Zidovudine, Interferon Alfa-2b, PEG-Interferon Alfa-2b in Patients With HTLV-I Associated Adult T-Cell Leukemia/Lymphoma

• Sponsor: University of Miami (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00854581
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 13
• Location: 1
• Arms: 4
• Duration (Months): 48
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma; Precancerous/Nonmalignant Condition	Biological: PEG-interferon alfa-2b; Biological: Interferon alfa-2b; Drug: Valproic Acid; Drug: Zidovudine	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prospective Study of the Molecular Characteristics of Sensitive and Resistant Disease in Patients With HTLV-I Associated Adult T Cell Leukemia Treated With Zidovudine (AZT) Plus Interferon Alpha-2b
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Induction (Up to Day 21) For one cycle, up to Day 21. All participants are enrolled to induction therapy phase, then move to the maintenance therapy phase if they achieve complete response (PR) or partial response (PR). Participants who achieve a clinical CR at Day 14 response assessment will go on to Part 1 maintenance therapy. Patients who achieve a PR will receive 7 more days of induction therapy and then go on to Part 1 Maintenance Therapy.: Zidovudine: Days 1-2: 1.5 grams intravenously (IV) twice daily Days 3-21: 1.5 grams IV twice daily Interferon alfa-2b (IFN): 5 10 million units (mu) intravenously twice daily	Biological: Interferon alfa-2b; Administered intravenously.; Drug: Zidovudine; Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).; Other Names: Retrovir AZT
Experimental: Part 1 Maintenance (Up to Day 60) From Treatment Day 14 or 21 to start of Month 3 (Day 60). Study participants move on to Part 1 Maintenance Therapy only if they achieve complete response (CR) or partial response (PR) after induction therapy. Restaging and molecular evaluation of disease at start of Month 3: Zidovudine: 600 mg orally twice daily in all phases of Maintenance Therapy PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly Participants then proceed to Part 2 maintenance.	Biological: PEG-interferon alfa-2b; Administered subcutaneously.; Other Names: PEG-IFN-alfa2b ; Drug: Zidovudine; Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).; Other Names: Retrovir AZT
Experimental: Part 2A Maintenance (Up to 12 Months) Participants achieving a CR with undetectable clonal disease. Participants will receive therapy for as long as response is maintained: Zidovudine: 600 mg orally twice daily PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly	Biological: PEG-interferon alfa-2b; Administered subcutaneously.; Other Names: PEG-IFN-alfa2b ; Drug: Zidovudine; Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).; Other Names: Retrovir AZT
Experimental: Part 2B Maintenance (Up to 12 Months) Participants achieving a CR with minimal residual disease (by multiplex PCR) or PR in Part 1: Zidovudine: 600 mg or 300 mg orally twice daily, per protocol PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly, per protocol Valproic acid, 250 mg orally twice daily, per protocol	Biological: PEG-interferon alfa-2b; Administered subcutaneously.; Other Names: PEG-IFN-alfa2b ; Drug: Valproic Acid; Administered orally.; Other Names: Depakene ; Drug: Zidovudine; Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).; Other Names: Retrovir AZT

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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

Secondary Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida	United States	33136

Sponsors and Collaborators

• University of Miami
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Juan Carlos Ramos, MD, University of Miami

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Juan C. Ramos, Associate Professor of Clinical, University of Miami
• ClinicalTrials.gov Identifier: NCT00854581
• Other Study ID Numbers: 20070805; SCCC-2007055; 5P01CA128115-02
• First Posted: Mar 3, 2009
• Last Update Posted: Apr 17, 2018
• Last Verified: Dec 1, 2017

• Keywords provided by Juan C. Ramos, Associate Professor of Clinical, University of Miami: 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
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, T-Cell; Leukemia-Lymphoma, Adult T-Cell; Precancerous Conditions; Interferons; Interferon-alpha; Interferon alpha-2; Zidovudine; Peginterferon alfa-2b; Valproic Acid

