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

Sponsor

Andres J. M. Ferreri (Other)

Overall Status

Completed

CT.gov ID

NCT03536039

Collaborator

AGC Biologics S.p.A. (Industry)

Enrollment

Location

Arm

Actual Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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:

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.
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.
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 Design

Study Type:

Interventional

Actual Enrollment :

28 participants

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)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 :

Jan 27, 2016

Actual Primary Completion Date :

Jan 27, 2019

Actual Study Completion Date :

Jan 27, 2020

Arms and Interventions

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 Names: mabthera Drug: Doxorubicin dose of 50 mg/mq Other Names: adriamicina Drug: Cyclophosphamide dose of 750 mg/mq Other Names: endoxan Drug: Vincristine dose of 1.4 mg/mq (max 2 mg) Drug: Prednisone 75 mg Other Names: deltacortene

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 Names:

mabthera

Drug: Doxorubicin

dose of 50 mg/mq

Other Names:

adriamicina

Drug: Cyclophosphamide

dose of 750 mg/mq

Other Names:

endoxan

Drug: Vincristine

dose of 1.4 mg/mq (max 2 mg)

Drug: Prednisone

75 mg

Other Names:

deltacortene

Outcome Measures

Primary Outcome Measures

ORR: CR and PR based on IPCG response criteria [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

Duration of Response (DOR) [18 months]
DOR will be assessed for all responsive patients; time to documentation of tumor response to failure
Progression-free survival (PFS) [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) [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. [12 months]
Tolerability will be assessed for all enrolled patients; it is defined by of grade 3-4 AEs according to NCI CTCAE.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.