Brentuximab Vedotin + Rituximab as Frontline Therapy for Pts w/ CD30+ and/or EBV+ Lymphomas

This study is currently recruiting participants.
Verified April 2014 by Northwestern University
Sponsor:
Collaborator:
Seattle Genetics, Inc.
Information provided by (Responsible Party):
Adam Petrich, Northwestern University
ClinicalTrials.gov Identifier:
NCT01805037
First received: February 27, 2013
Last updated: April 4, 2014
Last verified: April 2014
  Purpose

The purpose of this study is to evaluate how safe and effective the combination of two different drugs (brentuximab vedotin and rituximab) is in patients with certain types of lymphoma. This study is for patients who have a type of lymphoma that expresses a tumor marker called CD30 and/or a type that is associated with the Epstein-Barr virus (EBV-related lymphoma) and who have not yet received any treatment for their cancer, except for dose-reduction or discontinuation (stoppage) of medications used to prevent rejection of transplanted organs (for those patients who have undergone transplantation). This study is investigating the combination of brentuximab vedotin and rituximab as a first treatment for lymphoma patients


Condition Intervention Phase
Adult Grade III Lymphomatoid Granulomatosis
Adult Nasal Type Extranodal NK/T-cell Lymphoma
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-cell Lymphoma
Contiguous Stage II Adult Burkitt Lymphoma
Contiguous Stage II Adult Diffuse Large Cell Lymphoma
Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma
Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma
Contiguous Stage II Adult Lymphoblastic Lymphoma
Contiguous Stage II Grade 1 Follicular Lymphoma
Contiguous Stage II Grade 2 Follicular Lymphoma
Contiguous Stage II Grade 3 Follicular Lymphoma
Contiguous Stage II Mantle Cell Lymphoma
Contiguous Stage II Marginal Zone Lymphoma
Contiguous Stage II Small Lymphocytic Lymphoma
Cutaneous B-cell Non-Hodgkin Lymphoma
Epstein-Barr Virus Infection
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Hepatosplenic T-cell Lymphoma
Intraocular Lymphoma
Nodal Marginal Zone B-cell Lymphoma
Noncontiguous Stage II Adult Burkitt Lymphoma
Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma
Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma
Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma
Noncontiguous Stage II Adult Lymphoblastic Lymphoma
Noncontiguous Stage II Grade 1 Follicular Lymphoma
Noncontiguous Stage II Grade 2 Follicular Lymphoma
Noncontiguous Stage II Grade 3 Follicular Lymphoma
Noncontiguous Stage II Mantle Cell Lymphoma
Noncontiguous Stage II Marginal Zone Lymphoma
Noncontiguous Stage II Small Lymphocytic Lymphoma
Noncutaneous Extranodal Lymphoma
Peripheral T-cell Lymphoma
Post-transplant Lymphoproliferative Disorder
Progressive Hairy Cell Leukemia, Initial Treatment
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
Recurrent Adult Grade III Lymphomatoid Granulomatosis
Recurrent Adult Hodgkin Lymphoma
Recurrent Adult Immunoblastic Large Cell Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Adult T-cell Leukemia/Lymphoma
Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Mycosis Fungoides/Sezary Syndrome
Recurrent Small Lymphocytic Lymphoma
Refractory Hairy Cell Leukemia
Small Intestine Lymphoma
Splenic Marginal Zone Lymphoma
Stage I Adult Burkitt Lymphoma
Stage I Adult Diffuse Large Cell Lymphoma
Stage I Adult Diffuse Mixed Cell Lymphoma
Stage I Adult Diffuse Small Cleaved Cell Lymphoma
Stage I Adult Hodgkin Lymphoma
Stage I Adult Immunoblastic Large Cell Lymphoma
Stage I Adult Lymphoblastic Lymphoma
Stage I Adult T-cell Leukemia/Lymphoma
Stage I Cutaneous T-cell Non-Hodgkin Lymphoma
Stage I Grade 1 Follicular Lymphoma
Stage I Grade 2 Follicular Lymphoma
Stage I Grade 3 Follicular Lymphoma
Stage I Mantle Cell Lymphoma
Stage I Marginal Zone Lymphoma
Stage I Small Lymphocytic Lymphoma
Stage IA Mycosis Fungoides/Sezary Syndrome
Stage IB Mycosis Fungoides/Sezary Syndrome
Stage II Adult Hodgkin Lymphoma
Stage II Adult T-cell Leukemia/Lymphoma
Stage II Cutaneous T-cell Non-Hodgkin Lymphoma
Stage IIA Mycosis Fungoides/Sezary Syndrome
Stage IIB Mycosis Fungoides/Sezary Syndrome
Stage III Adult Burkitt Lymphoma
Stage III Adult Diffuse Large Cell Lymphoma
Stage III Adult Diffuse Mixed Cell Lymphoma
Stage III Adult Diffuse Small Cleaved Cell Lymphoma
Stage III Adult Hodgkin Lymphoma
Stage III Adult Immunoblastic Large Cell Lymphoma
Stage III Adult Lymphoblastic Lymphoma
Stage III Adult T-cell Leukemia/Lymphoma
Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
Stage III Grade 1 Follicular Lymphoma
Stage III Grade 2 Follicular Lymphoma
Stage III Grade 3 Follicular Lymphoma
Stage III Mantle Cell Lymphoma
Stage III Marginal Zone Lymphoma
Stage III Small Lymphocytic Lymphoma
Stage IIIA Mycosis Fungoides/Sezary Syndrome
Stage IIIB Mycosis Fungoides/Sezary Syndrome
Stage IV Adult Burkitt Lymphoma
Stage IV Adult Diffuse Large Cell Lymphoma
Stage IV Adult Diffuse Mixed Cell Lymphoma
Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
Stage IV Adult Hodgkin Lymphoma
Stage IV Adult Immunoblastic Large Cell Lymphoma
Stage IV Adult Lymphoblastic Lymphoma
Stage IV Adult T-cell Leukemia/Lymphoma
Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
Stage IV Grade 1 Follicular Lymphoma
Stage IV Grade 2 Follicular Lymphoma
Stage IV Grade 3 Follicular Lymphoma
Stage IV Mantle Cell Lymphoma
Stage IV Marginal Zone Lymphoma
Stage IV Small Lymphocytic Lymphoma
Stage IVA Mycosis Fungoides/Sezary Syndrome
Stage IVB Mycosis Fungoides/Sezary Syndrome
T-cell Large Granular Lymphocyte Leukemia
Testicular Lymphoma
Untreated Hairy Cell Leukemia
Waldenström Macroglobulinemia
Drug: brentuximab vedotin
Biological: rituximab
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I-II Trial of Brentuximab Vedotin Plus Rituximab as Frontline Therapy for Patients With CD30+ and/or EBV+ Lymphomas

Resource links provided by NLM:


Further study details as provided by Northwestern University:

Primary Outcome Measures:
  • For Phase I: Determine the Dose Limiting Toxicity (DLT) of brentuximab vedotin and rituximab in combination [ Time Frame: The 1st 21 days ] [ Designated as safety issue: Yes ]
    The DLT of brentuximab vedotin and rituximab in combination will be assessed at baseline and each week during the first 21 days (1 cycle=21 days).

  • Phase I: Determine the Maximum Tolerated Dose (MTD) of brentuximab vedotin and rituximab in combination [ Time Frame: The 1st 21 days ] [ Designated as safety issue: Yes ]
    The safety of brentuximab vedotin and rituximab in combination will be assessed at baseline and each week during the first 21 days (1 cycle=21 days) which will assist in providing the MTD, also known as the Recommended Phase II Dose, which will be the dose given in Phase II of the trial.

  • For Phase II: Efficacy of study treatment will be measured by anti-tumor activity as detected from imaging scans [ Time Frame: Prior to beginning treatment in week 5 ] [ Designated as safety issue: No ]
    The efficacy, or anti-tumor activity, of brentuximab vedotin and rituximab will be measured at baseline and before receiving treatment in week 5. This will be evaluated by assessing PET or CT imaging scans.

  • For Phase II: Efficacy of study treatment will be measured by anti-tumor activity as detected from imaging scans [ Time Frame: Prior to beginning treatment in week 11 ] [ Designated as safety issue: No ]
    The efficacy, or anti-tumor activity, of brentuximab vedotin and rituximab will be measured before receiving treatment in week 11. This will be evaluated by assessing PET or CT imaging scans.


Secondary Outcome Measures:
  • Phase II: Further evaluate toxicity of treatment by evaluating adverse events [ Time Frame: Prior to dosing at week 5 or until disease progression (maximum 1 year) ] [ Designated as safety issue: Yes ]
    Toxicity, both frequency and severity, will continue to be measured by monitoring the occurence of adverse events. Assessments of toxicity will occur prior to treatment for week 5.

  • Phase II: Further evaluate toxicity of treatment by evaluating adverse events [ Time Frame: Prior to dosing at week 11 or until disease progression (maximum 1 year) ] [ Designated as safety issue: Yes ]
    Toxicity, both frequency and severity, will continue to be measured by monitoring the occurence of adverse events. Assessments of toxicity will occur prior to treatment for week 11.

  • Phase II: Further evaluate efficacy of treatment by measuring Progression Free Survival (PFS) [ Time Frame: Time elapsed from start of treatment to date of disease progression (maximum 3 years) ] [ Designated as safety issue: No ]
    Study treatment efficacy will be evaluated using PET or CT scan images to determine Progression Free Survival which is measured from treatment initiation until tumor progression

  • Phase II: Further evaluate efficacy of treatment by measuring Overall Survival (OS) [ Time Frame: Time elapsed from start of treatment to date of disease progression (maximum 3 years) ] [ Designated as safety issue: No ]
    Efficacy of treatment will be evaluated using PET or CT scan images to determine Overall Survival which is measured as time from treatment initiation until disease progression, patients will be followed up to 3 years.

  • Determining the effects of the combination of brentuximab vedotin and rituximab on biomarkers of Epstein-Barr Virus [ Time Frame: At baseline and once per cycle (1 cycle=3 weeks) for the duration of treatment up to 1 year ] [ Designated as safety issue: No ]
    The effect of study treatment on biomarkers of the Epstein-Barr Virus will be evaluated from blood collected at baseline and once per treatment cycle (every 3 weeks).

  • Continued efficacy of treatment evaluation as measured by time between treatment initiation and time of first cytotoxic chemotherapy [ Time Frame: Time from start of study treatment to time of first dose of cytotoxic chemotherapy (maximum of 1 year) ] [ Designated as safety issue: No ]
    Efficacy of study treatment will also be determined by evaluating the amount of time from start of study treatment to time of first dose of cytotoxic chemotherapy (administered to treat lymphoma).

  • Rates of graft rejection as another measurement of efficacy [ Time Frame: Time from 1st dose until end of treatment (maximum 1 year) ] [ Designated as safety issue: No ]
    Graft rejection during study treatment will be measured to evaluate therapy efficacy.


Other Outcome Measures:
  • Correlate response and outcomes relating to treatment with protein expression and Epstein-Barr virus biomarkers and blood levels [ Time Frame: At baseline, once during each 3 week cycle, and after 1 year of treatment ] [ Designated as safety issue: No ]
    For future studies, tissue samples and blood collected at baseline, once per cycle (3 weeks), and at the conclusion of 1 year of treatment will be used to correlate response and outcomes from therapy with protein expression, biomarkers, and blood levels.


Estimated Enrollment: 33
Study Start Date: March 2013
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (brentuximab vedotin, rituximab)

INDUCTION: Patients receive brentuximab vedotin IV over 30 minutes once weekly for 3 weeks and rituximab IV once weekly for 4 weeks. Patients unable to achieve CR may receive additional optional consolidation therapy identical to induction therapy.

MAINTENANCE THERAPY: Patients receive brentuximab vedotin IV once every 3 weeks and rituximab IV once every 6 weeks. Treatment repeats every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Drug: brentuximab vedotin
Given IV
Other Names:
  • Adcetris
  • anti-CD30 ADC SGN-35
  • anti-CD30 antibody-drug conjugate SGN-35
  • antibody-drug conjugate SGN-35
  • SGN-35
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety of brentuximab vedotin and rituximab in patients with lymphoid malignancies that are cluster of differentiation (CD) 30 positive (+) and/or Epstein-Barr virus (EBV)+, and to determine the recommended phase 2 dose (RP2D) of the combination. (Phase I) II. To evaluate the efficacy, as measured by response rates, of brentuximab vedotin and rituximab in patients with lymphoid malignancies that are CD30+ and/or EBV+. (Phase II)

SECONDARY OBJECTIVES:

I. To further evaluate the frequency and severity of toxicity. (Phase II) II. To further evaluate the clinical efficacy of the combination of brentuximab vedotin and rituximab, as measured by progression free survival (PFS) and overall survival (OS) at one year after the end of treatment. (Phase II) III. To determine the effects of the combination of brentuximab vedotin and rituximab on markers of EBV activation and proliferation. (Phase II) IV. Further evaluate efficacy as measured by time to cytotoxic chemotherapy. (Phase II) V. Further evaluate efficacy as measured by observed rates of graft rejection. (Phase II)

TERTIARY OBJECTIVES:

I. To determine whether and to what extent CD30 expression predicts for response and outcome.

II. To determine whether and to what extent expression of EBV markers predicts for response and outcome.

III. To determine whether changes in serum levels of EBV correlate with response and subsequent loss of response to therapy.

OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin followed by a phase II study.

INDUCTION: Patients receive brentuximab vedotin intravenously (IV) over 30 minutes once weekly for 3 weeks and rituximab IV once weekly for 4 weeks. Patients unable to achieve complete remission (CR) may receive additional optional consolidation therapy identical to induction therapy.

MAINTENANCE THERAPY: Patients receive brentuximab vedotin IV once every 3 weeks and rituximab IV once every 6 weeks. Treatment repeats every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, and then every 6 months for 2 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed CD30+ and/or EBV+ lymphoid malignancy; in addition, there must be evidence of CD20 expression (at any level)
  • In cases of post-transplant lymphoproliferative disorder (PTLD) arising in patients who are pharmacologically immunosuppressed, reduction of immunosuppression (RI) must be attempted prior to or in conjunction with enrollment, with the exception of those for whom RI would pose excessive threat of clinically significant graft rejection (as judged by local investigator)
  • No prior chemotherapy or radiotherapy for PTLD or diffuse large B-cell lymphoma (DLBCL), with the exception of corticosteroids for 10 or fewer days at any dose (no washout period required)
  • No prior surgical intervention, unless performed for the sake of tissue diagnosis or on an urgent basis for disease-related threat to life, limb, or organ function
  • Bi-dimensionally measurable disease (at least 1 cm)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Absolute neutrophil count >= 750/mcL
  • Platelets >= 50,000/mcl
  • Total bilirubin =< 2 X institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum pyruvate glutamate transaminase [SPGT]) =< 3 X institutional ULN
  • Creatinine =< 2 X institutional ULN
  • NOTE: Patients who do not meet the above criteria because of disease involvement of the organ in question, or because of acute systemic illness due to lymphoma, may enroll with permission of the study Principal Investigator (PI) and approval from the Data Monitoring Committee; this flexibility be allowed due to the heterogeneity of the patient population, the wide range of complications seen in the initial presentation of EBV-related malignancy, and the frequent difficulty encountered in attempting to clearly document that organ dysfunction is the result of an underlying lymphoproliferative disorder
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