Study Results

Participant Flow

Arm/Group Title	Induction + Maintenance
Arm/Group Description	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).
Period Title: Induction (Up to Day 21)
STARTED	13
COMPLETED	7
NOT COMPLETED	6
Period Title: Induction (Up to Day 21)
STARTED	7
COMPLETED	5
NOT COMPLETED	2
Period Title: Induction (Up to Day 21)
STARTED	5
COMPLETED	2
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Induction + Maintenance
Arm/Group Description	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).
Overall Participants	13
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 92.3%
>=65 years	1 7.7%
Sex: Female, Male (Count of Participants)
Female	10 76.9%
Male	3 23.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	11 84.6%
White	0 0%
More than one race	2 15.4%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
Brazil	1 7.7%
Dominican Republic	1 7.7%
Haiti	3 23.1%
Jamaica	5 38.5%
St. Croix	1 7.7%
Trinidad	2 15.4%
Region of Enrollment (Count of Participants)
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Achieving Clinical Response to Protocol Therapy Who Lack IRF-4 and/or c-Rel Expression.
Description	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

Outcome Measure Data

Analysis Population Description

All participants who had a treatment response (PR or CR)

Arm/Group Title	Induction + Maintenance
Arm/Group Description	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).
Measure Participants	6
Participants with tumors lacking IRF-4	5 38.5%
Participants with tumors lacking c-Rel	2 15.4%

2. Primary Outcome

Title	Presence of Minimal Residual Disease at 3 and 6 Months of Maintained Remission and at 1 Year Post Initiation of Therapy
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Part 2B Maintenance (Up to 12 Months)
Arm/Group Description	Participants achieving a CR with minimal residual disease (by multiplex PCR) or PR in Part 1: Zidovudine: 600 mg or 300 mg orally twice daily, per protocol PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly, per protocol Valproic acid, 250 mg orally twice daily, per protocol Valproic Acid: Administered orally.
Measure Participants	3
3 months, CR w/minimal residual disease	3 23.1%
6 months, CR w/minimal residual disease	1 7.7%
12 months, CR w/minimal residual disease	0 0%

3. Primary Outcome

Title	Expressions of c-Rel, IRF-4 and Other Molecular Events in Participants
Description	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

Outcome Measure Data

Analysis Population Description

Study participants were tested for these markers at baseline, but only IRF4 was re-tested at relapse

Arm/Group Title	Induction + Maintenance
Arm/Group Description	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).
Measure Participants	12
Baseline IRF-4 Expression, Positive	3 23.1%
Baseline IRF-4 Expression, Negative	9 69.2%
IRF-4 Expression at Relapse, Newly Positive	2 15.4%
Baseline c-Rel Expression, Faintly Positive	3 23.1%
Baseline c-Rel Expression, Positive	2 15.4%
Baseline c-Rel Expression, Negative	3 23.1%
Baseline p53 Expression, Positive	1 7.7%
Baseline p53 Expression, Negative	5 38.5%
Baseline p15/16 alterations, homozygous deletion	1 7.7%
Baseline p15/16 alterations, heterozygous deletion	2 15.4%
Baseline p15/16 alterations, no deletions	2 15.4%

4. Primary Outcome

Title	Number of Participants Exhibiting NF-kB Inhibition Upon Treatment With AZT in Vivo
Description	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

Outcome Measure Data

Analysis Population Description

Participants receiving Zidovudine (AZT) therapy who achieved complete response (CR) or partial response (PR).

Arm/Group Title	Induction (Up to Day 21)
Arm/Group Description	For one cycle, up to Day 21. All participants are enrolled to induction therapy phase, then move to the maintenance therapy phase if they achieve complete response (PR) or partial response (PR). Participants who achieve a clinical CR at Day 14 response assessment will go on to Part 1 maintenance therapy. Patients who achieve a PR will receive 7 more days of induction therapy and then go on to Part 1 Maintenance Therapy.: Zidovudine: Days 1-2: 1.5 grams intravenously (IV) twice daily Days 3-21: 1.5 grams IV twice daily Interferon alfa-2b (IFN): 5 10 million units (mu) intravenously twice daily Interferon alfa-2b: Administered intravenously. Zidovudine: Administered intravenously during Induction Therapy; orally during Maintenance Therapy in all Phases (1, 2A and 2B).
Measure Participants	4
CR with Decrease in NF-kB Complex (p50 complexes)	1 7.7%
CR with no clear effect NF-kB	1 7.7%
PR with Decrease in p50, and Increase in p65	1 7.7%

5. Primary Outcome

Title	The Effect of Valproic Acid Therapy on Persistence of Clonal Disease in Patients Who Achieve Clinical Remission
Description	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.

Outcome Measure Data

Analysis Population Description

Participants achieving CR or PR in Part 1 Maintenance and moving on to Part 2B Maintenance therapy

Arm/Group Title	Part 2B Maintenance (Up to 12 Months)
Arm/Group Description	Participants achieving a CR with minimal residual disease (by multiplex PCR) or PR in Part 1: Zidovudine: 600 mg or 300 mg orally twice daily, per protocol PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly, per protocol Valproic acid, 250 mg orally twice daily, per protocol Valproic Acid: Administered orally.
Measure Participants	3
3 months, CR or PR, with molecular remission	0 0%
6 months, CR with molecular remission	1 7.7%
9 months, CR with molecular remission	1 7.7%
12 months, CR with molecular remission	1 7.7%

6. Secondary Outcome

Title	Failure-free Survival (FFS)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Induction + Maintenance
Arm/Group Description	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).
Measure Participants	13
Median (95% Confidence Interval) [months]	2.7

7. Secondary Outcome

Title	Overall Survival
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Induction + Maintenance
Arm/Group Description	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).
Measure Participants	13
Median (95% Confidence Interval) [months]	7.8

Adverse Events

Arm/Group Title	Induction Therapy		Part 1 Maintenance		Part 2A Maintenance		Part 2B Maintenance
Arm/Group Description	For one cycle, up to Day 21. All participants are enrolled to induction therapy phase, then move to the maintenance therapy phase if they achieve complete response (PR) or partial response (PR). Participants who achieve a clinical CR at Day 14 response assessment will go on to Part 1 maintenance therapy. Patients who achieve a PR will receive 7 more days of induction therapy and then go on to Part 1 Maintenance Therapy.: Zidovudine: Days 1-2: 1.5 grams intravenously (IV) twice daily Days 3-21: 1.5 grams IV twice daily Interferon alfa-2b (IFN): 5 10 million units (mu) intravenously twice daily		From Treatment Day 14 or 21 to start of Month 3 (Day 60). Study participants move on to Part 1 Maintenance Therapy only if they achieve complete response (CR) or partial response (PR) after induction therapy. Restaging and molecular evaluation of disease at start of Month 3: Zidovudine: 600 mg orally twice daily in all phases of Maintenance Therapy PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly Participants then proceed to Part 2 maintenance.		Participants achieving a CR with undetectable clonal disease. Participants will receive therapy for as long as response is maintained: Zidovudine: 600 mg orally twice daily PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly		Participants achieving a CR with minimal residual disease (by multiplex PCR) or PR in Part 1: Zidovudine: 600 mg or 300 mg orally twice daily, per protocol PEG-Interferon alfa-2b: 1.5 ug/kg subcutaneously (SQ) once weekly, per protocol Valproic acid, 250 mg orally twice daily, per protocol
All Cause Mortality
	Induction Therapy		Part 1 Maintenance		Part 2A Maintenance		Part 2B Maintenance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/13 (38.5%)		2/7 (28.6%)		0/2 (0%)		1/3 (33.3%)
Serious Adverse Events
	Induction Therapy		Part 1 Maintenance		Part 2A Maintenance		Part 2B Maintenance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)		1/7 (14.3%)		1/2 (50%)		1/3 (33.3%)
Blood and lymphatic system disorders
Hemoglobin	0/13 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1
Leukocytes	0/13 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1
Neutrophils	0/13 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1
Gastrointestinal disorders
Abdominal pain	0/13 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	0/3 (0%)	0
Nausea	0/13 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/3 (0%)	0
Vomiting	0/13 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/3 (0%)	0
Infections and infestations
Infection - Other	2/13 (15.4%)	2	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Infection, Catheter-related	1/13 (7.7%)	1	0/7 (0%)	0	1/2 (50%)	1	0/3 (0%)	0
Sepsis	1/13 (7.7%)	1	0/7 (0%)	0	1/2 (50%)	1	0/3 (0%)	0
Urinary tract infection	0/13 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/3 (0%)	0
Metabolism and nutrition disorders
Hypercalcemia	0/13 (0%)	0	1/7 (14.3%)	1	0/2 (0%)	0	0/3 (0%)	0
Renal and urinary disorders
Renal failure	0/13 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/3 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/13 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	Induction Therapy		Part 1 Maintenance		Part 2A Maintenance		Part 2B Maintenance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/13 (92.3%)		2/7 (28.6%)		1/2 (50%)		3/3 (100%)
Blood and lymphatic system disorders
Edema limbs	3/13 (23.1%)	3	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Edema: Head and Neck	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Febrile Neutropenia	1/13 (7.7%)	2	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Hemoglobin	3/13 (23.1%)	7	1/7 (14.3%)	1	1/2 (50%)	1	1/3 (33.3%)	1
Leukocytes	2/13 (15.4%)	4	0/7 (0%)	0	1/2 (50%)	1	1/3 (33.3%)	1
Lymphatics - Other	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Neutrophils	4/13 (30.8%)	6	0/7 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1
Cardiac disorders
Sinus tachycardia	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Endocrine disorders
Scleral necrosis	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Gastrointestinal disorders
Abdominal Distension	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Abdominal Pain	0/13 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/3 (0%)	0
Anorexia	2/13 (15.4%)	2	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Dyspepsia	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Heartburn	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Mucositis oral	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Nausea	1/13 (7.7%)	2	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Vomiting	1/13 (7.7%)	2	0/7 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1
General disorders
Chills	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Fatigue	0/13 (0%)	0	2/7 (28.6%)	2	0/2 (0%)	0	2/3 (66.7%)	3
Fever	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Rigors/chills	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Infections and infestations
Abdominal Infection	0/13 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1
Infection - Other	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Infection, Bladder (urinary)	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Infection, normal ANC, Catheter-related	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Infection, Urinary tract NOS	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Sepsis	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Sinusitis	0/13 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1
Urinary tract infection	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Investigations
Neutrophil count decreased	5/13 (38.5%)	7	0/7 (0%)	0	1/2 (50%)	2	2/3 (66.7%)	2
Platelet count decreased	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Metabolism and nutrition disorders
Alanine aminotransferase increased	0/13 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/3 (0%)	0
Alkaline phosphatase increased	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Aspartate aminotransferase increased	2/13 (15.4%)	4	1/7 (14.3%)	1	1/2 (50%)	1	0/3 (0%)	0
Hypercalcemia	2/13 (15.4%)	3	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Hypokalemia	3/13 (23.1%)	4	2/7 (28.6%)	2	0/2 (0%)	0	0/3 (0%)	0
Hypomagnesemia	6/13 (46.2%)	8	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Hyponatremia	2/13 (15.4%)	3	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Hypophosphatemia	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Nervous system disorders
Peripheral sensory neuropathy	2/13 (15.4%)	2	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Psychiatric disorders
Depression	1/13 (7.7%)	1	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/13 (7.7%)	2	1/7 (14.3%)	1	0/2 (0%)	0	0/3 (0%)	0
Nasal congestion	0/13 (0%)	0	0/7 (0%)	0	0/2 (0%)	0	1/3 (33.3%)	1
Pulmonary - Other	1/13 (7.7%)	2	0/7 (0%)	0	0/2 (0%)	0	0/3 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	0/13 (0%)	0	0/7 (0%)	0	1/2 (50%)	1	0/3 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.