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RCHOP Chemoimmunotherapy Preceded BY BBB Permeabilization by t-NGR Necrosis Factor (INGRID)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03536039
Recruitment Status : Unknown
Verified May 2018 by Andres J. M. Ferreri, IRCCS San Raffaele.
Recruitment status was:  Recruiting
First Posted : May 24, 2018
Last Update Posted : May 24, 2018
AGC Biologics S.p.A.
Information provided by (Responsible Party):
Andres J. M. Ferreri, IRCCS San Raffaele

Tracking Information
First Submitted Date  ICMJE July 7, 2017
First Posted Date  ICMJE May 24, 2018
Last Update Posted Date May 24, 2018
Actual Study Start Date  ICMJE January 27, 2016
Estimated Primary Completion Date January 27, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 23, 2018)
ORR: CR and PR based on IPCG response criteria [ Time Frame: up to 18 weeks ]
Activity in terms of overall response rate (ORR): Complete Response (CR) and Partial Response (PR) of R-CHOP21 chemo-immunotherapy preceded by BBBP by NGR-hTNF.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: May 23, 2018)
  • Duration of Response (DOR) [ Time Frame: 18 months ]
    DOR will be assessed for all responsive patients; time to documentation of tumor response to failure
  • Progression-free survival (PFS) [ Time Frame: 12 months ]
    PFS will be assessed for all treated patients; it is defined as the interval between the time of entry onto trial and failure (relapsing or progressive disease), death from any cause or date of the last visit of follow-up
  • Overall survival (OS) [ Time Frame: 12 months ]
    OS will be assessed for all enrolled patients; it is defined as the time from entry onto trial until death from any cause or date of the last visit of follow-up.
  • Tolerability: defined by of grade 3-4 AEs according to NCI CTCAE. [ Time Frame: 12 months ]
    Tolerability will be assessed for all enrolled patients; it is defined by of grade 3-4 AEs according to NCI CTCAE.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE RCHOP Chemoimmunotherapy Preceded BY BBB Permeabilization by t-NGR Necrosis Factor
Official Title  ICMJE Monoinstitutional Phase II Trial Addressing Tolerability and Activity of RCHOP Chemoimmunotherapy Preceded by BBB Permeabilization by t-NGR Necrosis Factor in Patients With Relapsed/Refractory Primary Central Nervous System Lymphoma
Brief 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
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
Condition  ICMJE Lymphoma, Large B-Cell, Diffuse
Intervention  ICMJE
  • Drug: NGR-hTNF
    dose of 0.8 mcg/sqm
  • Other: RITUXIMAB
    dose of 375 mg/mq
    Other Name: mabthera
  • Drug: Doxorubicin
    dose of 50 mg/mq
    Other Name: adriamicina
  • Drug: Cyclophosphamide
    dose of 750 mg/mq
    Other Name: endoxan
  • Drug: Vincristine
    dose of 1.4 mg/mq (max 2 mg)
  • Drug: Prednisone
    75 mg
    Other Name: deltacortene
Study Arms  ICMJE Experimental: NGR-hTNF + R-CHOP
Treatment includes one course of conventional R-CHOP followed by 5 courses of conventional R-CHOP (rituximab, Cyclophosphamide, vincristine, doxorubicin, prednisone) in conjunction with intravenous delivery of NGR-hTNF. Chemoimmunotherapy courses will be delivered every 3 weeks; day 22 is to be considered as day 1 of the subsequent course
  • Drug: NGR-hTNF
  • Other: RITUXIMAB
  • Drug: Doxorubicin
  • Drug: Cyclophosphamide
  • Drug: Vincristine
  • Drug: Prednisone
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: May 23, 2018)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 27, 2020
Estimated Primary Completion Date January 27, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria

  • Histological or cytological diagnosis of (D)LBCL
  • Disease exclusively localized into the CNS (brain, meninges, cranial nerves, eyes and/or spinal cord) both at first diagnosis and failure
  • Progressive or recurrent disease
  • Previous treatment with high-dose-methotrexate-based chemotherapy ± WBRT
  • Presence of at least one target lesion, bidimensionally measurable
  • Age 18 - 80 years
  • ECOG performance status 0-3
  • Adequate bone marrow (platelets >75.000/mm3, hemoglobin >8 g/dl, ANC >1.000/mm3), renal (serum creatinine <2 times UNL and creatinine clearance ≥40 mL/min), cardiac (VEF ≥50%), and hepatic (SGOT/SGPT <3 times UNL, bilirubin and alkaline phosphatase <2 times UNL) function.
  • Given written informed consent prior to any study specific procedures, with the understanding that the patient has the right to withdraw from the study at any time, without any prejudice. Informed consent signed by a patient's guardian is acceptable if the patient is not able to decide inclusion in the study due to cognitive impairment

5.3 Exclusion criteria

  • Known HIV disease or other chronic immunodeficiency
  • Patients with positive flow cytometry examination of the CSF, but negative results in CSF conventional cytology, and without any other evidence of CNS disease
  • Patients with concomitant extra-CNS disease at presentation or relapse
  • Symptomatic coronary artery disease, cardiac arrhythmias not well controlled with medication or myocardial infarction within the last 6 months (New York Heart Association Class III or IV heart disease)
  • Any other serious medical condition which could impair the ability of the patient to participate in the trial
  • Concurrent treatment with other antineoplastic drugs
  • Therapy with PPI (Proton Pump Inhibitors, that may interfere with chromogranine levels, see above). For gastroprotective therapy H2-blockers (i.e. ranitidine) are allowed.
  • Pregnant and lactating female patients. Sexually active patients of child bearing potential must implement adequate contraceptive measures during study participation.
  • Previous or concurrent malignancies at other sites diagnosed or relapsed within the last 3 years of follow-up. Patients with surgically cured in situ carcinomas and basal cell carcinoma of the skin are allowed.
  • Presence of any psycological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03536039
Other Study ID Numbers  ICMJE INGRID
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Andres J. M. Ferreri, IRCCS San Raffaele
Study Sponsor  ICMJE Andres J. M. Ferreri
Collaborators  ICMJE AGC Biologics S.p.A.
Investigators  ICMJE
Principal Investigator: Andrés Jose Maria Ferreri, MD San raffaele hospital
PRS Account IRCCS San Raffaele
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP