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

Primary Purpose

Lymphoma, Large B-Cell, Diffuse

Status

Completed

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

NGR-hTNF

RITUXIMAB

Doxorubicin

Cyclophosphamide

Vincristine

Prednisone

About this trial

This is an interventional treatment trial for Lymphoma, Large B-Cell, Diffuse focused on measuring CNS lymphoma, BBB permeabilization, R-CHOP, TNF

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

Ospedale San Raffaele

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

NGR-hTNF + R-CHOP

Arm Description

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

Outcomes

Primary Outcome Measures

ORR: CR and PR based on IPCG response criteria

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)

DOR will be assessed for all responsive patients; time to documentation of tumor response to failure

Progression-free survival (PFS)

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)

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.

Tolerability will be assessed for all enrolled patients; it is defined by of grade 3-4 AEs according to NCI CTCAE.

Full Information

NCT ID

NCT03536039

First Posted

July 7, 2017

Last Updated

August 2, 2022

Sponsor

Andres J. M. Ferreri

Collaborators

AGC Biologics S.p.A.

1. Study Identification

Unique Protocol Identification Number

NCT03536039

Brief Title

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

Acronym

INGRID

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Completed

Study Start Date

January 27, 2016 (Actual)

Primary Completion Date

January 27, 2019 (Actual)

Study Completion Date

January 27, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Andres J. M. Ferreri

Collaborators

AGC Biologics S.p.A.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Lymphoma, Large B-Cell, Diffuse

Keywords

CNS lymphoma, BBB permeabilization, R-CHOP, TNF

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

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)

Allocation

N/A

Enrollment

28 (Actual)

8. Arms, Groups, and Interventions

Arm Title

NGR-hTNF + R-CHOP

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

NGR-hTNF

Intervention Description

dose of 0.8 mcg/sqm

Intervention Type

Other

Intervention Name(s)

RITUXIMAB

Other Intervention Name(s)

mabthera

Intervention Description

dose of 375 mg/mq

Intervention Type

Drug

Intervention Name(s)

Doxorubicin

Other Intervention Name(s)

adriamicina

Intervention Description

dose of 50 mg/mq

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

endoxan

Intervention Description

dose of 750 mg/mq

Intervention Type

Drug

Intervention Name(s)

Vincristine

Intervention Description

dose of 1.4 mg/mq (max 2 mg)

Intervention Type

Drug

Intervention Name(s)

Prednisone

Other Intervention Name(s)

deltacortene

Intervention Description

75 mg

Primary Outcome Measure Information:

Title

ORR: CR and PR based on IPCG response criteria

Description

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.

Time Frame

up to 18 weeks

Secondary Outcome Measure Information:

Title

Duration of Response (DOR)

Description

DOR will be assessed for all responsive patients; time to documentation of tumor response to failure

Time Frame

18 months

Title

Progression-free survival (PFS)

Description

Time Frame

12 months

Title

Overall survival (OS)

Description

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.

Time Frame

12 months

Title

Tolerability: defined by of grade 3-4 AEs according to NCI CTCAE.

Description

Tolerability will be assessed for all enrolled patients; it is defined by of grade 3-4 AEs according to NCI CTCAE.

Time Frame

12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Andrés Jose Maria Ferreri, MD

Organizational Affiliation

San raffaele hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Ospedale San Raffaele

City

Milan

ZIP/Postal Code

20132

Country

Italy

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

12805341

Citation

Ferreri AJ, Abrey LE, Blay JY, Borisch B, Hochman J, Neuwelt EA, Yahalom J, Zucca E, Cavalli F, Armitage J, Batchelor T. Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol. 2003 Jun 15;21(12):2407-14. doi: 10.1200/JCO.2003.01.135.

Results Reference

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PubMed Identifier

24108809

Citation

Connell JJ, Chatain G, Cornelissen B, Vallis KA, Hamilton A, Seymour L, Anthony DC, Sibson NR. Selective permeabilization of the blood-brain barrier at sites of metastasis. J Natl Cancer Inst. 2013 Nov 6;105(21):1634-43. doi: 10.1093/jnci/djt276. Epub 2013 Oct 9.

Results Reference

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PubMed Identifier

12189241

Citation

Curnis F, Sacchi A, Corti A. Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J Clin Invest. 2002 Aug;110(4):475-82. doi: 10.1172/JCI15223.

Results Reference

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PubMed Identifier

23743670

Citation

Corti A, Curnis F, Rossoni G, Marcucci F, Gregorc V. Peptide-mediated targeting of cytokines to tumor vasculature: the NGR-hTNF example. BioDrugs. 2013 Dec;27(6):591-603. doi: 10.1007/s40259-013-0048-z.

Results Reference

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PubMed Identifier

19568235

Citation

Gregorc V, Santoro A, Bennicelli E, Punt CJ, Citterio G, Timmer-Bonte JN, Caligaris Cappio F, Lambiase A, Bordignon C, van Herpen CM. Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours. Br J Cancer. 2009 Jul 21;101(2):219-24. doi: 10.1038/sj.bjc.6605162. Epub 2009 Jun 30.

Results Reference

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PubMed Identifier

16379040

Citation

van Laarhoven HW, Gambarota G, Heerschap A, Lok J, Verhagen I, Corti A, Toma S, Gallo Stampino C, van der Kogel A, Punt CJ. Effects of the tumor vasculature targeting agent NGR-TNF on the tumor microenvironment in murine lymphomas. Invest New Drugs. 2006 Jan;24(1):27-36. doi: 10.1007/s10637-005-4540-2.

Results Reference

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PubMed Identifier

15955902

Citation

Abrey LE, Batchelor TT, Ferreri AJ, Gospodarowicz M, Pulczynski EJ, Zucca E, Smith JR, Korfel A, Soussain C, DeAngelis LM, Neuwelt EA, O'Neill BP, Thiel E, Shenkier T, Graus F, van den Bent M, Seymour JF, Poortmans P, Armitage JO, Cavalli F; International Primary CNS Lymphoma Collaborative Group. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005 Aug 1;23(22):5034-43. doi: 10.1200/JCO.2005.13.524. Epub 2005 Jun 13.

Results Reference

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PubMed Identifier

17325700

Citation

Reni M, Zaja F, Mason W, Perry J, Mazza E, Spina M, Bordonaro R, Ilariucci F, Faedi M, Corazzelli G, Manno P, Franceschi E, Pace A, Candela M, Abbadessa A, Stelitano C, Latte G, Ferreri AJ. Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer. 2007 Mar 26;96(6):864-7. doi: 10.1038/sj.bjc.6603660. Epub 2007 Feb 27.

Results Reference

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

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