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

Lymphoma, Large B-Cell, Diffuse Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03536039
• Other study ID #: INGRID
• Status: Completed
• Phase: Phase 2
• Start date: January 27, 2016
• Est. completion date: January 27, 2020

Study information

• Verified date: August 2022
• Source: IRCCS San Raffaele
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: January 27, 2020
• Est. primary completion date: January 27, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Large B-Cell, Diffuse
• Necrosis

Intervention

Drug:
• NGR-hTNF
dose of 0.8 mcg/sqm

Other:
• RITUXIMAB
dose of 375 mg/mq

Drug:
• Doxorubicin
dose of 50 mg/mq
• Cyclophosphamide
dose of 750 mg/mq
• Vincristine
dose of 1.4 mg/mq (max 2 mg)
• Prednisone
75 mg

Locations

Country	Name	City	State
Italy	Ospedale San Raffaele	Milan

Sponsors (2)

Lead Sponsor	Collaborator
Andres J. M. Ferreri	AGC Biologics S.p.A.

Country where clinical trial is conducted

Italy, 

References & Publications (8)

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. Epub 2005 Jun 13. — View 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. — View 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. Review. — View 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. — View 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. — View 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. — View 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. Epub 2007 Feb 27. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Duration of Response (DOR)	DOR will be assessed for all responsive patients; time to documentation of tumor response to failure	18 months
Secondary	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	12 months
Secondary	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.	12 months
Secondary	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.	12 months