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Brentuximab Vedotin and Combination Chemotherapy in Treating Patients With Stage II-IV HIV-Associated Hodgkin Lymphoma

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ClinicalTrials.gov Identifier: NCT01771107
Recruitment Status : Active, not recruiting
First Posted : January 18, 2013
Last Update Posted : June 18, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
AIDS-Related Hodgkin Lymphoma Ann Arbor Stage II Hodgkin Lymphoma Ann Arbor Stage IIA Hodgkin Lymphoma Ann Arbor Stage IIB Hodgkin Lymphoma Ann Arbor Stage III Hodgkin Lymphoma Ann Arbor Stage IIIA Hodgkin Lymphoma Ann Arbor Stage IIIB Hodgkin Lymphoma Ann Arbor Stage IV Hodgkin Lymphoma Ann Arbor Stage IVA Hodgkin Lymphoma Ann Arbor Stage IVB Hodgkin Lymphoma Classic Hodgkin Lymphoma HIV Infection TNFRSF8 Positive Drug: Brentuximab Vedotin Drug: Dacarbazine Drug: Doxorubicin Hydrochloride Other: Pharmacological Study Drug: Vinblastine Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Trial of AVD and Brentuximab Vedotin (SGN-35) in the Treatment of Stage II-IV HIV-Associated Hodgkin Lymphoma
Actual Study Start Date : March 7, 2013
Estimated Primary Completion Date : October 16, 2021


Arm Intervention/treatment
Experimental: Treatment (brentuximab and combination chemotherapy)
Patients receive doxorubicin hydrochloride 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.
Drug: Brentuximab Vedotin
Given IV
Other Names:
  • ADC 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-35

Drug: Dacarbazine
Given IV
Other Names:
  • 4-(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-139007

Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • 5,12-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
  • Rubex

Other: Pharmacological Study
Correlative studies

Drug: Vinblastine
Given IV
Other Names:
  • Vincaleucoblastine
  • VLB




Primary Outcome Measures :
  1. Maximal tolerated dose of brentuximab vedotin when combined with doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine (AVD) chemotherapy regimen (Phase I) [ Time Frame: 28 days ]
    Defined as the dose level at which =< 1 of 6 subjects experience dose limiting toxicity.

  2. Progression-free survival for patients using brentuximab vedotin plus AVD regimen with HIV-associated advanced stage Hodgkin lymphoma (Phase II) [ Time Frame: 2 years ]
    Will be done using Kaplan-Meier estimates and corresponding 95% confidence intervals based on standard errors using Greenwood's formula.


Secondary Outcome Measures :
  1. Incidence of adverse events of AVD and brentuximab vedotin with highly active antiretroviral therapy (HAART) [ Time Frame: Up to 5 years ]
    The frequency of adverse events and their severity will be tabulated to evaluate tolerance of AVD and brentuximab vedotin with HAART.

  2. Partial response rate [ Time Frame: 2 years ]
    Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates.

  3. Partial response rate [ Time Frame: 5 years ]
    Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates.

  4. Complete response rate [ Time Frame: 2 years ]
    Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates.

  5. Complete response rate [ Time Frame: 5 years ]
    Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates.

  6. Overall survival [ Time Frame: 2 years ]
  7. Overall survival [ Time Frame: 5 years ]
  8. Event-free survival [ Time Frame: 2 years ]
    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 human immunodeficiency virus (HIV)-associated Hodgkin lymphoma.

  9. Event-free survival [ Time Frame: 5 years ]
    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.

  10. CD4 counts [ Time Frame: Up to 1 year ]
    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.

  11. CD8 counts [ Time Frame: Up to 1 year ]
    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.

  12. Viral load [ Time Frame: Up to 1 year ]
    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.

  13. Prognostic value of fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) in patient with HIV and Hodgkin lymphoma (HL) with respect to 2 year progression free survival [ Time Frame: Baseline ]
    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.

  14. Prognostic value of FDG-PET in patient with HIV and HL with respect to 2 year progression free survival [ Time Frame: 8 weeks (after 2 courses) ]
    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.

  15. Prognostic value of FDG-PET in patient with HIV and HL with respect to 2 year progression free survival [ Time Frame: 24 weeks (end of treatment) ]
    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.

  16. HAART status [ Time Frame: Baseline ]
    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.

  17. Characterization of histologic subtypes in HIV-HL in the HAART era [ Time Frame: Baseline ]
  18. Incidence of neurotoxicity in combination with HAART and AVD and brentuximab vedotin [ Time Frame: Up to 5 years ]
    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 versus those patients not on HAART.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV positive; documentation of HIV-1 infection by means of any one of the following:

    • Documentation of HIV diagnosis in the medical record by a licensed health care provider;
    • Documentation of receipt of antiretroviral therapy (ART) by a licensed health care provider;
    • HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating > 1000 RNA copies/mL;
    • Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 western blot confirmation or HIV rapid multispot antibody differentiation assay
    • NOTE: A "licensed" assay refers to a United States (US) Food and Drug Administration (FDA)-approved assay, which is required for all investigational new drug (IND) studies
  • 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

    • Strong CYP3A4 inhibitors that treat HIV
    • Other strong CYP3A inhibitors
    • Moderate CYP3A4 inhibitors should be used with caution but are not excluded; if 2 moderate CYP3A4 inhibitors are used concurrently, one must be discontinued at least 7 days (1 week) prior to the initiation of chemotherapy
    • P-glycoprotein inhibitors
    • If patients are taking any of these excluded medications, they must be discontinued at least 7 days (1 week) prior to the initiation of chemotherapy All concomitant medications must be reviewed by the study chair or co-chair prior to enrollment by email; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of

Exclusion Criteria:

  • Patients with prior anthracycline therapy will be excluded
  • Female participants who are pregnant or breast-feeding; confirmation that the subject is not pregnant must be established by a negative serum beta (b)-human chorionic gonadotropin (b-hCG) or urine pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women
  • 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, or second malignancy requiring active treatment
  • Prior malignancy within 2 years before enrollment 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); participants with prior malignancies must have completed all therapy at least 2 years before enrollment with no evidence of disease since therapy completion
  • Grade 2 or greater peripheral neuropathy
  • Evidence of progressive multifocal leukoencephalopathy (PML) identified on the pretreatment magnetic resonance imaging (MRI)
  • Central nervous system disease
  • Patients with history of John Cunningham (JC) virus identified in the cerebrospinal fluid (CSF) or previous history of PML will be excluded from the study
  • Cirrhosis secondary to any cause will be excluded

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01771107


Locations
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United States, California
UC San Diego Moores Cancer Center
La Jolla, California, United States, 92093
UCLA Center for Clinical AIDS Research and Education
Los Angeles, California, United States, 90035
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States, 90095
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States, 95817
United States, Florida
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States, 33136
United States, Illinois
John H Stroger Jr Hospital of Cook County
Chicago, Illinois, United States, 60612
United States, Louisiana
Louisiana State University Health Science Center
New Orleans, Louisiana, United States, 70112
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Boston Medical Center
Boston, Massachusetts, United States, 02118
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Missouri
Siteman Cancer Center at Washington University
Saint Louis, Missouri, United States, 63110
Washington University - Jewish
Saint Louis, Missouri, United States, 63110
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Montefiore Medical Center-Einstein Campus
Bronx, New York, United States, 10461
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Pennsylvania
Pennsylvania Oncology Hematology Associates
Philadelphia, Pennsylvania, United States, 19106
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
United States, Washington
Virginia Mason Medical Center
Seattle, Washington, United States, 98101
Harborview Medical Center
Seattle, Washington, United States, 98104
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
France
Centre Hospitalier Universitaire (CHU) de Toulouse
Cedex, France, 31059
Hopital Antoine Beclere
Clamart, France, 92140
Henri Mondor University-Hospital Center
Creteil, France, 94000
Hopital l'Archet-CHU de Nice
Nice, France, 06202
Hopital Saint Louis
Paris, France, 75010
Hospital Saint-Antoine
Paris, France, 75012
Centre Hospitalier Lyon-Sud
Pierre Benite, France, 69310
Chu Purpan
Toulouse, France, 31059
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Paul G Rubinstein AIDS Malignancy Consortium

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01771107     History of Changes
Other Study ID Numbers: NCI-2013-00046
NCI-2013-00046 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
085
2014-003678-18
AMC-085 ( Other Identifier: AIDS Malignancy Consortium )
AMC-085 ( Other Identifier: CTEP )
UM1CA121947 ( U.S. NIH Grant/Contract )
First Posted: January 18, 2013    Key Record Dates
Last Update Posted: June 18, 2019
Last Verified: April 2019

Additional relevant MeSH terms:
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Lymphoma
HIV Infections
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoconjugates
Doxorubicin
Liposomal doxorubicin
Vinblastine
Dacarbazine
Imidazole
Antineoplastic Agents, Immunological
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antineoplastic Agents