Brentuximab Vedotin and Bendamustine for the Treatment of Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma (ALCL)

Study Overview
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Brief Summary
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This is a phase 1/2 multicenter study to assess the safety and effectiveness of brentuximab vedotin and bendamustine, when given together, in patients with Hodgkin Lymphoma or Anaplastic Large Cell Lymphoma (ALCL) that has either returned or did not respond to initial treatment(s). Patients will be accrued at Columbia University Medical Center (CUMC) and at two subsites in Canada.

Detailed Description
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Brentuximab vedotin will be administered as an outpatient IV infusion on day 1 of each 21-day cycle. Bendamustine will be given as an outpatient infusion on days 1 and 2 of a 21-day cycle. Patients may receive prophylactic pegfilgrastim on day 3 of each cycle, or filgrastim for 5 to 10 days, per investigator's discretion. Patients can receive a maximum of 6 cycles of therapy.

Official Title
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A Phase I/II Clinical Trial of the Combination of Brentuximab Vedotin and Bendamustine in Patients With Relapsed or Refractory Hodgkin Lymphoma or Anaplastic Large Cell Lymphoma

Conditions
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Hodgkin Lymphoma, Anaplastic Large Cell Lymphoma

Intervention / Treatment
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* Drug: Brentuximab Vedotin
* Drug: Bendamustine
* Drug: Neulasta


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed relapsed or refractory HL or ALCL. Documented CD30+ expression from either original diagnosis or a tumor biopsy in the relapsed setting. For patients with HL, subjects are eligible after failure or having declined autologous stem cell transplant or at least two prior multi-agent chemotherapy regimens if they are not autologous stem cell transplant candidates. For patients with ALCL, subjects are eligible after failure of at least one prior multi-agent chemotherapy regimen and if they are not eligible for or have declined autologous stem cell transplant. Must have received first line chemotherapy. No upper limit for the number of prior therapies. Patients with prior autologous or allogeneic stem cell transplant are eligible as long as they meet all other criteria. Measurable or evaluable disease, as defined in 2008 Revised Response Criteria for Malignant Lymphoma(33) Age > or = 18 years ECOG performance status 0,1 or 2 Patient's must have adequate organ and marrow function as defined below Absolute neutrophil count > or = 1,000 (1.0 x 109/L) Platelets > or = 50,000 (50 x 109/L) Total Bilirubin < or = 1.5 x institutional limits unless documented Gilbert's syndrome (then < 2.5 x institutional upper limit) AST (SGOT)/ALT (SGPT) < or = 2.0 x institutional upper limit of normal (unless known hepatic involvement then < 3.5 x institutional upper limit) Creatinine within normal institutional limits OR creatinine clearance > or = 50mL/min for patients with creatinine levels above institutional normal If female of childbearing age, negative serum pregnancy test within 7 days prior to the first dose of brentuximab vedotin in this study Must be willing to use contraception during the study, and for 30 days following the last dose of study drug. Able to understand and to sign a written consent document Exclusion Criteria: Prior treatment with brentuximab vedotin and bendamustine in combination. May have received prior therapy with brentuximab vedotin or bendamustine separately. Received either brentuximab vedotin or bendamustine within 3 months of receiving their first dose of protocol based therapy. If brentuximab vedotin or bendamustine was previously received, had disease progression during the first 3 cycles of either brentuximab vedotin or bendamustine. Systemic steroids that have not been stabilized to the equivalent of < 10 mg/day of prednisone 7 days prior to the initiation of the trial. ANY concurrent investigational agents. Exposure to chemotherapy, radiotherapy, biologics or investigational agents within 3 weeks prior enrollment in the study. Known cerebral or meningeal disease. Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix). If there is a history of prior malignancy the patients must be disease free and off treatment for > or = 3 years. Uncontrolled intercurrent illness including but not limited to: ongoing or active infection, systemic congestive heart failure Class III or IV by NYHA criteria, unstable angina pectoris, or cardiac arrhythmia, or in patients status post allogeneic transplantation with uncontrolled graft versus host disease (GVHD). Pre-existing neuropathy grade III or greater. Pregnant or nursing. Known hypersensitivity to brentuximab vedotin, bendamustine, or mannitol. Known Human Immunodeficiency Virus (HIV) positive, or hepatitis A, hepatitis B or hepatitis C; if hepatitis Bsurface antigen positive or Bcore antibody positive must have normal liver function tests and be willing and able to take anti-hepatitis medication such as lamivudine or equivalent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brentuximab Vedotin / Bendamustine<br>Subjects with relapsed or refractory Hodgkin Lymphoma or Anaplastic Large Cell Lymphoma will receive Brentuximab Vedotin in combination with Bendamustine, and prophylactic Neulasta | Drug: Brentuximab Vedotin<br>* Dose escalation in phase I of the study from 1.2-1.8 mg/kg, IV infusions over 30 minutes on day 1 of each 21-day cycle.<br>* Other names: SGN35;Drug: Bendamustine<br>* Dose escalation in phase I of the study from 60-100 mg/m2, IV infusion on days 1 and 2 of each 21-day cycle.<br>* Other names: Bendamustine HCl;Drug: Neulasta<br>* (Non-experimental) Standard procedure prophylactic pegfilgrastim on day 3 of any subsequent cycle after cycle 1, or filgrastim for 5 to 10 days, per investigator's discretion.<br>* Other names: pegfilgrastim;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of brentuximab vedotin and bendamustine (phase 1) | The highest dose that does not cause unacceptable side effects. | Up to 1.5 years | 
| Dose limiting toxicities (DLT) of brentuximab vedotin and bendamustine (phase 1) | A toxicity that prevents further administration of the agent at that dose level. | Up to 1.5 years | 
| Overall Response Rate for the combination of brentuximab vedotin and bendamustine (phase 2) | The percentage of subjects whose cancer shrinks or disappears after study treatment - Complete Response and Partial Response. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DoR) (phase 1) | Time from documentation of tumor response to disease progression. | Up to 3 years | 
| Progression free survival (PFS) (phase 1) | The length of time during and after the study treatment that a subject lives with the disease but it does not get worse. | Up to 3 years | 
| Overall Survival (OS) (phase 2) | The length of time from either the date of diagnosis or the start of study treatment that subjects diagnosed with the disease are still alive. | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hodgkin Lymphoma, Hodgkin Disease, Hodgkin's Disease, Anaplastic Large Cell Lymphoma, ALCL, SGN+Benda, Bendamustine, Brentuximab Vedotin