Maintenance All participants are enrolled to induction therapy first, then move to the maintenance therapy Parts 1 and 2A or 2B if they achieve complete response (PR) or partial response (PR). | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Induction (Up to Day 21) | Death | 1 |
| Induction (Up to Day 21) | Lack of Efficacy | 4 |
| Induction (Up to Day 21) | Physician Decision | 1 |
| Part 2 Maintenance (Up to 12 Months) | Lack of Efficacy | 3 |
Baseline characteristics
| Characteristic | Induction + Maintenance |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Race/Ethnicity, Customized Brazil | 1 Participants |
| Race/Ethnicity, Customized Dominican Republic | 1 Participants |
| Race/Ethnicity, Customized Haiti | 3 Participants |
| Race/Ethnicity, Customized Jamaica | 5 Participants |
| Race/Ethnicity, Customized St. Croix | 1 Participants |
| Race/Ethnicity, Customized Trinidad | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment United States | 13 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 13 | 2 / 7 | 0 / 2 | 1 / 3 |
| other Total, other adverse events | 12 / 13 | 2 / 7 | 1 / 2 | 3 / 3 |
| serious Total, serious adverse events | 2 / 13 | 1 / 7 | 1 / 2 | 1 / 3 |
Outcome results
Primary
Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants
Expressions of c-Rel, IRF-4 or other molecular events (p53, p16 mutations) including expansion of novel clones obtained at time of relapse will be compared to baseline data using paired t-test.
Time frame: At time of relapse or disease progression, assessed up to 12 months
Population: Study participants were tested for these markers at baseline, but only IRF4 was re-tested at relapse
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | Baseline IRF-4 Expression, Positive | 3 participants |
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | IRF-4 Expression at Relapse, Newly Positive | 2 participants |
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | Baseline c-Rel Expression, Faintly Positive | 3 participants |
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | Baseline p53 Expression, Positive | 1 participants |
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | Baseline IRF-4 Expression, Negative | 9 participants |
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | Baseline c-Rel Expression, Positive | 2 participants |
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | Baseline c-Rel Expression, Negative | 3 participants |
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | Baseline p53 Expression, Negative | 5 participants |
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | Baseline p15/16 alterations, homozygous deletion | 1 participants |
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | Baseline p15/16 alterations, heterozygous deletion | 2 participants |
| Induction + Maintenance | Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants | Baseline p15/16 alterations, no deletions | 2 participants |
Primary
Number of Participants Exhibiting NF-kB Inhibition Upon Treatment With AZT in Vivo
Number of patients exhibiting NF-kb inhibition upon treatment with AZT in vivo. Investigation of whether AZT functions as an inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in vivo by analyzing serially collected leukemic samples during the first 48 hours of treatment with AZT only. The investigators will report the number of participants exhibiting NF-kB inhibition upon treatment with AZT in vivo and correlate with response using two-sample t-test.
Time frame: During 48 hours of first AZT therapy
Population: Participants receiving Zidovudine (AZT) therapy who achieved complete response (CR) or partial response (PR).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Induction + Maintenance | Number of Participants Exhibiting NF-kB Inhibition Upon Treatment With AZT in Vivo | CR with Decrease in NF-kB Complex (p50 complexes) | 1 participants |
| Induction + Maintenance | Number of Participants Exhibiting NF-kB Inhibition Upon Treatment With AZT in Vivo | CR with no clear effect NF-kB | 1 participants |
| Induction + Maintenance | Number of Participants Exhibiting NF-kB Inhibition Upon Treatment With AZT in Vivo | PR with Decrease in p50, and Increase in p65 | 1 participants |
Primary
Number of Patients Achieving Clinical Response to Protocol Therapy Who Lack IRF-4 and/or c-Rel Expression.
Number of patients achieving clinical response (complete response (CR) + partial response (PR)) who lack interferon regulatory factor 4 (IRF-4) or c-Rel biomarker expression. Treatment response was assessed according to the International Consensus Review's adult T-cell leukemia/lymphoma (ATLL) consensus report by Tsukasaki et al published in the Journal of Clinical Oncology (JCO) in 2009. For imaging, Cheson criteria was used to assess response: * Complete response (CR): Disappearance of all clinical, microscopic, and radiographic evidence of disease. All lymph nodes regressed to normal size (≤ 1.5 cm), and previously involved nodes that were 1.1 to 1.5 cm decreased to ≤ 1.0 cm. In addition, abnormally elevated peripheral blood absolute lymphocyte count (ALC) \< 4 x 10\^9 /L. * Partial response (PR): ≥ 50% reduction in measurable disease and abnormal lymphocyte count in peripheral blood. * CR or PR had to persist for a period of at least 4 weeks.
Time frame: Up to 12 months post-initiation of protocol therapy
Population: All participants who had a treatment response (PR or CR)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Induction + Maintenance | Number of Patients Achieving Clinical Response to Protocol Therapy Who Lack IRF-4 and/or c-Rel Expression. | Participants with tumors lacking IRF-4 | 5 participants |
| Induction + Maintenance | Number of Patients Achieving Clinical Response to Protocol Therapy Who Lack IRF-4 and/or c-Rel Expression. | Participants with tumors lacking c-Rel | 2 participants |
Primary
Presence of Minimal Residual Disease at 3 and 6 Months of Maintained Remission and at 1 Year Post Initiation of Therapy
Number of participants achieving complete response (CR) with minimal residual disease at 3, 6 and 12 months post-initiation of protocol therapy. Treatment response was assessed according to the International Consensus Review's adult T-cell leukemia/lymphoma (ATLL) consensus report by Tsukasaki et al published in the Journal of Clinical Oncology (JCO) in 2009. For imaging, Cheson criteria was used to assess response: * Complete response (CR): Disappearance of all clinical, microscopic, and radiographic evidence of disease. All lymph nodes regressed to normal size (≤ 1.5 cm), and previously involved nodes that were 1.1 to 1.5 cm decreased to ≤ 1.0 cm. In addition, abnormally elevated peripheral blood absolute lymphocyte count (ALC) \< 4 x 10\^9 /L. * Partial response (PR): ≥ 50% reduction in measurable disease and abnormal lymphocyte count in peripheral blood. * CR or PR had to persist for a period of at least 4 weeks.
Time frame: 3, 6 and 12 months.
Population: Participants who achieved CR with minimal residual disease in Part 1 Maintenance therapy at Month 3 and moved on the Part 2B maintenance for up to 12 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Induction + Maintenance | Presence of Minimal Residual Disease at 3 and 6 Months of Maintained Remission and at 1 Year Post Initiation of Therapy | 3 months, CR w/minimal residual disease | 3 participants |
| Induction + Maintenance | Presence of Minimal Residual Disease at 3 and 6 Months of Maintained Remission and at 1 Year Post Initiation of Therapy | 6 months, CR w/minimal residual disease | 1 participants |
| Induction + Maintenance | Presence of Minimal Residual Disease at 3 and 6 Months of Maintained Remission and at 1 Year Post Initiation of Therapy | 12 months, CR w/minimal residual disease | 0 participants |
Primary
The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission
Number of participants achieving a molecular remission after starting valproic acid as evidenced by disappearance of T-cell clonality as measured by gene rearrangement studies using multiplex PCR
Time frame: 3, 6 and 12 months.
Population: Participants achieving CR or PR in Part 1 Maintenance and moving on to Part 2B Maintenance therapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Induction + Maintenance | The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission | 3 months, CR or PR, with molecular remission | 0 participants |
| Induction + Maintenance | The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission | 6 months, CR with molecular remission | 1 participants |
| Induction + Maintenance | The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission | 9 months, CR with molecular remission | 1 participants |
| Induction + Maintenance | The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission | 12 months, CR with molecular remission | 1 participants |
Secondary
Failure-free Survival (FFS)
Failure-free survival is the elapsed time from the date of initiation of study treatment until date of documented disease progression, relapse after response, or death from any cause. For patients alive and free of relapse or progression, follow-up time was censored at the last documented date of failure-free status.
Time frame: From date of treatment initiation until date of documented disease progression, relapse after response, or death from any cause, assessed up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Induction + Maintenance | Failure-free Survival (FFS) | 2.7 months |
Secondary
Overall Survival
Overall survival (OS) is the elapsed time from the date of initiation of study treatment until date of death from any cause. In the absence of death, the follow-up was censored at date of last contact.
Time frame: From date of treatment initiation until date of death, assessed up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Induction + Maintenance | Overall Survival | 7.8 months |