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

• Phase 1: Maximum tolerated dose (MTD) of brentuximab vedotin and bendamustine [ Time Frame: up to 1.5 years ] [ Designated as safety issue: Yes ]
• Phase 1: Dose limiting toxicities (DLT) of brentuximab vedotin and bendamustine. [ Time Frame: up to 1.5 years ] [ Designated as safety issue: Yes ]
• Phase 2: Overall Response Rate (CR + PR) for the combination of brentuximab vedotin and bendamustine [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

• Phase 1: Progression free survival (PFS) and duration of response (DOR) for all patients. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
• Phase 1: Overall response rate (ORR) (complete response (CR) + partial response (PR)) for all patients [ Time Frame: up to 1.5 years ] [ Designated as safety issue: No ]
• Phase 2: Safety and tolerability of the combination of brentuximab vedotin and bendamustine [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
• Phase 2: Duration of response, Progression free survival and Overall Survival (OS) for the combination of brentuximab vedotin and bendamustine [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

• Serum Tarc levels in patients as a function of treatment with brentuximab vedotin and bendamustine. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
• Level of peripheral blood lymphocyte expression of programmed death-1 (PD-1) as a function of treatment with brentuximab vedotin and bendamustine. [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
• Decline in serum levels of IL-10 and IL-6 as a function of treatment with brentuximab vedotin and bendamustine [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

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.

Brentuximab Vedotin will be given to patients on day 1 of each 21 day cycle and Bendamustine will be given to patients on days 1 AND 2 of each 21 day cycle. Days 3-21 will be for rest.

This is a phase 1/2 open label, multicenter study to assess the safety and efficacy of brentuximab vedotin in combination with bendamustine in patients with relapsed or refractory Hodgkin Lymphoma (HL) or other CD30+ expressing hematologic malignancies. Dose escalation in phase 1 will proceed according to a standard 3 + 3 dose escalation design. There will be no intracohort dose escalation. Three patients will be assigned to the starting dose level 1. If no dose limiting toxicities (DLT) are observed after one cycle of treatment, and if the start of cycle 2 treatment is not delayed greater than 7 days for any toxicity possibly related to drug, trial accrual proceeds to the next dose level and another cohort of 3 patients is enrolled. If 1 patient in a cohort experiences a DLT, then the cohort is expanded to 6, if 2 or more patients in this cohort experience a DLT then the dose level decreases. If none of the additional patients experience a DLT (1 out of 6) then dose escalation continues. The maximum tolerated dose (MTD) is defined as the highest dose level at which <33% of the dose cohort (0 of 3 or 1 of 6) experience a DLT in the first cycle.

• Hodgkin Lymphoma
• Anaplastic Large Cell Lymphoma

• Drug: Adcetris
  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.
  Other Names:

  • Brentuximab Vedotin
  • SGN35
• Drug: Bendamustine
  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.
  Other Names:

  • Treanda
  • Bendamustine HCl

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 > 18 years
• ECOG performance status 0,1 or 2

• Patient's must have adequate organ and marrow function as defined below

  • Absolute neutrophil count > 1,000 (1.0 x 109/L)
  • Platelets > 50,000 (50 x 109/L)
  • Total Bilirubin < 1.5 x institutional limits unless documented Gilbert's syndrome (then <2.5 x institutional upper limit)
  • AST (SGOT)/ALT (SGPT) < 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 > 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 > 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 active 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.

• British Columbia Cancer Agency
• Princess Margaret Hospital, Canada