    • Has not undergone a hysterectomy or bilateral oophorectomy; or
    • Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
  • Patients must be free of any prior malignancies for >= 1 year; NOTE: the exception to this would be currently treated squamous cell and basal cell carcinoma of the skin, carcinoma in situ of the cervix, breast, or bladder, or surgically removed melanoma in situ of the skin (stage 0) with histologically confirmed free margins of excision; in addition, it is well-recognized that patients at highest risk for EBV-related lymphoma (ie, those with chronic immunosuppression) are also at high risk for various malignancies, both invasive and non-invasive; therefore, exceptions may also be granted on a case-by-case basis, at the discretion of the PI with approval from the Data Monitoring Committee, for those patients with good clinical control of active malignancy, if the EBV-related lymphoma is considered to be a more immediate threat to the subject's health and/or life
  • Ability to understand and the willingness to sign a written informed consent; all patients must have signed, witnessed informed consent prior to registration

Exclusion Criteria:

  • Chemotherapy (including monoclonal antibodies) or radiotherapy, administered for any condition, within 4 weeks prior to entering the study or incomplete recovery from adverse events due to agents administered more than 4 weeks earlier
  • Ongoing treatment with any other investigational agents
  • Known central nervous system (CNS) involvement of lymphoma
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to brentuximab vedotin and/or rituximab
  • 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
  • Known human immunodeficiency virus (HIV) infection
  • Known John Cunningham (JC) virus infection and/or progressive multifocal leukoencephalopathy (PML)
  • Clinically active hepatitis A, B, or C infections; NOTE: patients with chronic hepatitis C (HCV) or hepatitis B (HBV) infection may enroll if other laboratory criteria are met; those with HBV surface antigen positivity may enroll only if maintained on appropriate suppressive antiviral therapy, per treating investigator's discretion, for the duration of enrollment in the trial
  • Pregnancy or active nursing of an infant
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01805037

Contacts
Contact: Study Coordinator (312)695-1301 cancertrials@northwestern.edu

Locations
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Adam M. Petrich, MD    312-695-6180    apetrich@nmff.org   
Principal Investigator: Adam M. Petrich, MD         
Sub-Investigator: Leo Gordon, MD         
Sub-Investigator: Jane Winter, MD         
Sub-Investigator: Shuo Ma, MD, PhD         
Sub-Investigator: Steven Rosen, MD         
Sub-Investigator: Amy Chadburn, MD         
University of Chicago Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: Sonali M. Smith, MD    773-834-2895    smsmith@medicine.bsd.uchicago.edu   
Principal Investigator: Sonali M. Smith, MD         
United States, Massachusetts
University of Massachusetts Memorial Health Care Not yet recruiting
Worcester, Massachusetts, United States, 01605
Contact: Andrew M. Evens, MD    508-334-3550    laura.lefko@umassmed.edu   
Principal Investigator: Andrew M. Evens, MD         
Sponsors and Collaborators
Northwestern University
Seattle Genetics, Inc.
Investigators
Principal Investigator: Adam Petrich, MD Northwestern University
  More Information

No publications provided

Responsible Party: Adam Petrich, Principal Investigator, Northwestern University
ClinicalTrials.gov Identifier: NCT01805037     History of Changes
Other Study ID Numbers: NU 12H09, NCI-2012-03090, STU00072695
Study First Received: February 27, 2013
Last Updated: April 4, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Additional relevant MeSH terms:
Hodgkin Disease
Burkitt Lymphoma
Immunoblastic Lymphadenopathy
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Hairy Cell
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Lymphomatoid Granulomatosis
Lymphoproliferative Disorders
Waldenstrom Macroglobulinemia
Mycoses
Mycosis Fungoides
Sezary Syndrome
Virus Diseases
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Large-Cell, Immunoblastic
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Lymphoma, T-Cell, Peripheral
Epstein-Barr Virus Infections
Lymphoma, Large-Cell, Anaplastic
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Extranodal NK-T-Cell
Lymphoma, Mantle-Cell

ClinicalTrials.gov processed this record on April 15, 2014