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

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ClinicalTrials.gov Identifier: NCT03536039
Recruitment Status : Recruiting
First Posted : May 24, 2018
Last Update Posted : May 24, 2018
Sponsor:
Collaborator:
MolMed S.p.A.
Information provided by (Responsible Party):
Andres J. M. Ferreri, IRCCS San Raffaele

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.

Condition or disease Intervention/treatment Phase
Lymphoma, Large B-Cell, Diffuse Drug: NGR-hTNF Other: RITUXIMAB Drug: Doxorubicin Drug: Cyclophosphamide Drug: Vincristine Drug: Prednisone Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
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
Official Title: 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
Actual Study Start Date : January 27, 2016
Estimated Primary Completion Date : January 27, 2019
Estimated Study Completion Date : January 27, 2020


Arm Intervention/treatment
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
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Duration of Response (DOR) [ Time Frame: 18 months ]
    DOR will be assessed for all responsive patients; time to documentation of tumor response to failure

  2. 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

  3. 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.

  4. 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.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03536039


Contacts
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Contact: Andrés Jose Maria Ferreri, MD 00390226437649 ferreri.andres@hsr.it
Contact: Teresa Calimeri, MD 00390226437612 calimeri.teresa@hsr.it

Locations
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Italy
Ospedale San Raffaele Recruiting
Milan, Italy, 20132
Contact: Andrés Jose Maria Ferreri, MD    00390226437649    ferreri.andres@hsr.it   
Contact: Teresa Calimeri, MD    00390226437642    calimeri.teresa@hsr.it   
Sponsors and Collaborators
Andres J. M. Ferreri
MolMed S.p.A.
Investigators
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Principal Investigator: Andrés Jose Maria Ferreri, MD San raffaele hospital

Publications:

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Responsible Party: Andres J. M. Ferreri, Principal Investigator, IRCCS San Raffaele
ClinicalTrials.gov Identifier: NCT03536039     History of Changes
Other Study ID Numbers: INGRID
First Posted: May 24, 2018    Key Record Dates
Last Update Posted: May 24, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Andres J. M. Ferreri, IRCCS San Raffaele:
CNS lymphoma
BBB permeabilization
R-CHOP
TNF
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Large B-Cell, Diffuse
Necrosis
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pathologic Processes
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Prednisone
Cyclophosphamide
Rituximab
Doxorubicin
Liposomal doxorubicin
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors