Testing the Addition of an Anti-cancer Drug, Lenalidomide, to the Usual Combination Chemotherapy Treatment (EPOCH) for Adult T-Cell Leukemia-Lymphoma (ATL)

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of lenalidomide when given together with usual combination chemotherapy (etoposide, prednisone, vincristine sulfate [Oncovin], cyclophosphamide, and doxorubicin hydrochloride [hydroxydaunorubicin hydrochloride], or EPOCH) in treating adult T-cell leukemia-lymphoma. Lenalidomide may help shrink or slow the growth of adult T-cell leukemia-lymphoma. Drugs used in chemotherapy, such as etoposide, vincristine, cyclophosphamide, and doxorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Anti-inflammatory drugs such as prednisone lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Giving lenalidomide and the usual combination chemotherapy may work better in treating adult T-cell leukemia-lymphoma compared to the usual combination chemotherapy alone.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the safest and most tolerable dose and schedule of lenalidomide to combine with etoposide, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin hydrochloride) (EPOCH) chemotherapy in adult T-cell leukemia-lymphoma (ATL/ATLL). SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To determine if lenalidomide and EPOCH activity results in significant improvement in remission rates and duration of remissions as compared to historical controls. III. To determine if lenalidomide and EPOCH activity correlates with T-cell receptor (TCR) pathway gene mutational spectrum. IV. To determine effects of lenalidomide and EPOCH on human T-cell leukemia virus type 1 (HTLV-1) proviral deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) loads. V. To determine effects of lenalidomide and EPOCH on HTLV-1 clonality. OUTLINE: This is a dose-escalation study of lenalidomide. INDUCTION THERAPY: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-14 of 21 day cycles or days 1-21 or 1-28 of 28 day cycles. Patients also receive doxorubicin hydrochloride intravenously (IV) continuously on days 1-4, vincristine sulfate IV continuously on days 1-4, etoposide IV continuously on days 1-4, prednisone PO on days 1-5, and cyclophosphamide IV over 1-4 hours on day 5. Treatment repeats every 21 or 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients with complete response (CR), partial response (PR), or stable disease (SD) may receive up to 2 additional cycles of lenalidomide, doxorubicin hydrochloride, vincristine sulfate, etoposide, prednisone, and cyclophosphamide at the discretion of the investigator and/or up to an additional 2 years of lenalidomide in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 2 years.

Official Title
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A Phase 1 Study of Lenalidomide in Combination With EPOCH Chemotherapy for HTLV-Associated Adult T-Cell Leukemia-Lymphoma (ATLL)

Conditions
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Acute Adult T-Cell Leukemia/Lymphoma, Adult T-Cell Leukemia/Lymphoma, Chronic Adult T-Cell Leukemia/Lymphoma, HTLV-1 Infection

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Doxorubicin Hydrochloride
* Drug: Etoposide
* Drug: Lenalidomide
* Drug: Prednisone
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed CD2+, CD3+, or CD4+ acute, lymphoma or poor-risk chronic subtypes of ATLL including previously untreated or previously treated individuals who have received no more than 1 previous cycle of combination chemotherapy. If the patient has a cycle of EPOCH prior to entering on the study, doses of EPOCH during the first cycle with lenalidomide should be altered as described for cycle 2 EPOCH modifications below For patients who receive a cycle of EPOCH prior to enrollment on the protocol, cycle 2 (the first cycle on protocol) dose of EPOCH is altered according to toxicities in cycle 1 Patients previously treated with azidothymidine (AZT), interferon (IFN), bexarotene, or mogamulizumab are eligible. Patients with stable disease at high risk of relapse from prior non-combination chemotherapy containing treatment are eligible to participate Documentation of HTLV infection by enzyme-linked immunosorbent assay (ELISA) in individuals with confirmation of HTLV-1 infection (by immunoblot or polymerase chain reaction [PCR]) or a consistent clinical picture (including two of three of: 1) CD4+ leukemia or lymphoma, 2) hypercalcemia, and/or 3) Japanese, Caribbean, or South American birthplace) is required for enrollment. Confirmation of HTLV-1 infection is required to continue the subject on protocol after the first cycle of therapy. Patients will be enrolled based on reports from local or referral labs (e.g., Mayo Clinic or LabCorp). Confirmation will be performed by Ratner Lab at Washington University, retrospectively, but this is not a Clinical Laboratory Improvement Amendments (CLIA) assay and is not reimbursed by insurance Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Absolute neutrophil count >= 1,000/mm^3 unless decreased due to bone marrow (BM) involvement with lymphoma Platelets >= 75,000/mm^3 unless decreased due to BM involvement with lymphoma Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), if potentially due to lymphoma, in the dose-expansion cohort, the first cycle may be given without lenalidomide and if transaminitis and bilirubinemia improves to meet parameters, participant may be enrolled Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x institutional ULN, if potentially due to lymphoma, in the dose-expansion cohort, the first cycle may be given without lenalidomide and if transaminitis and bilirubinemia improve to meet parameters, participant may be enrolled Creatinine =< institutional ULN OR glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better Patients must have a life expectancy > 12 weeks Patients must have no serious active infection requiring therapy at the time of study entry Patients must not require the concurrent use of chemotherapy, interferon, zidovudine, arsenic, radiation therapy, or other specific anti-tumor therapy, during the course of this study The effects of lenalidomide on the developing human fetus are unknown. Immunodulatory derivative (immunomodulatory imide drug [IMiD]) agents as well as other therapeutic agents used in this trial are known to be teratogenic. Females of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to, and again within 24 hours of starting lenalidomide, and must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counselled at a minimum of every 28 days about pregnancy precautions and risk of fetal exposure. Should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study, she should inform her treating physician immediately. FCBP must use adequate contraception for at least 28 days after discontinuation from study. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for at least 28 days after discontinuation from study Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible Exclusion Criteria: Patients that have received prior IMiDs for treatment of ATLL Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study Patients who have not recovered from adverse events (AEs) due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) within 14 days prior to enrollment, with the exception of alopecia Patients who are receiving any other investigational agents or have received them within 14 days prior to enrollment History of allergic reactions attributed to compounds of similar chemical or biologic composition to lenalidomide or other agents used in study. Anaphylactic reactions including death have been reported with cyclophosphamide. Possible cross-sensitivity with other alkylating agents can occur Patients unable to take aspirin or prophylactic doses of low molecular weight heparin or direct oral anticoagulants will not be eligible for maintenance treatment with lenalidomide, but may enroll and receive induction therapy with lenalidomide plus EPOCH Patients with urinary outflow obstruction (contraindication for cyclophosphamide) Patients with any form of demyelinating disease should not be given vincristine sulfate injection Patients with uncontrolled intercurrent illness Patients with psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because lenalidomide is an IMiD agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lenalidomide, breastfeeding should be discontinued if the mother is treated with lenalidomide. These potential risks may also apply to other agents used in this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (lenalidomide, EPOCH)<br>INDUCTION THERAPY: Patients receive lenalidomide PO QD on days 1-14 of 21 day cycles or days 1-21 or 1-28 of 28 day cycles. Patients also receive doxorubicin hydrochloride IV continuously on days 1-4, vincristine sulfate IV continuously on days 1-4, etoposide IV continuously on days 1-4, prednisone PO on days 1-5, and cyclophosphamide IV over 1-4 hours on day 5. Treatment repeats every 21 or 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients with CR, PR, or SD may receive up to 2 additional cycles of lenalidomide, doxorubicin hydrochloride, vincristine sulfate, etoposide, prednisone, and cyclophosphamide at the discretion of the investigator and/or up to an additional 2 years of lenalidomide in the absence of disease progression or unacceptable toxicity. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | Will determine the MTD for lenalidomide in combination with etoposide, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin hydrochloride) (EPOCH) chemotherapy. | Up to the end of induction therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Will be summarized using descriptive statistics. Binomial proportions and their 95% confidence intervals will be used to estimate the response rates of therapy. | Up to 2 years after completion of study treatment | 
| Duration of response | Will be summarized using descriptive statistics. The Kaplan-Meier method will be used to evaluate the response duration. | From the time measurement criteria are met for complete response (CR) or partial response (PR) until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years after completion of study treatment | 
| Progression-free survival | Profession-free survival will be determined by the number of weeks from the time of initiation of therapy until there is evidence of tumor progression by acute T-cell leukemia (ATL) response criteria of Tuskasaki, 2009. | Up to 2 years after completion of study treatment | 
| Overall survival | Over survival will be determined by the number of week of weeks from the time of initiation of therapy until death. | Up to 2 years after completion of study treatment | 
| T-cell receptor pathway gene mutational spectrum | T-cell receptor pathway gene mutation will be determined by targeted next-generation sequence after hybridization to specific oligonucleotide capture probes corresponding to the sequence most commonly mutation in ATL as defined by Kataoka et al, 2015. | Up to 2 years after completion of study treatment | 
| Human T-cell leukemia virus type 1 (HTLV-1) proviral deoxyribonucleic acid and ribonucleic acid loads | Analysis of variance methods will be used to evaluate the effects of treatment and time on the viral load measurements, as well as measurements of viral transcripts. | Up to 2 years after completion of study treatment | 
| HTLV-1 clonality | HTLV-1 clonality will be determined by next generation sequence analysis of viral integration sites resulting in a distribution of the number of reads for each integration site plotted per integration site, as described by Gillet et al. 2011. | Up to 2 years after completion of study treatment | 
| Incidence of toxicities | The incidence of toxicities will be estimated using the binomial proportion and its 95% confidence interval. | Up to the end of induction therapy |