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A Phase I-II Trial of Brentuximab Vedotin Plus Rituximab as Frontline Therapy for Patients With CD30+ and/or EBV+ Lymphomas


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
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

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Trial Information

A Phase I-II Trial of Brentuximab Vedotin Plus Rituximab as Frontline Therapy for Patients With CD30+ and/or EBV+ Lymphomas


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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

For Phase I: Determine the Dose Limiting Toxicity (DLT) of brentuximab vedotin and rituximab in combination

Outcome Description:

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).

Outcome Time Frame:

The 1st 21 days

Safety Issue:

Yes

Principal Investigator

Adam Petrich, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Northwestern University

Authority:

United States: Institutional Review Board

Study ID:

NU 12H09

NCT ID:

NCT01805037

Start Date:

March 2013

Completion Date:

Related Keywords:

  • 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
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Immunoblastic Lymphadenopathy
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Hairy Cell
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Lymphoproliferative Disorders
  • Waldenstrom Macroglobulinemia
  • Mycoses
  • Mycosis Fungoides
  • Sezary Syndrome
  • Virus Diseases
  • Lymphoma, B-Cell
  • 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
  • Leukemia, Large Granular Lymphocytic

Name

Location

Northwestern UniversityChicago, Illinois  60611
University of ChicagoChicago, Illinois  60637
University of Massachusetts Memorial Health CareWorcester, Massachusetts  01605