Clinical Trials /

Doxorubicin Hydrochloride, Vinblastine, Dacarbazine, Brentuximab Vedotin, and Nivolumab in Treating Patients With Stage I-II Hodgkin Lymphoma

NCT03233347

Description:

This phase II trial evaluates how well AVD (doxorubicin hydrochloride, vinblastine, dacarbazine) in combination with brentuximab vedotin and nivolumab work in treating patients with stage I-II Hodgkin lymphoma. Drugs used in the chemotherapy, such as doxorubicin hydrochloride, vinblastine, dacarbazine, and brentuximab vedotin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, and/or by stopping them from spreading. Targeted agent, such as nivolumab, may interfere with the ability of cancer cells to grow and spread by enhancing the immune system. Giving doxorubicin hydrochloride, vinblastine, dacarbazine, brentuximab vedotin, and nivolumab may improve survival of patients with stage I-II Hodgkin lymphoma.

Related Conditions:
  • Classical Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Doxorubicin Hydrochloride, Vinblastine, Dacarbazine, Brentuximab Vedotin, and Nivolumab in Treating Patients With Stage I-II Hodgkin Lymphoma
  • Official Title: A Phase II Trial of PET-Directed Therapy Using AVD (Doxorubicin, Vinblastine, and Dacarbazine) Plus Brentuximab Vedotin Induction Chemotherapy, With or Without Brentuximab Vedotin Plus Nivolumab, Followed by Nivolumab Consolidation for Patients With Previously Untreated Non-Bulky Limited Stage Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: ACCRU-LY-1601
  • SECONDARY ID: NCI-2017-01308
  • SECONDARY ID: ACCRU-LY-1601
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03233347

Conditions

  • Ann Arbor Stage I Hodgkin Lymphoma
  • Ann Arbor Stage IA Hodgkin Lymphoma
  • Ann Arbor Stage IB Hodgkin Lymphoma
  • Ann Arbor Stage II Hodgkin Lymphoma
  • Ann Arbor Stage IIA Hodgkin Lymphoma
  • Ann Arbor Stage IIB Hodgkin Lymphoma
  • Classic Hodgkin Lymphoma

Interventions

DrugSynonymsArms
Brentuximab VedotinADC SGN-35, Adcetris, Anti-CD30 Antibody-Drug Conjugate SGN-35, Anti-CD30 Monoclonal Antibody-MMAE SGN-35, Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35, cAC10-vcMMAE, SGN-35Treatment (combination chemotherapy, nivolumab)
Dacarbazine4-(Dimethyltriazeno)imidazole-5-carboxamide, 5-(Dimethyltriazeno)imidazole-4-carboxamide, Asercit, Biocarbazine, Dacarbazina, Dacarbazina Almirall, Dacarbazine - DTIC, Dacatic, Dakarbazin, Deticene, Detimedac, DIC, Dimethyl (triazeno) imidazolecarboxamide, Dimethyl Triazeno Imidazol Carboxamide, Dimethyl Triazeno Imidazole Carboxamide, dimethyl-triazeno-imidazole carboxamide, Dimethyl-triazeno-imidazole-carboximide, DTIC, DTIC-Dome, Fauldetic, Imidazole Carboxamide, Imidazole Carboxamide Dimethyltriazeno, WR-139007Treatment (combination chemotherapy, nivolumab)
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 (combination chemotherapy, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (combination chemotherapy, nivolumab)
VinblastineVincaleucoblastine, VLBTreatment (combination chemotherapy, nivolumab)

Purpose

This phase II trial evaluates how well AVD (doxorubicin hydrochloride, vinblastine, dacarbazine) in combination with brentuximab vedotin and nivolumab work in treating patients with stage I-II Hodgkin lymphoma. Drugs used in the chemotherapy, such as doxorubicin hydrochloride, vinblastine, dacarbazine, and brentuximab vedotin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, and/or by stopping them from spreading. Targeted agent, such as nivolumab, may interfere with the ability of cancer cells to grow and spread by enhancing the immune system. Giving doxorubicin hydrochloride, vinblastine, dacarbazine, brentuximab vedotin, and nivolumab may improve survival of patients with stage I-II Hodgkin lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate progression-free survival (PFS) at 3 years in patients with previously
      untreated stage I or II non-bulky Hodgkin lymphoma (HL) who received doxorubicin
      hydrochloride, vinblastine, dacarbazine (AVD) plus brentuximab vedotin (BV) induction therapy
      followed by nivolumab (N)VB consolidation therapy.

      SECONDARY OBJECTIVES:

      I. To estimate the overall survival (OS) rate at 3 years in patients with previously
      untreated stage I or II non-bulky HL who received AVD plus BV induction therapy followed by
      NVB consolidation therapy.

      II. To estimate the percentage of patients with untreated stage I or II non-bulky HL who are
      positron emission tomography (PET) positive versus PET negative after 3 cycles of AVD plus BV
      induction therapy.

      III. To estimate PFS and OS at 3 and 5 years separately for patients who are PET negative
      versus PET positive after 3 cycles of AVD plus BV induction followed by NVB consolidation
      therapy.

      IV. To estimate time to progression (TTP) in patients with previously untreated stage I or II
      non-bulky HL who received AVD plus BV induction therapy followed by NVB consolidation
      therapy.

      V. To estimate the overall response rate and the number of patients who convert to complete
      response (CMR) after NVB in patients with partial response (PMR) at the end of AVD plus BV
      induction therapy.

      VI. To evaluate the toxicity and tolerability of AVD plus BV induction followed by NVB
      consolidation therapy as assessed via the National Cancer Institute Common Terminology
      Criteria for Adverse Events (NCI-CTCAE version [v]4).

      EXPLORATORY OBJECTIVES:

      I. Optional biopsy tissue samples will be collected for future analysis. II. Optional blood
      sample will be collected for future analysis.

      OUTLINE:

      Patients receive doxorubicin hydrochloride intravenously (IV) over 3-5 minutes, vinblastine
      IV over 3-5 minutes, and dacarbazine IV over >= 30 minutes, and brentuximab vedotin IV over
      30 minutes on days 1 and 15. Treatment repeats every 28 days for 3 courses in the absence of
      disease progression or unacceptable toxicity. Patients with PET-positive then receive
      brentuximab vedotin IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment
      repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable
      toxicity. PET-positive patients then receive nivolumab IV over 30 minutes on day 1. Treatment
      repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable
      toxicity. PET-negative patients receive nivolumab IV over 30 minutes on day 1 starting after
      AVD and BV treatment. Treatment repeats every 2 weeks for 8 courses in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 4 and 8 weeks, every 3 or 6
      months for 2 years, and then once a year for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (combination chemotherapy, nivolumab)ExperimentalPatients receive doxorubicin hydrochloride IV over 3-5 minutes, vinblastine IV over 3-5 minutes, and dacarbazine IV over >= 30 minutes, and brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients with PET-positive then receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. PET-positive patients then receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. PET-negative patients receive nivolumab IV over 30 minutes on day 1 starting after AVD and BV treatment. Treatment repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable toxicity.
  • Brentuximab Vedotin
  • Dacarbazine
  • Doxorubicin Hydrochloride
  • Nivolumab
  • Vinblastine

Eligibility Criteria

        Inclusion Criteria:

          -  Measurable disease (>= 1.5 cm) as assessed by 2 dimensional measurement by computed
             tomography (CT)

          -  Previously untreated stage I or II non-bulky (defined as a mass measuring < 10 cm in
             the longest dimension by CT) classical Hodgkin lymphoma

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

          -  Life expectancy >= 3 months

          -  Documented negative serologic testing for human immunodeficiency virus (HIV),
             hepatitis B (unless serologically positive due to prior vaccination), and hepatitis C
             =< 1 year prior to registration

          -  Carbon monoxide diffusing capability (DLCO) > 60% (hemoglobin adjusted) by pulmonary
             function test (PFT)s

          -  White blood cell >= 2,000 /mm^3 without transfusion support > 7 days prior to
             registration

          -  Hemoglobin >= 8.5 g/dL without transfusion support > 7 days prior to registration

          -  Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 without transfusion support > 7
             days prior to registration

          -  Platelet count >= 75,000/mm^3 without transfusion support > 7 days prior to
             registration

          -  Alanine and aspartate aminotransferase (ALT/AST) =< 2.5 x upper limit of normal (ULN)
             obtained =< 14 days prior to registration

          -  Total serum bilirubin =< 1.5 x ULN (if documented Gilberts syndrome =< 3 x ULN)
             obtained =< 14 days prior to registration

          -  Serum creatinine =< 1.5 x ULN or measured calculated creatinine clearance >= 40 ml/min
             for subject with creatinine levels > 1.5 x institutional ULN (per Cockcroft-Gault
             formula) obtained =< 14 days prior to registration

          -  Negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of
             human chorionic gonadotropin [HCG]) within 7 days prior to registration in women of
             child-bearing potential (WOCBP)

          -  Sexually active female of reproductive capability ie, WOCBP, has agreed to use a
             medically accepted form of contraception from time of registration to completion of
             study therapy through 24 weeks (6 months) after last dose of NVB or BV; Note: Females
             of non-child-bearing potential are those who are postmenopausal for > 1 year or who
             have had a bilateral tubal ligation or hysterectomy

          -  Male subjects agree to use an adequate method of contraception starting with the first
             dose of study therapy through 31 weeks after the last dose of study therapy

          -  Provide informed written consent

          -  Willing to return to enrolling institution for follow-up (during the active monitoring
             phase of the study)

               -  Note: During the active monitoring phase of a study (i.e., active treatment and
                  observation), participants must be willing to return to the consenting
                  institution for follow-up

        Exclusion Criteria:

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception

          -  Prior therapies including involved field radiation therapy

          -  Bulky disease (defined as a nodal mass measuring >= 10 cm by CT)

          -  Known central nervous system (CNS) involvement

          -  Moderate or severe hepatic insufficiency Child-Pugh score > 6

          -  Severe renal impairment (i.e. creatinine clearance < 40 mL/min)

          -  Symptomatic cardiac disease including ventricular dysfunction, left ventricular
             ejection fraction < 45%, symptomatic coronary artery disease or symptomatic
             arrhythmias

          -  Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
             form of immunosuppressive therapy =< 7 days prior to registration

          -  Known history of active TB (Bacillus tuberculosis)

          -  Requires therapy with agents that have a predisposition for hepatoxicity

          -  Hypersensitivity to NVB or any of its excipients or to any component of AVD + BV
             therapy

          -  Requires immunosuppressive doses of corticosteroid therapy (> 10 mg/day prednisone
             equivalents) for >= 2 weeks prior to registration

          -  Active, known, or suspected autoimmune disease that requires systemic treatment (i.e.
             with use of disease modifying agents, corticosteroids or immunosuppressive drugs);
             Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment; subjects are permitted to enroll if they have vitiligo,
             type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
             requiring hormone replacement, psoriasis not requiring systemic treatment, or
             conditions not expected to recur in the absence of an external trigger

          -  Active infection requiring systemic IV antibiotic therapy

          -  History of Steven?s Johnson?s syndrome, toxic epidermal necrolysis syndrome (TENs) or
             motor neuropathy

          -  History or current evidence of any condition, therapy, or laboratory abnormality that
             might confound the results of the trial, interfere with the subject?s participation
             for the full duration of the trial, or is not in the best interest of the subject to
             participate, in the opinion of the treating investigator

          -  Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the trial

          -  Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

          -  Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
             detected)

