RCHOP Chemoimmunotherapy Preceded BY BBB Permeabilization by t-NGR Necrosis Factor
Condition: Lymphoma, Large B-Cell, Diffuse
MeSH terms: Lymphoma; Lymphoma, Large B-Cell, Diffuse; Necrosis
Study type: Interventional
Phase: Phase 2

Summary: 
      Patients with primary central nervous system lymphoma (PCNSL) are treated with
      high-dose-methotrexate-based chemotherapy, which requires hospitalization and extensive
      expertise to manage related toxicity. Treatment with R-CHOP, the most commonly used
      combination against aggressive lymphomas, could overcome these difficulties, but CNS
      bioavailability of related drugs is poor due to their limited capability to cross the
      blood-brain barrier (BBB). Tumor necrosis factor (TNF) induces selective BBB permeabilization
      and enhances CNS access of anticancer drugs in animal models. The addition of NGR peptide
      improves biological properties of TNF, resulting in increased drug availability and antitumor
      synergistic effect, without increased toxicity. Thus, the addition of NGR-hTNF to R-CHOP may
      result in improved CNS drug availability and activity in patients with relapsed/refractory
      PCNSL; this hypothesis is being tested in this ongoing phase II trial called "INGRID". This
      trial will consider HIV-negative patients (age 18-80 ys; ECOG PS ≤3) with relapsed/refractory
      PCNSL previously treated with high-dose-methotrexate-based chemotherapy± radiotherapy, and
      with measurable disease.
    

Detailed description: 
      There are three planned analyses:

        1. An exploratory analysis (proof of principle) on the first 10 enrolled patients. In the
           case the experimental treatment will be safe and some tumor responses will be recorded,
           the chairman, after due multidisciplinary discussion, could propose to proceed with an
           open, non-comparative phase II trial, with overall response rate (complete and partial
           responses) as primary endpoint. The maximum overall response rate considered of low
           interest will be 30%, and the minimum response rate considered of interest will be 50%;
           to demonstrate that difference, a total of 28 patients will be needed (one-sided test;
           trype I error .10; power .9). Importantly, BBB permeabilization will be investigated
           using different methods. Variations in tumor microvasculature and vessel permeability
           will be assessed by DCE- and DSC-MRI. Permeability will be assessed in contrast-enhanced
           lesions, perilesional areas and normal appearing brain; results will expressed as KTRANS
           values normalized using contralateral normal appearing white matter, and compared by
           Wilcoxon Signed Rank Test. Concentrations of R-CHOP drugs were assessed on matched CSF
           and serum/plasma samples.Moreover, BBB permeability will be also assessed by
           99mTc-diethylene-triamine-pentacetic acid (99mTc-DTPA) brain scintigraphy.

        2. First of the two stages of Simon Minimax design, where 12 patients will be entered
           (including the 10 patients of the exploratory phase) and, if at least 4 responses will
           be observed, the study will be continued until a total of 28 patients will be entered.

        3. Second stage of Simon Minimax design: final analysis of activity on the whole series
           (n=28); the experimental treatment will be declared active if at least 12 responses will
           be observed.
    

Intervention name(s): NGR-hTNF; RITUXIMAB; Doxorubicin; Cyclophosphamide; Vincristine; Prednisone
Intervention type(s): Drug; Other; Drug; Drug; Drug; Drug
Intervention description(s): dose of 0.8 mcg/sqm; dose of 375 mg/mq; dose of 50 mg/mq; dose of 750 mg/mq; dose of 1.4 mg/mq (max 2 mg); 75 mg
Other intervention name(s): mabthera; adriamicina; endoxan; deltacortene
Intervention MeSH terms: Prednisone; Cyclophosphamide; Rituximab; Doxorubicin; Vincristine
Intervention model: Single Group Assignment
Intervention model description: Patients will receive NGR-hTNF at dose of 0.8 mcg/sqm 1 hour before standard R-CHOP (cyclophosphamide-doxorubicin-vincristine-prednisone-rituximab) regimen every 3 weeks for six courses (except for course #1 in which only standard R-CHOP regimen will be administered)
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: CNS lymphoma; BBB permeabilization; R-CHOP; TNF