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

Status: Active

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.

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) 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 72 hours (hrs) 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

Locations & Contacts

California

Duarte
City of Hope Comprehensive Cancer Center
Status: Active
Contact: Dina Marie Johnson
Phone: 626-218-2846
Email: djohnson@coh.org

Minnesota

Rochester
Mayo Clinic
Status: Active
Contact: Kim Hitchcock
Phone: 507-284-2511
Email: hitchcock.kimberly@mayo.edu

Nebraska

Omaha
University of Nebraska Medical Center
Status: Active
Contact: Eugene Douglas Sehi
Phone: 402-559-8514
Email: Esehi@unmc.edu

New Jersey

Hackensack
Hackensack University Medical Center
Status: Active
Contact: Joshua Zenreich
Phone: 551-996-4248
Email: Joshua.Zenreich@hackensackmeridian.org

North Carolina

Charlotte
Carolinas Medical Center / Levine Cancer Institute
Status: Active
Contact: Donna Acampora
Phone: 980-442-2319
Email: Donna.Acampora@carolinashealthcare.org

Pennsylvania

Philadelphia
University of Pennsylvania / Abramson Cancer Center
Status: Active
Contact: Terease S Waite
Phone: 267-324-8497
Email: Terese.Waite@uphs.upenn.edu

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: Active
Contact: Lynda O'Rear
Phone: 615-343-6320
Email: lynda.orear@vanderbilt.edu

Texas

Houston
M D Anderson Cancer Center
Status: Active
Contact: Nafis Deen
Phone: 713-792-2860
Email: NMDeen@mdanderson.org

Washington

Seattle
University of Washington Medical Center
Status: Active
Contact: Heather Rasmussen
Phone: 206-606-7140
Email: hrasmuss@seattlecca.org

Trial Objectives and Outline

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).

TERTIARY 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 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 60 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 Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Academic and Community Cancer Research United

Principal Investigator
Steven I. Park

Trial IDs

Primary ID ACCRU-LY-1601
Secondary IDs NCI-2017-01308
Clinicaltrials.gov ID NCT03233347