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

NCT03536039 | Completed Phase 2 DMC

• 1 other identifier: INGRID
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

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.

Conditions

Lymphoma, Large B-Cell, Diffuse

Keywords

CNS lymphoma; BBB permeabilization; R-CHOP; TNF

Outcome Measures

Primary Outcomes (1)

• 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.

  up to 18 weeks

Secondary Outcomes (4)

• Duration of Response (DOR)

  18 months

• Progression-free survival (PFS)

  12 months

• Overall survival (OS)

  12 months

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

  12 months

Study Arms (1)

NGR-hTNF + R-CHOP

EXPERIMENTAL

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

Interventions

NGR-hTNF DRUG

dose of 0.8 mcg/sqm

NGR-hTNF + R-CHOP

RITUXIMAB OTHER

dose of 375 mg/mq

Also known as: mabthera

NGR-hTNF + R-CHOP

Doxorubicin DRUG

dose of 50 mg/mq

Also known as: adriamicina

NGR-hTNF + R-CHOP

Cyclophosphamide DRUG

dose of 750 mg/mq

Also known as: endoxan

NGR-hTNF + R-CHOP

Vincristine DRUG

dose of 1.4 mg/mq (max 2 mg)

NGR-hTNF + R-CHOP

Prednisone DRUG

75 mg

Also known as: deltacortene

NGR-hTNF + R-CHOP

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Andres J. M. Ferreri: lead
• AGC Biologics S.p.A.: collaborator

Study Sites (1)

Ospedale San Raffaele

Milan, 20132, Italy

Location

Related Publications (8)

• 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.

  PMID: 12805341 BACKGROUND

• 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.

  PMID: 24108809 BACKGROUND

• 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.

  PMID: 12189241 BACKGROUND

• 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.

  PMID: 23743670 BACKGROUND

• 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.

  PMID: 19568235 BACKGROUND

• 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.

  PMID: 16379040 BACKGROUND

• 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.

  PMID: 15955902 BACKGROUND

• 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.

  PMID: 17325700 BACKGROUND

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

tumor necrosis factor-alpha, CNGRC fusion protein, human; Rituximab; Doxorubicin; Cyclophosphamide; Vincristine; Prednisone; deltacortene

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds

Study Officials

• Andrés Jose Maria Ferreri, MD

  San raffaele hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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)

Study Record Dates

• First Submitted: July 7, 2017
• First Posted: May 24, 2018
• Study Start: January 27, 2016
• Primary Completion: January 27, 2019
• Study Completion: January 27, 2020
• Last Updated: August 3, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)