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

Primary Purpose

Adult Grade III Lymphomatoid Granulomatosis, Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
brentuximab vedotin
rituximab
laboratory biomarker analysis
Sponsored by
Northwestern University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Grade III Lymphomatoid Granulomatosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Northwestern University
  • University of Chicago
  • Tufts University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (brentuximab vedotin, rituximab)

Arm Description

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.

Outcomes

Primary Outcome Measures

For Phase I: The Recommended Phase 2 Dose of Brentuximab Vedotin in Combination With Rituximab.
To identify the recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD) of brentuximab vedotin in combination with rituximab. The dose limiting toxicity monitoring period for brentuximab vedotin and rituximab is first 21 days (during induction).The RP2D/MTD will be defined as the highest dose of brentuximab vedotin that causes dose limiting toxicities (DLTs) in <2 of 6 patients. The Phase I portion of the study follows a 3+3 design. Brentuximab has two dose levels: Level 1 (starting dose) 1.2 mg/kg IV, and Level -1 (de-escalation dose): 0.8 mg/kg IV. Toxicity will be assessed using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03.
Phase 1: Number of Dose Limiting Toxicities of Brentuximab Vedotin and Rituximab in Patients With Immunosuppressed Lymphoid Malignancies.
Dose limiting toxicities (DLT) will be monitored for Phase 1 patients for the first 21 days of Induction (the DLT monitoring period) to evaluate safety. In general, a non-hematologic DLT is defined as any Grade ≥ 3 toxicity, and a hematologic DLT is defined as any Grade ≥ 4 toxicity, both by CTCAE v4.03 criteria.
Phase II: Percent of Participants With an Overall Response
Overall response will be defined as the detection of Partial Response (PR) or Complete Response (CR) by CT or PET/CT, and/or resolution of marrow-only involvement. Response will be assessed according to the Revised Response Criteria for Malignant Lymphoma (Cheson, et al). CR is defined as a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms, if present before therapy. A post-treatment residual mass of any size is permitted as long as it is PET negative. If a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on CT to normal size. A PR is defined as At least a 50% decrease in sum of the product of the diameters of up to six of the largest dominant nodes or nodal masses. No increase should be observed in the size of other nodes, liver, or spleen.

Secondary Outcome Measures

Number of Participants With Adverse Events Possibly Related to Study Drug Graded 3, 4, and 5
Toxicity, both frequency and severity, will continue to be measured by monitoring the occurrence of adverse events. Adverse events will be defined as those included in CTCAE v 4.03. AEs that were determined to be at least possibly related to study drug and graded 3, 4, 5 are included here. Grade 1 (mild): the event causes discomfort without disruption of normal daily activities. Grade 2 (moderate): the event causes discomfort that affects normal daily activities. Grade 3 (severe): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Grade 4 (Life-threatening): the patient was at risk of death at the time of the event. Grade 5 (fatal): the event caused death.
Percentage of Participants Without Progression (Progression Free Survival (PFS))
Study treatment efficacy will be evaluated using PET or CT scan images to determine Progression Free Survival (PFS). PFS is defined as the duration of time from start of treatment to time of progression. Response criteria will be those specified by Cheson, et al as the Revised Response Criteria for Malignant Lymphoma. Progressive Disease (PD) is defined as the appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size, or at least a 50% increase from nadir in the diameter of any previously involved nodes, or in a single involved node, or the size of other lesions. All patients who have had at least one dose of study treatment will be evaluable for PFS with censoring of patients who are lost to follow-up. PFS will be reported as percentage of participants without progression.
Percentage of Participants Alive at 2 Years (Overall Survival)
Overall survival (OS) will be measured from treatment initiation until death from any cause for up to 1 year post-treatment discontinuation. Overall survival is defined as the duration of time from start of treatment to time of death. All patients who have had at least one dose of study treatment will be evaluable for OS. OS will be reported as percentage of participants alive at 2 years post treatment discontinuation, with censoring of patients who are lost to follow-up.
Number of Participants With Best Overall Response (BOR)
The best overall response (BOR) is the best response recorded from the start of the treatment until disease progression/recurrence. Best response assessed by CT or PET/CT according to the Revised Response Criteria for Malignant Lymphoma (Cheson et. al). Responses include Complete Response (CR), Partial Response (PR), and Stable Disease (SD). CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms, if present before therapy. If a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on CT to normal size. PR: At least a 50% decrease in sum of the product of the diameters of up to six of the largest dominant nodes or nodal masses. No increase should be observed in the size of other nodes, liver, or spleen. SD: neither CR or PR, or progressive disease (PD). PD: Appearance of new lesion > 1.5 cm in any axis, or at least a 50% increase from nadir in the diameter of any previously involved nodes.
Number of Participants With Epstein Barr Virus (EBV) Activation and Number of Participants Without EBV Activation
EBV activation will be evaluated in all patients who receive at least one dose of study treatment and have an evaluable tissue microarray (TMA) collected at baseline. EBV activation and proliferation will be measured by viral loads from blood collections as measured at time of enrollment and monthly thereafter in all enrolled patients, until completion of study therapy. Epstein Barr Virus (EBV) quantitative PCR is used to an aid in monitoring EBV-related disease. Lab thresholds vary at sites however, labs results are considered either "negative" or "abnormal". Number of participants who experienced EBV activation, i.e an abnormal lab result (YES) and patients who did not experience EBV activation, i.e. a negative lab result (NO) will be reported.
Time to Initiation of Cytotoxic Chemotherapy
Time to initiation of cytotoxic chemotherapy will be defined as the time elapsed between study treatment initiation, and time of first non-targeted cytotoxic chemotherapy (off study treatment). Time to cytotoxic chemotherapy will be evaluated in all patients who receive at least one dose of study treatment.
Number of Participants With Graft Rejection vs Without Graft Rejection
Graft rejection will be defined as any of the following: documentation of new or progressive rejection by tissue biopsy of the graft; re-transplantation due to graft rejection; clinical diagnosis of new or progressive graft rejection, since start of treatment on protocol, as given by the patient's transplant physician. Escalation of intensity of immunosuppression will not, by itself, be considered evidence of graft rejection. Note: patients with clinically active graft rejection will not be excluded from trial enrollment, but will not be considered to have treatment emergent graft rejection unless progression of rejection is documented. Rates of graft rejection will be evaluated in all patients who receive at least one dose of study treatment.

Full Information

First Posted
February 27, 2013
Last Updated
August 30, 2021
Sponsor
Northwestern University
Collaborators
Seagen Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01805037
Brief Title
Brentuximab Vedotin + Rituximab as Frontline Therapy for Pts w/ CD30+ and/or EBV+ Lymphomas
Official Title
A Phase I-II Trial of Brentuximab Vedotin Plus Rituximab as Frontline Therapy for Patients With CD30+ and/or EBV+ Lymphomas
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Terminated
Why Stopped
Lack of funding
Study Start Date
March 5, 2013 (Actual)
Primary Completion Date
September 18, 2017 (Actual)
Study Completion Date
December 31, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Northwestern University
Collaborators
Seagen Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (brentuximab vedotin, rituximab)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
brentuximab vedotin
Other Intervention Name(s)
Adcetris, anti-CD30 ADC SGN-35, anti-CD30 antibody-drug conjugate SGN-35, antibody-drug conjugate SGN-35, SGN-35
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
rituximab
Other Intervention Name(s)
IDEC-C2B8, IDEC-C2B8 monoclonal antibody, Mabthera, MOAB IDEC-C2B8, Rituxan
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
For Phase I: The Recommended Phase 2 Dose of Brentuximab Vedotin in Combination With Rituximab.
Description
To identify the recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD) of brentuximab vedotin in combination with rituximab. The dose limiting toxicity monitoring period for brentuximab vedotin and rituximab is first 21 days (during induction).The RP2D/MTD will be defined as the highest dose of brentuximab vedotin that causes dose limiting toxicities (DLTs) in <2 of 6 patients. The Phase I portion of the study follows a 3+3 design. Brentuximab has two dose levels: Level 1 (starting dose) 1.2 mg/kg IV, and Level -1 (de-escalation dose): 0.8 mg/kg IV. Toxicity will be assessed using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03.
Time Frame
The first 21 days of Induction
Title
Phase 1: Number of Dose Limiting Toxicities of Brentuximab Vedotin and Rituximab in Patients With Immunosuppressed Lymphoid Malignancies.
Description
Dose limiting toxicities (DLT) will be monitored for Phase 1 patients for the first 21 days of Induction (the DLT monitoring period) to evaluate safety. In general, a non-hematologic DLT is defined as any Grade ≥ 3 toxicity, and a hematologic DLT is defined as any Grade ≥ 4 toxicity, both by CTCAE v4.03 criteria.
Time Frame
The first 21 days of induction
Title
Phase II: Percent of Participants With an Overall Response
Description
Overall response will be defined as the detection of Partial Response (PR) or Complete Response (CR) by CT or PET/CT, and/or resolution of marrow-only involvement. Response will be assessed according to the Revised Response Criteria for Malignant Lymphoma (Cheson, et al). CR is defined as a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms, if present before therapy. A post-treatment residual mass of any size is permitted as long as it is PET negative. If a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on CT to normal size. A PR is defined as At least a 50% decrease in sum of the product of the diameters of up to six of the largest dominant nodes or nodal masses. No increase should be observed in the size of other nodes, liver, or spleen.
Time Frame
Every 12 weeks for up to 1 year on treatment (Range of cycles attempted from induction, +/- consolidation, + maintenance = 1-17 cycles) Induction = 4 weeks, consolidation = 4 weeks, 1 maintenance cycle = 3 weeks
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events Possibly Related to Study Drug Graded 3, 4, and 5
Description
Toxicity, both frequency and severity, will continue to be measured by monitoring the occurrence of adverse events. Adverse events will be defined as those included in CTCAE v 4.03. AEs that were determined to be at least possibly related to study drug and graded 3, 4, 5 are included here. Grade 1 (mild): the event causes discomfort without disruption of normal daily activities. Grade 2 (moderate): the event causes discomfort that affects normal daily activities. Grade 3 (severe): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Grade 4 (Life-threatening): the patient was at risk of death at the time of the event. Grade 5 (fatal): the event caused death.
Time Frame
From time of treatment to 30 days post discontinuation (range of cycles attempted from induction +/- consolidation, & maintenance = 1-17 cycles) About 1 year Induction = 4 weeks, consolidation = 4 weeks, 1 maintenance cycle = 3 weeks
Title
Percentage of Participants Without Progression (Progression Free Survival (PFS))
Description
Study treatment efficacy will be evaluated using PET or CT scan images to determine Progression Free Survival (PFS). PFS is defined as the duration of time from start of treatment to time of progression. Response criteria will be those specified by Cheson, et al as the Revised Response Criteria for Malignant Lymphoma. Progressive Disease (PD) is defined as the appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size, or at least a 50% increase from nadir in the diameter of any previously involved nodes, or in a single involved node, or the size of other lesions. All patients who have had at least one dose of study treatment will be evaluable for PFS with censoring of patients who are lost to follow-up. PFS will be reported as percentage of participants without progression.
Time Frame
start of treatment to time of progression (up to 2 years after treatment discontinuation)
Title
Percentage of Participants Alive at 2 Years (Overall Survival)
Description
Overall survival (OS) will be measured from treatment initiation until death from any cause for up to 1 year post-treatment discontinuation. Overall survival is defined as the duration of time from start of treatment to time of death. All patients who have had at least one dose of study treatment will be evaluable for OS. OS will be reported as percentage of participants alive at 2 years post treatment discontinuation, with censoring of patients who are lost to follow-up.
Time Frame
From start of treatment to 2 years post treatment discontinuation
Title
Number of Participants With Best Overall Response (BOR)
Description
The best overall response (BOR) is the best response recorded from the start of the treatment until disease progression/recurrence. Best response assessed by CT or PET/CT according to the Revised Response Criteria for Malignant Lymphoma (Cheson et. al). Responses include Complete Response (CR), Partial Response (PR), and Stable Disease (SD). CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms, if present before therapy. If a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on CT to normal size. PR: At least a 50% decrease in sum of the product of the diameters of up to six of the largest dominant nodes or nodal masses. No increase should be observed in the size of other nodes, liver, or spleen. SD: neither CR or PR, or progressive disease (PD). PD: Appearance of new lesion > 1.5 cm in any axis, or at least a 50% increase from nadir in the diameter of any previously involved nodes.
Time Frame
Every 12 weeks for up to 1 year on treatment (Range of cycles attempted from induction, +/- consolidation, + maintenance = 1-17 cycles) Induction = 4 weeks, consolidation = 4 weeks, 1 maintenance cycle = 3 weeks
Title
Number of Participants With Epstein Barr Virus (EBV) Activation and Number of Participants Without EBV Activation
Description
EBV activation will be evaluated in all patients who receive at least one dose of study treatment and have an evaluable tissue microarray (TMA) collected at baseline. EBV activation and proliferation will be measured by viral loads from blood collections as measured at time of enrollment and monthly thereafter in all enrolled patients, until completion of study therapy. Epstein Barr Virus (EBV) quantitative PCR is used to an aid in monitoring EBV-related disease. Lab thresholds vary at sites however, labs results are considered either "negative" or "abnormal". Number of participants who experienced EBV activation, i.e an abnormal lab result (YES) and patients who did not experience EBV activation, i.e. a negative lab result (NO) will be reported.
Time Frame
Time from start of study treatment to last dose of study drug (Range of cycles attempted from induction, +/- consolidation, + maintenance = 1-17 cycles, up to 1 year) Induction = 4 weeks, consolidation = 4 weeks, 1 maintenance cycle = 3 weeks
Title
Time to Initiation of Cytotoxic Chemotherapy
Description
Time to initiation of cytotoxic chemotherapy will be defined as the time elapsed between study treatment initiation, and time of first non-targeted cytotoxic chemotherapy (off study treatment). Time to cytotoxic chemotherapy will be evaluated in all patients who receive at least one dose of study treatment.
Time Frame
Up to 3 years from treatment discontinuation
Title
Number of Participants With Graft Rejection vs Without Graft Rejection
Description
Graft rejection will be defined as any of the following: documentation of new or progressive rejection by tissue biopsy of the graft; re-transplantation due to graft rejection; clinical diagnosis of new or progressive graft rejection, since start of treatment on protocol, as given by the patient's transplant physician. Escalation of intensity of immunosuppression will not, by itself, be considered evidence of graft rejection. Note: patients with clinically active graft rejection will not be excluded from trial enrollment, but will not be considered to have treatment emergent graft rejection unless progression of rejection is documented. Rates of graft rejection will be evaluated in all patients who receive at least one dose of study treatment.
Time Frame
From start of treatment to 3 years post treatment discontinuation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adam Petrich, MD
Organizational Affiliation
Northwestern University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Tufts University School of Medicine
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States

12. IPD Sharing Statement

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

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