Real World Data on Ibrutinib Use in PCNSL Rel/Ref

PCNSL Clinical Trial

— ReWIPretro  

Official title:

Studio Osservazionale Retrospettivo Multicentrico Sull'Utilizzo di Ibrutinib in Monoterapia o in Associazione a Immunochemioterapia Secondo Schema R-CHOP in Pazienti Adulti Con Diagnosi di PCNSL Ricaduto o Refrattario

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05782374
• Other study ID #: Observational
• Status: Recruiting
• Start date: August 10, 2022
• Est. completion date: August 10, 2023

Study information

• Verified date: March 2023
• Source: IRCCS San Raffaele
• Contact: Andres Ferreri, md
• Phone: 0226435603
• Email: ferreri.clinicaltrials[@]hsr.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

PCNSL is a rare and aggressive subtype of B lymphoma that has been recognized as a distinct disease entity in the latest edition of the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissue and is defined as DLBCL that develops exclusively in the brain parenchyma, spinal cord, leptomeninges and eye. In patients under 70 years of age without severe comorbidities, first-line treatment with induction chemo-immunotherapy according to the MATRix scheme (Methotrexate, Cytarabine, Tiothepa, Rituximab) and subsequent consolidation with HDCT followed by ASCT achieved the best results in terms of PFS and OS. Data on patients enrolled in a randomized phase 2 study showed an OS of 70% at a median FU of 88 months. In patients> 70 years of age or with low KPS, the prognosis remains significantly lower in the younger population. Several population studies have shown a stable increase over the past 30 years in terms of PFS and OS in patients aged under 70 years, while in patients over 70 years or with KPS <70%, the survival curves are not satisfactory. in part because these patients are often referred to BSC alone, despite the benefit in PFS and OS demonstrated with HD-MTX-based treatments (≥1 g / m2) combined with oral alkylating agents or cytarabine in high doses.

Description:

Historically, HDCT followed by ASCT has not been considered a feasible option for elderly patients, although recent data collected in the "real life" setting and a pilot study conducted in Germany demonstrate that maintenance of the dose intensity of HD-MTX and treatment completion with HDCT / ASCT-based consolidation are similar to those in clinical studies. However, 20 to 50% of newly diagnosed PCNSL patients do not achieve a complete response with currently available treatment regimens, highlighting the need for improved induction strategies. Furthermore, even after a complete response, patients with PCNSL may experience relapse, especially in the elderly. First-line treatment failure usually occurs (70-75% of cases) within the first two years and the prognosis of this population is extremely poor as demonstrated in a retrospective study of more than 250 patients with PCNSL R / R who reported median PFS and OS at first relapse / progression of 2.2 and 3.5 months, respectively. Similar results have also been highlighted in several prospective studies in which the PFS and OS curves are equivalent. There is currently no standard of treatment for the treatment of patients with PCNSL R/R. Data extrapolated from the long-term FU of a randomized phase 2 trial suggests that patients with relapses more than 36 months after the end of first-line methotrexate-based immuno-chemotherapy could benefit from a rechallenge with the same treatment. On the other hand, for patients refractory or with relapses within 36 months or not eligible for HD-MTX, the best therapeutic choice is represented by enrollment in a clinical trial. In the absence of this option, the therapeutic choice is based on the experience of phase 2 studies.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: August 10, 2023
• Est. primary completion date: January 10, 2023
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Histological or cytological diagnosis of DLBCL

• Disease localized exclusively in the CNS (brain, meninges, cranial nerves, eyes and / or spinal cord) both at first diagnosis and at failure

• Progressive or recurrent disease

• Previous treatment with high-dose methotrexate-based chemotherapy ± WBRT

• Age 18 - 80 years

• ECOG performance status 0-3

• Adequate hematopoiesis (platelets> 25,000 / 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 liver function (SGOT / SGPT <3 times UNL, bilirubin and alkaline phosphatase <2 times UNL).

• Patients who have been given treatment with ibrutinib, alone or in combination with immunochemotherapy, and who have or have not received the same.

Exclusion Criteria:

• Patients with concomitant extra-CNS disease at presentation or relapse

• Symptomatic coronary heart disease, cardiac arrhythmias not well controlled with drugs, or myocardial infarction within the past 6 months (New York Heart Association class III or IV heart disease)

• Any other serious medical condition that could compromise the patient's ability to adhere to treatment.

• Presence of any psychological, family, sociological or geographical condition that may hinder compliance with the study protocol and the follow-up program.

• In therapy with strong CYP3A inhibitors

Related Conditions & MeSH terms

• PCNSL

Intervention

Drug:
• Ibrutinib
ibrutinib alone or in combination with R-CHOP or R-CHOP like

Locations

Country	Name	City	State
Italy	Ospedale San Raffaele	Milan

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS San Raffaele

Country where clinical trial is conducted

Italy, 

References & Publications (5)

Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, Celico C, Falautano M, Nonis A, La Rosee P, Binder M, Fabbri A, Ilariucci F, Krampera M, Roth A, Hemmaway C, Johnson PW, Linton KM, Pukrop T, Gorlov JS, Balzarotti M, Hess G, Keller U, Stilgenbauer S, Panse J, Tucci A, Orsucci L, Pisani F, Zanni M, Krause SW, Schmoll HJ, Hertenstein B, Rummel M, Smith J, Thurner L, Cabras G, Pennese E, Ponzoni M, Deckert M, Politi LS, Finke J, Ferranti A, Cozens K, Burger E, Ielmini N, Cavalli F, Zucca E, Illerhaus G; IELSG32 study investigators. Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial. Leukemia. 2022 Jul;36(7):1870-1878. doi: 10.1038/s41375-022-01582-5. Epub 2022 May 13. — View Citation

Kaji FA, Martinez-Calle N, Bishton MJ, Figueroa R, Adlington J, O'Donoghue M, Smith S, Byrne P, Paine S, Sovani V, Auer D, James E, Bessell EM, Grainge MJ, Fox CP. Improved survival outcomes despite older age at diagnosis: an era-by-era analysis of patients with primary central nervous system lymphoma treated at a single referral centre in the United Kingdom. Br J Haematol. 2021 Nov;195(4):561-570. doi: 10.1111/bjh.17747. Epub 2021 Aug 8. — View Citation

Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021 Aug 2;23(8):1231-1251. doi: 10.1093/neuonc/noab106. — View Citation

Schorb E, Fox CP, Kasenda B, Linton K, Martinez-Calle N, Calimeri T, Ninkovic S, Eyre TA, Cummin T, Smith J, Yallop D, De Marco B, Krampera M, Trefz S, Orsucci L, Fabbri A, Illerhaus G, Cwynarski K, Ferreri AJM. Induction therapy with the MATRix regimen in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system - an international study of feasibility and efficacy in routine clinical practice. Br J Haematol. 2020 Jun;189(5):879-887. doi: 10.1111/bjh.16451. Epub 2020 Jan 29. — View Citation

Sieg N, Naendrup JH, Godel P, Balke-Want H, Simon F, Deckert M, Gillessen S, Kreissl S, Brockelmann PJ, Borchmann P, von Tresckow B, Heger JM. Treatment patterns and disease course of previously untreated Primary Central Nervous System Lymphoma: Feasibility of MTX-based regimens in clinical routine. Eur J Haematol. 2021 Aug;107(2):202-210. doi: 10.1111/ejh.13639. Epub 2021 May 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To evaluate the efficacy in terms of overall rate of responses in patients treatment	To evaluate the efficacy in terms of overall rate of responses to treatment (ORR = sum of complete responses [CR] + partial responses [PR]) according to the IPCG 2005 criteria in a retrospective cohort of patients with relapsed / refractory PCNSL undergoing treatment with ibrutinib given as monotherapy or in combination with R-CHOP immuno-chemotherapy.	6MONTH
Secondary	Evaluate the effectiveness in terms of overall survival (OS);	Evaluate the overall survival (OS) after the treatment	6MONTH
Secondary	Evaluate the effectiveness in terms of progression-free survival (PFS);	Verify the no progression of the lymphoma after the treatment	6MONTH
Secondary	Verification of the safety of the ibrutinib monotherapy and in combination with R-CHOP	To evaluate the safety of ibrutinib administered alone and in combination with R-CHOP in the PCNSL R / R patient population;	6MONTH
Secondary	To evaluate the role of consolidation therapy with high-dose chemotherapy	To evaluate the role of consolidation therapy with high-dose chemotherapy and autologous transplant or radiotherapy (ASCT or RT) and of ibrutinib maintenance therapy;	6MONTH
Secondary	Frequency of invasive fungal infections after prophylactic antifungal therapy	Assess the frequency of invasive fungal infections and the effectiveness of prophylactic antifungal therapy in the patients treated with R-CHOP	6MONTH