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Hodgkin's Lymphoma

Phase II Pilot Study of Bortezomib, Ifosfamide, and Vinorelbine Ditartrate in Pediatric Patients and Young Adults With Refractory or Recurrent Hodgkin's Lymphoma

TypeStatusAge RangeSponsorProtocol ID
TreatmentActiveUnder 30COGAHOD0521

Outline

This is a multicenter, open-label, pilot study.

Patients receive ifosfamide IV continuously over days 1-4, vinorelbine ditartrate IV over 6-10 minutes on days 1 and 5, bortezomib IV on days 1, 4, and 8, and filgrastim (G-CSF) IV or subcutaneously beginning on day 6 and continuing until blood counts recover or peripheral blood stem cells (PBSC) are harvested. Treatment repeats every 21 days for up to 2 or 4 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo autologous PBSC harvesting according to institutional guidelines after the second course of therapy.

After completion of study treatment, patients are followed every 6 months for 2 years and then annually thereafter.

Objectives

Primary

  1. Determine the efficacy and safety of bortezomib (as a chemosensitizing agent) in pediatric patients and young adults with primary refractory Hodgkin's lymphoma (HL) or HL in first relapse. 
  2. Determine response rate in patients treated with bortezomib, ifosfamide, and vinorelbine ditartrate (IVB) and compare it to the historical response rate in patients treated with ifosfamide and vinorelbine ditartrate alone.

Secondary

  1. Determine the overall response rate (complete and partial response) and induction success rate after 2 or 4 courses of therapy and the reinduction rate (complete response) after 4 courses of therapy. 
  2. Determine the proportion of patients able to mobilize sufficient hematopoietic stem cells (CD34+) after 2 courses of IVB.

Expected Enrollment

A total of 48 patients will be accrued for this study.

Mechanism of Action

A dipeptide boronic acid analogue with antineoplastic activity. Bortezomib reversibly inhibits the 26S proteasome, a large protease complex that degrades ubiquinated proteins. By blocking the targeted proteolysis normally performed by the proteasome, bortezomib disrupts various cell signaling pathways, leading to cell cycle arrest, apoptosis, and inhibition of angiogenesis. Specifically, the agent inhibits nuclear factor (NF)-kappaB, a protein that is constitutively activated in some cancers, thereby interfering with NF-kappaB-mediated cell survival, tumor growth, and angiogenesis. In vivo, bortezomib delays tumor growth and enhances the cytotoxic effects of radiation and chemotherapy.

Entry Criteria

Disease Characteristics:

  • Histologically confirmed Hodgkin's lymphoma at time of relapse or disease progression, meeting all of the following criteria:
    • Stage I-IV disease
    • Meets 1 of the following criteria:
      • Mixed cellularity 
      • Lymphocytic depletion (LD) LD, diffuse fibrosis 
      • LD, reticular 
      • Lymphocyte predominance (LP) 
      • LP, diffuse 
      • LP, nodular 
      • Nodular sclerosis (NS) 
      • NS, cellular phase 
      • NS, lymphocytic predominance 
      • NS, mixed cellularity 
      • NS, LD 
      • Not otherwise specified
    • No morphologically unclassifiable disease
    • Primary refractory disease OR disease in first relapse, except for the following: 
      • Patients achieving a complete response after treatment on protocol COG AHOD0431 who experience a biopsy-proven recurrence after doxorubicin hydrochloride, vincristine, prednisone, and cyclophosphamide without involved-field radiotherapy 
      • Patients on the observation-only arm of protocol COG-AHOD0431
  • Measurable disease, defined as 1 of the following:
    • Any nodal mass with the longest traverse diameter > 2 cm 
    • Any measurable, focal mass lesion of a visceral organ (e.g., liver, spleen, or kidney)
  • Patients with metastatic disease to bone marrow and granulocytopenia, anemia, and/or thrombocytopenia are allowed provided both of the following criteria are met: 
    • Platelet count ≥ 20,000/mm³ (platelet transfusion allowed)
    • Hemoglobin ≥ 8 g/dL (packed red blood cell transfusion allowed)

Patient Characteristics:

Age

  • Patients must be under 30 years of age at the time of study enrollment

Performance Status

  • Karnofsky performance status (PS) 60-100% (for patients > 16 years of age) OR Lanksy PS 60-100% (for patients ≤ 16 years of age)

Life expectancy

  • Life expectancy ≥ 2 months

Hematopoetic

  • Absolute neutrophil count ≥ 1,000/mm³ 
  • Platelet count ≥ 75,000/mm³ (transfusion independent) (for patients with no bone marrow involvement)

Hepatic

  • AST and ALT ≤ 2.5 times ULN 
  • Bilirubin ≤ 1.5 times ULN

Renal

  • Creatinine ≤ 1.5 times upper limit of normal (ULN) 
  • Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min

Cardiovascular

  • Shortening fraction ≥ 27% by echocardiogram OR LVEF ≥ 50% by gated radionuclide study

Pulmonary

  • Not specified

Other

  • Patients with a seizure disorder are eligible if on a nonenzyme-inducing anticonvulsant and seizures are well controlled 
  • No CNS toxicity > grade 2 
  • No serious intercurrent illnesses 
  • No known hypersensitivity to E.coli-derived proteins, filgrastim (G-CSF), or any component of the study drugs 
  • No peripheral neuropathy > grade 1 
  • No known hypersensitivity to bortezomib, boron, or mannitol 
  • Not pregnant or nursing 
  • Negative pregnancy test 
  • Fertile patients must use effective contraception

Prior / Concurrent Therapy:

Biologic therapy

  • No prior bortezomib or other proteasome inhibitors

Chemotherapy

  • At least 3 weeks since prior chemotherapy (4 weeks for nitrosoureas)

Endocrine Therapy

  • Concurrent corticosteroids allowed for treatment or prophylaxis of anaphylactic reactions

Radiotherapy

  • Not specified

Surgery

  • Not specified

Other

  • More than 14 days since prior investigational drugs 
  • Benzodiazepine or gabapentin allowed
  • No concurrent enzyme inducing anticonvulsants that alter p450 metabolism, including phenytoin, carbamazepine, phenobarbital, or other anticonvulsants 
  • No other concurrent chemotherapy or immunomodulating agents (including steroids) 
  • No dexamethasone or aprepitant as an antiemetic
  • Recovered from prior therapy

Trial Contact Information

Rebecca Turner, MS, CCRP
Cincinnati Children's Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org