          -  Received a live vaccine =< 30 days prior to registration; Note: Seasonal influenza
             vaccines for injection are generally inactivated flu vaccines and are allowed;
             however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines,
             and are not allowed; routine vaccinations, including seasonal influenza, must be given
             >= 2 weeks prior to registration

          -  History of allergies and adverse drug reaction to study drug components

          -  History of another primary malignancy that has not been in remission for at least 3
             years; (Note: The following are exempt for the 3-year limit: nonmelanoma skin cancer,
             fully excised melanoma in situ [stage 0], curatively treated localized prostate
             cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion
             on papanicolaou [PAP] smear)

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens

          -  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

          -  Receiving any other investigational agent which would be considered as a treatment for
             the primary neoplasm

          -  History of progressive promyelocytic leukemia (PML), known history of pancreatitis,
             active grade 3 or higher viral, bacterial or fungal infection =< 2 weeks prior to
             registration and documented history of cerebrovascular event (stroke or transient
             ischemic attack [TIA]) =< 6 months prior to registration
      
Maximum Eligible Age:60 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival
Time Frame:From registration, where progression is by computed tomography (CT)-based or positron emission tomography (PET)-CT based criteria, assessed at 3 years
Safety Issue:
Description:The distribution of progression-free survival time will be estimated using the method of Kaplan-Meier and the efficacy will be determined by the log rank statistic. Overall progression-free survival at 3 years will be reported.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:Time from registration to death due to any cause, assessed at 3 years
Safety Issue:
Description:The distribution of overall survival time will be estimated using the method of Kaplan-Meier.
Measure:The proportion of patients who are positron emission tomography (PET) negative
Time Frame:After 3 courses (84 days)
Safety Issue:
Description:Will be estimated by the number of patients who are PET negative divided by the total number of evaluable patients.
Measure:Proportion of patients who are positron emission tomography (PET) positive
Time Frame:After 3 courses (84 days)
Safety Issue:
Description:Will be estimated by the number of patients who are PET positive divided by the total number of evaluable patients.
Measure:Progression free survival
Time Frame:From registration, where progression is by CT-based or PET-CT based criteria, assessed at 84 days
Safety Issue:
Description:Differences between the groups will be assessed by log-rank statistics.
Measure:Progression free survival
Time Frame:From registration, where progression is by CT-based or PET-CT based criteria, assessed at 3 years
Safety Issue:
Description:Differences between the groups will be assessed by log-rank statistics.
Measure:Progression free survival
Time Frame:From registration, where progression is by CT-based or PET-CT based criteria, assessed at 5 years
Safety Issue:
Description:Differences between the groups will be assessed by log-rank statistics.
Measure:Overall survival
Time Frame:Time from registration to death due to any cause, assessed at 84 days
Safety Issue:
Description:Differences between the groups will be assessed by log-rank statistics.
Measure:Overall survival
Time Frame:Time from registration to death due to any cause, assessed at 3 years
Safety Issue:
Description:Differences between the groups will be assessed by log-rank statistics.
Measure:Overall survival
Time Frame:Time from registration to death due to any cause, assessed at 5 years
Safety Issue:
Description:Differences between the groups will be assessed by log-rank statistics.
Measure:Overall response rate
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated by the number of patients with a partial response or better divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true overall response rate will be calculated.
Measure:Time to progression
Time Frame:Time from registration to the earliest date of documentation of disease progression, assessed up to 5 years
Safety Issue:
Description:The distribution of time to progression will be estimated using the method of Kaplan-Meier.
Measure:The proportion of patients who convert from partial response at the end of induction therapy to complete response after brentuximab vedotin plus nivolumab (NVB)
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated by the number of patients who convert divided by the total number of evaluable patients who receive at least one dose of NVB induction therapy. Exact binomial 95% confidence intervals for the true conversion rate will be calculated.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Academic and Community Cancer Research United

Last Updated

June 7, 2019