Recurrent Mantle Cell Lymphoma Clinical Trial
Official title:
A Phase I-II Trial of Brentuximab Vedotin Plus Rituximab as Frontline Therapy for Patients With CD30+ and/or EBV+ Lymphomas
| Verified date | August 2021 |
| Source | Northwestern University |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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
| Status | Terminated |
| Enrollment | 20 |
| Est. completion date | December 31, 2018 |
| Est. primary completion date | September 18, 2017 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | 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 |
| Country | Name | City | State |
|---|---|---|---|
| United States | Tufts University School of Medicine | Boston | Massachusetts |
| United States | Northwestern University | Chicago | Illinois |
| United States | University of Chicago | Chicago | Illinois |
| Lead Sponsor | Collaborator |
|---|---|
| Northwestern University | Seagen Inc. |
United States,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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. | The first 21 days of Induction | |
| Primary | 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. | The first 21 days of induction | |
| Primary | 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. | 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 | 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. | 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 | |
| Secondary | 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. | start of treatment to time of progression (up to 2 years after treatment discontinuation) | |
| Secondary | 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. | From start of treatment to 2 years post treatment discontinuation | |
| Secondary | 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. | 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 | 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 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 | |
| Secondary | 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. | Up to 3 years from treatment discontinuation | |
| Secondary | 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. | From start of treatment to 3 years post treatment discontinuation |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Withdrawn |
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