Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
About
This pilot phase I/II trial studies the side effects and the best dose of brentuximab vedotin when given together with combination chemotherapy and to see how well they work in treating patients with stage II-IV human immunodeficiency virus (HIV)-associated Hodgkin lymphoma. Brentuximab vedotin is a monoclonal antibody, called brentuximab, linked to a chemotherapy drug called vedotin. Brentuximab attaches to CD30-positive cancer cells in a targeted way and delivers vedotin to kill them. Drugs used in chemotherapy, such as doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine, 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. Giving brentuximab vedotin together with combination chemotherapy may kill more cancer cells.
Full description
PRIMARY OBJECTIVES I. To identify the maximum tolerated dose (MTD) of brentuximab vedotin when combined with the doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine (AVD) chemotherapy regimen in the treatment of HIV-associated stage II-IV Hodgkin lymphoma. (Phase I) II. Establish an estimate of the two-year progression-free survival (PFS) for participants with HIV-associated stage II-IV Hodgkin lymphoma when treated using brentuximab vedotin plus the AVD chemotherapy regimen. (Phase II)
SECONDARY OBJECTIVES:
I. To evaluate the toxicity of AVD and brentuximab vedotin with highly active antiretroviral therapy (HAART).
II. To estimate the partial response (PR) rate, complete response (CR) rate, overall survival (OS), and event free survival (EFS) at 2 and 5 years.
III. To evaluate the effect of AVD and brentuximab vedotin on cluster of differentiation (CD)4 and CD8 counts after cycle 1, 4, at the end of therapy, and every 3 months after treatment completion for one year.
IV. To investigate the prognostic value of fludeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans at baseline, after cycle 2, and at treatment completion, with respect to 2-year progression free survival.
V. To evaluate HAART status at baseline and to correlate this with tumor response to therapy and OS and PFS.
VI. To characterize the histologic subtypes in HIV-Hodgkin lymphoma (HL) in the highly active antiretroviral therapy (HAART) era.
VII. To assess the neurotoxicity of HAART in combination with AVD and brentuximab vedotin.
VIII. To evaluate effect of AVD and brentuximab vedotin on viral load after cycles 1, 4, at the completion of therapy, and every 3 months after treatment completion for one year.
IX. To perform pharmacokinetic and immunogenicity studies to determine drug levels during therapy.
X. To perform micro ribonucleic acid (miRNA) profile analysis on the HIV-HL tumor specimens and to correlate miRNA expression with OS, PFS, tumor response to therapy, histologic subtype of HIV-HL, and HIV disease characteristics.
XI. To perform tissue microarray analysis on HIV-HL tumor specimens and to correlate the markers studied with OS, PFS, and tumor response to therapy.
XII. To identify Epstein-Barr virus (EBV)-associated tumor derived deoxyribonucleic acid (DNA) in the plasma of study participants and to correlate these levels during therapy with disease response and OS. (Phase II) XIII. To identify cytokines in the plasma of participants during therapy that can be used as tumor and prognostic markers. (Phase II) XIV. To assess latent and expressed HIV reservoirs before, during, and post chemotherapy. To understand how cytotoxic chemotherapeutic agents affect HIV expression.
OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin followed by a phase II study.
Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine sulfate IV, and dacarbazine IV on days 1 and 15. Patients also receive brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
HIV positive; documentation of HIV-1 infection by means of any one of the following:
Histologic diagnosis of CD30-positive classical HL as defined by the 2008 World Health Organization (WHO) Classification of Hematological diseases; nodular lymphocyte predominant Hodgkin lymphoma is not eligible
Stage II, III or IV disease as defined by the Ann Arbor Staging System
Participants must have previously untreated HIV-classical HL (cHL), with the exception of up to 14 consecutive days of steroids, emergency radiation, or 1 prior cycle of cyclophosphamide to reduce tumor burden and improve hyperbilirubinemia in the setting of lymphoma related liver involvement
Normal baseline cardiac ejection fraction >= 50%
Serum creatinine of =< 1.5 mg/dL; if creatinine > 1.5 mg/dL, creatinine clearance must be >= 60 mL/minute
Absolute neutrophil count (ANC) >= 1000/uL
Platelets >= 75,000/uL unless related to bone marrow involvement by HIV-cHL
Total bilirubin must be < 1.5 x the upper limit of normal, unless the elevation of bilirubin is thought to be secondary to Gilbert's syndrome or combined antiretroviral therapy (cART); if, however, the elevated bilirubin is felt to be secondary to antiretroviral therapy, the total bilirubin must be =< 3.5 mg/dL, provided that the direct bilirubin is normal and the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x the upper limit of normal; also, if the elevated bilirubin is thought to be secondary to cHL the same criteria for hyperbilirubinemia should be applied; however 1 prior cycle of cyclophosphamide is permitted in attempt to make the participant eligible; patients should not be excluded from study participation unless dosing cannot be safely established
Female participants must have a negative pregnancy test within 1 week of enrollment and all participants must agree to use two reliable methods of contraception simultaneously if conception is possible during the study and for 6 months after stopping treatment; should a woman subject become pregnant or suspect she is pregnant while the subject is participating in this study, she should inform her treating physician immediately; the participant will then be removed from protocol therapy; participants who father a child while participating in the study will be permitted to continue with the protocol; the participant, however, is required to notify the investigator if he fathers a child
Ability to understand and the willingness to sign a written informed consent document
Karnofsky performance status > 30% (given the aggressiveness of this disease and the often severely debilitated nature of the patients at initial presentation)
Measurable or non-measurable (evaluable) tumor parameter(s); non-measurable tumor parameters will be defined as not having bi-dimensional measurements (i.e., gastric or marrow involvement) but can be followed for response by other diagnostic tests such as gallium, PET imaging and/or bone marrow biopsy
Patients already receiving erythropoietin or granulocyte colony stimulating factor (GCSF) for treatment of HIV-related cytopenia are eligible
CD4 count >= 50 cells/ul
Participants are required to be on antiretroviral regimens that are in accordance with the current International Acquired Immune Deficiency Syndrome (AIDS) Society guidelines concurrently with chemotherapy; the specific agents are at the discretion of the investigator and the use of investigational agents currently available on an expanded access basis is allowed; use of experimental antiretroviral agents or those containing zidovudine (including Combivir and Trizivir) or ritonavir (includes Norvir or Kaletra), cobicistat, didanosine (Videx or Videx EC), or similar potent cytochrome P450 (CYP)3 inhibitors are prohibited; in order to be eligible, participants taking zidovudine or ritonavir, or cobicistat, didanosine, or other CYP3 inhibitors must change to a different regimen 7 days prior to therapy initiation; changes to HAART therapy during the study may be made if medically necessary (toxicity, failure of regimen, etc.); participants must be on HAART at least 7 days prior to therapy
Negative for hepatitis B, or if infected with hepatitis B, receiving anti-hepatitis B therapy; all participants will be required to be screened for hepatitis B; per Infectious Disease Society of America (IDSA) and Assistance for AIDS Specific Drugs (AASD) guidelines, those participants that show no immunity, defined by the lack of hepatitis B surface antigen antibody, and show evidence of chronic infection (i.e. hepatitis B surface antigen [HBsAg]+, hepatitis B core [HBcore]+, hepatitis B surface antibody [HBsAB]-) will be required to be on anti-hepatitis B therapy during the study in order to be eligible; patients will be permitted to enroll in the study provided normal liver function tests and no evidence of cirrhosis; the exact hepatitis B therapy will be at the discretion of the infection disease specialist or investigator; however all patients who present with acute hepatitis B or show normal transaminases and are hepatitis B virus HBsAg surface protein antigen (HBsAg) positive (+) and immunoglobulin M (IgM)+ for hepatitis core antigen will not be eligible for trial enrollment
Patients diagnosed with hepatitis C who are hepatitis C antibody positive, whether hepatitis C RNA level is measurable or not, must have no evidence of cirrhosis and have liver function tests
Brentuximab vedotin is partially metabolized via the CYP3A4 pathway and is cleared from the cells via the P-glycoprotein pump; therefore, participants must discontinue use of the following agents within 7 days prior to therapy
Exclusion criteria
Primary purpose
Allocation
Interventional model
Masking
41 participants in 1 patient group
Loading...
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal