A Pilot Trial of AVD and Brentuximab Vedotin (SGN-35) in the Treatment of Stage III-IV HIV-associated Hodgkin Lymphoma (AMC-085)

This phase II trial studies the side effects and the best dose of brentuximab vedotin and combination chemotherapy work in treating patients with stage III-IV human immunodeficiency virus (HIV)-associated Hodgkin lymphoma. Monoclonal antibodies, such as brentuximab vedotin, can block cancer growth by finding cancer cells and causing them to die. 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 or by stopping them from dividing. Giving brentuximab vedotin together with combination chemotherapy may kill more cancer cells.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Stage III Adult Hodgkin Lymphoma; Stage IV Adult Hodgkin Lymphoma; HIV-associated Hodgkin Lymphoma
• Intervention / Treatment: Drug: Dacarbazine; Drug: Doxorubicin Hydrochloride; Drug: Vinblastine; Drug: brentuximab vedotin

Detailed Description

OUTLINE: This is 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 courses 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.

PRIMARY OBJECTIVE:

• To establish an estimate of the two-year progression-free survival (PFS) for patients with HIV-associated stage III-IV Hodgkin lymphoma when treated using brentuximab vedotin plus the AVD chemotherapy regimen.

SECONDARY OBJECTIVE:

• To evaluate the toxicity of AVD and brentuximab vedotin with highly active antiretroviral therapy (HAART).
• To estimate the partial response (PR) rate, complete response (CR) rate, overall survival (OS), and event free survival (EFS) at 2 and 5 years.
• To evaluate the effect of AVD and brentuximab vedotin on CD4 and CD8 counts after cycle 1, 4, at the end of therapy, and every 3 months after treatment completion for one year.
• To investigate the prognostic value of FDG-PET/CT scans at baseline, after cycle 2, and at treatment completion, with respect to 2-year progression free survival.
• To evaluate HAART status at baseline and to correlate this with tumor response to therapy and OS and PFS.
• To characterize the histologic subtypes in HIV-HL in the HAART era.
• To assess the neurotoxicity of HAART in combination with AVD and brentuximab vedotin.
• To evaluate effect of AVD and brentuximab vedotin on viral load after cycle 1, 4, at the completion of therapy, and every 3 months after treatment completion for one year.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Clamart, France, 92140
    • APHP - Hôpital Antoine Béclère
  • Nice, France, 06202
    • CHU de Nice
  • Paris, France, 75475
    • Hôpital St Louis
  • Paris Cedex 12, France, 75571
    • APHP - Hopital Saint Antoine
  • Pierre Bénite, France, 69495
    • Centre Hospitalier Lyon Sud
  • Toulouse, France
    • CHU de Toulouse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of brentuximab vedotin in combination with AVD in patients <18 years of age, children are excluded from this study
2. HIV-1 infection, as documented by licensed HIV rapid test performed in conjunction with screening (or ELISA test kit and confirmed by Western blot or other approved test). A measurable HIV viral load alone is not sufficient for documentation of the diagnosis of HIV. Alternatively, this documentation may include a record that another physician has documented that the participant has HIV infection based on prior ELISA and western blot, or other approved diagnostic tests
3. Histologic diagnosis of CD30-positive classical HL as defined by the 2008 WHO Classification of Hematological diseases. Nodular lymphocyte predominant Hodgkin Lymphoma is not eligible
4. Stage III or IV disease as defined by the Ann Arbor Staging System
5. Participants must have previously untreated HIV-cHL, with the exception of up to 14 consecutive days of steroids or 1 prior cycle of cyclophosphamide to reduce tumor burden and improve hyperbilirubinemia in the setting of lymphoma related liver involvement
6. Normal baseline cardiac ejection fraction ≥ 50%
7. Serum creatinine of ≤ 1.5 mg/dL. If creatinine >1.5 mg/dL (132 micromol/L), creatinine clearance must be ≥ 60 mL/minute according to MDRD/Cockroft-Gault formula
8. ANC ≥ 1000/µL and platelets ≥ 75,000/µL unless related to bone marrow involvement by HIV-cHL
9. A direct bilirubin level of ≤ 2.0 mg/dL (34 µmol/L). If, however, the elevated bilirubin is felt to be secondary to antiretroviral therapy, the total bilirubin must be ≤ 3.5 mg/dL (59 µmol/L), provided that the direct bilirubin is normal and the AST and ALT ≤ 3 x the upper limit of normal. Also, if the elevated bilirubin is thought to be secondary to cHL the patients should not be excluded from study participation

10. Female subjects must have a negative pregnancy test within 1 week of enrollment and all subjects must agree to use two reliable methods of contraception simultaneously if conception is possible during the study

    • 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 patient will then be removed from protocol therapy
    • Subjects who father a child while participating in the study will be permitted to continue with the protocol. The subject, however, is required to notify the investigator if he fathers a child
11. Ability to understand and the willingness to sign a written informed consent document
12. Karnofsky performance status > 30% (given the aggressiveness of this disease and the often severely debilitated nature of the patients at initial presentation). See Appendix 20.519.5
13. 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
14. Patients already receiving erythropoietin or GCSF for treatment of HIV-related cytopenia are eligible
15. CD4 count ≥ 100 cells/µl and serum HIV viral load <50copies/ml
16. Subjects are required to be on antiretroviral regimens that are in accordance with the current International AIDS Society guidelines concurrently with chemotherapy. Use of experimental antiretroviral agents or those containing zidovudine or ritonavir, cobicistat or similar potent CYP3 inhibitors are prohibited, as explained in Section 5.7. In order to be eligible, patients taking zidovudine or ritonavir, or cobicistat or other CYP3 inhibitors must change to a different regimen 7 days prior to therapy initiation. Subjects must be on HAART for at least 12 weeks prior to therapy. See section 10.3
17. Patients will be required to obtain a pulmonary function test, despite the exclusion of bleomycin from protocol regimen. The subject's diffusing capacity of the lung for carbon monoxide (DLCO) adjusted for hemoglobin must be greater than 70% predicted to enter the study and to continue with brentuximab vedotin
18. Negative for Hepatitis B, or if infected with Hepatitis B, receiving anti-Hepatitis B therapy. All subjects will be required to be screened for Hepatitis B. Per IDSA and AASD guidelines, those subjects that show no immunity, defined by the lack of Hepatitis B surface antibody, and show evidence of chronic infection (i.e., HBsAg+, HBcore+, 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 (see Section 9.3) 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 HBsAg+ and IgM+ for Hepatitis core antigen will not be eligible for trial enrollment
19. 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 that conform to Section 9.3

Exclusion Criteria:

1. Patients with prior anthracycline therapy will be excluded
2. Female subjects who are pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum b-human chorionic gonadotropin (b-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women
3. Medical illness unrelated to HL, which in the opinion of the study physician will preclude administration of chemotherapy safely. This includes patients with uncontrolled infection (including opportunistic), chronic renal failure, myocardial infarction (MI) within the past 6 months, unstable angina, or cardiac arrhythmias other than chronic atrial fibrillation
4. Prior malignancy within 5 years of enrolment other than curatively treated cutaneous basal cell or squamous cell carcinoma, carcinoma in situ of the cervix, anal intraepithelial neoplasia, or cutaneous Kaposi's sarcoma (KS)
5. Grade 2 or greater peripheral neuropathy
6. Evidence of PML identified on the pretreatment MRI
7. Central nervous system disease
8. Patients with history of JC Virus identified in the CSF or previous history of PML will be excluded from the study
9. Cirrhosis secondary to any cause will be excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (BV + combination chemotherapy); Patients receive doxorubicin hydrochloride given 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 courses in the absence of disease progression or unacceptable toxicity.	Drug: Dacarbazine; Given IV; Drug: Doxorubicin Hydrochloride; Given IV; Drug: Vinblastine; Given IV; Other Names: Velban; Velsar; VLB; Drug: brentuximab vedotin; given IV; Other Names: SGN-35; anti-CD30 ADC SGN-35; anti-CD30 antibody-drug conjugate SGN-35; antibody-drug conjugate SGN-35; adcetris

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival for patients using brentuximab vedotin plus AVD regimen with HIV-associated advanced stage Hodgkin lymphoma (Phase II)	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		5 years
Overall survival		2 years
Incidence of adverse events of AVD and brentuximab vedotin with HAART	The frequency of adverse events and their severity will be tabulated to evaluate tolerance of AVD and brentuximab vedotin with HAART.	Up to 5 years
Partial response rate	Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates.	2 years
Partial response rate	Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates.	5 years
Complete response rate	Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates.	2 years
Complete response rate	Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates.	5 years
Event-free survival	Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates (i.e., partial response rate, complete response rate, overall response rate) and event free survival at 2 and 5 years of AVD and brentuximab vedotin for a treatment of patients with stage III/IV HIV-associated Hodgkin Lymphoma.	2 years
Event-free survival	Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates (i.e., partial response rate, complete response rate, overall response rate) and event free survival at 2 and 5 years of AVD and brentuximab vedotin for a treatment of patients with stage III/IV HIV-associated Hodgkin Lymphoma.	5 years
CD4 counts	Repeated measures analysis of variance (ANOVA) models will be used to evaluate the effect of AVD and brentuximab vedotin on CD4 counts after 1, 4, and 6 courses, and every 3 months after treatment completion for one year.	Up to 1 year
CD8 counts	Repeated measures ANOVA models will be used to evaluate the effect of AVD and brentuximab vedotin on CD8 counts after 1, 4, and 6 courses, and every 3 months after treatment completion for one year.	Up to 1 year
Viral load	Repeated measures ANOVA models will be used to evaluate the effect of AVD and brentuximab vedotin on viral load after 1, 4, and 6 courses, and every 3 months after treatment completion for one year.	Up to 1 year
Prognostic value of FDG-PET in patient with HIV and HL with respect to 2 year progression free survival	Log-rank analysis will be used to investigate the prognostic value of FDG-PET scans at baseline, after 2 courses and post-therapy in patients with HIV and HL with respect to progression free survival.	baseline
Prognostic value of FDG-PET in patient with HIV and HL with respect to 2 year progression free survival	Log-rank analysis will be used to investigate the prognostic value of FDG-PET scans at baseline, after 2 courses and post-therapy in patients with HIV and HL with respect to progression free survival.	8 weeks (after 2 courses
Prognostic value of FDG-PET in patient with HIV and HL with respect to 2 year progression free survival	Log-rank analysis will be used to investigate the prognostic value of FDG-PET scans at baseline, after 2 courses and post-therapy in patients with HIV and HL with respect to progression free survival.	24 weeks (end of treatment
HAART status	Log-rank analysis will be used to evaluate HAART status at baseline for difference in outcome in terms of overall survival and progression free survival. The frequency and proportion of different histologic subtypes will be calculated.	Baseline
Incidence of neurotoxicity in combination with HAART and AVD and brentuximab vedotin	Will be tabulated. A binomial test of proportions will be used to test the difference in additional toxicity between those patients taking AVD and brentuximab vedotin on HAART vs. those patients not on HAART.	Up to 5 years

Collaborators and Investigators

• Sponsor: The Lymphoma Academic Research Organisation
• Investigators: Study Director: Caroline Besson, MD, Lymphoma Study Association; Principal Investigator: Nicolas Mounier, Pr, Lymphoma Study Association

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): August 8, 2022

Study Registration Dates

• First Submitted: November 13, 2014
• First Submitted That Met QC Criteria: November 19, 2014
• First Posted (Estimated): November 21, 2014

Study Record Updates

• Last Update Posted (Actual): September 26, 2023
• Last Update Submitted That Met QC Criteria: September 25, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Hodgkin Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Immunotoxins; Antibodies; Immunoglobulins; Doxorubicin; Liposomal doxorubicin; Antibodies, Monoclonal; Dacarbazine; Brentuximab Vedotin; Vinblastine; Immunoconjugates
• Other Study ID Numbers: AMC-085 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO