Clinical Trials /

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

NCT04301076

Description:

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.

Related Conditions:
  • Adult T-Cell Leukemia/Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anti-cancer Drug, Lenalidomide, to the Usual Combination Chemotherapy Treatment ("EPOCH") for Adult T-Cell Leukemia-Lymphoma (ATL)
  • Official Title: A Phase 1 Study of Lenalidomide in Combination With EPOCH Chemotherapy for HTLV-Associated Adult T-Cell Leukemia-Lymphoma (ATLL)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-01535
  • SECONDARY ID: NCI-2020-01535
  • SECONDARY ID: 10335
  • SECONDARY ID: 10335
  • SECONDARY ID: UM1CA186689
  • SECONDARY ID: UM1CA186704
  • NCT ID: NCT04301076

Conditions

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

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (lenalidomide, EPOCH)
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexTreatment (lenalidomide, EPOCH)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Treatment (lenalidomide, EPOCH)
LenalidomideCC-5013, CC5013, CDC 501, RevlimidTreatment (lenalidomide, EPOCH)
Prednisone.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-PrednisoneTreatment (lenalidomide, EPOCH)
Vincristine SulfateKyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateTreatment (lenalidomide, EPOCH)

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (lenalidomide, EPOCH)ExperimentalINDUCTION 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.
  • Cyclophosphamide
  • Doxorubicin Hydrochloride
  • Etoposide
  • Lenalidomide
  • Prednisone
  • Vincristine Sulfate

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 2 years after completion of study treatment
Safety Issue:
Description:Will be summarized using descriptive statistics. Binomial proportions and their 95% confidence intervals will be used to estimate the response rates of therapy.
Measure:Duration of response
Time Frame: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
Safety Issue:
Description:Will be summarized using descriptive statistics. The Kaplan-Meier method will be used to evaluate the response duration.
Measure:Progression-free survival
Time Frame:Up to 2 years after completion of study treatment
Safety Issue:
Description:
Measure:Overall survival
Time Frame:Up to 2 years after completion of study treatment
Safety Issue:
Description:
Measure:T-cell receptor pathway gene mutational spectrum
Time Frame:Up to 2 years after completion of study treatment
Safety Issue:
Description:
Measure:Human T-cell leukemia virus type 1 (HTLV-1) proviral deoxyribonucleic acid and ribonucleic acid loads
Time Frame:Up to 2 years after completion of study treatment
Safety Issue:
Description: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.
Measure:HTLV-1 clonality
Time Frame:Up to 2 years after completion of study treatment
Safety Issue:
Description:
Measure:Incidence of toxicities
Time Frame:Up to the end of induction therapy
Safety Issue:
Description:The incidence of toxicities will be estimated using the binomial proportion and its 95% confidence interval.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 6, 2021