Temsirolimus in Recurrent Primary Central Nervous System (CNS) Lymphoma

Phase 2 Study of Temsirolimus in Refractory and Recurrent Primary CNS Lymphoma

This is an open-label trial investigating the efficacy of temsirolimus in recurrent or refractory primary CNS lymphoma (PCNSL) after initial chemotherapy with a high-dose methotrexate containing regimen. 37 patients are planned to be treated with weekly infusions of 25mg Temsirolimus (first 3 patients) or 75mg Temsirolimus (all other patients) up to a maximum of 12 months. The trial is designed in two stages, if less than one of the first 12 patients responds to treatment, the trial is stopped. In addition to efficacy, safety and penetration of temsirolimus into the cerebrospinal fluid will be investigated.

Study Overview

• Status: Unknown
• Conditions: Recurrent or Refractory Primary CNS Lymphoma
• Intervention / Treatment: Drug: temsirolimus

• Study Type: Interventional
• Enrollment (Anticipated): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 12200
    • Recruiting
    • Charite Campus Benjamin Franklin
    • Contact: Agnieszka Korfel, MD; Phone Number: 4096 +49308445; Email: agnieszka.korfel@charite.de
    • Contact: Philipp Kiewe, MD; Phone Number: 5225 +493064499; Email: philipp.kiewe@charite.de
    • Sub-Investigator: Philipp Kiewe, MD
    • Principal Investigator: Agnieszka Korfel, MD
    • Sub-Investigator: Martin Neumann, MD
    • Sub-Investigator: Stephan Kreher, MD
  • Bochum, Germany, 44892
    • Recruiting
    • Neurology, Knappschaftskrankenhaus Bochum, Bochum University
    • Contact: Uwe Schlegel, MD; Phone Number: +49-2342993701; Email: simone.middelhauve@kk-bochum.de
    • Contact: Simone Middelhauve; Phone Number: +49-2342993701; Email: simone.middelhauve@kk-bochum.de
  • Bonn, Germany, 53127
    • Recruiting
    • Neurology, University Hospital Bonn
    • Contact: Ulrich Herrlinger, MD; Phone Number: +49-222828719887; Email: christiane.landwehr@ukb.uni-bonn.de
    • Contact: Christiane Landwehr; Phone Number: +49-222828719887; Email: christiane.landwehr@ukb.uni-bonn.de
  • Frankfurt an der Oder, Germany, 15236
    • Not yet recruiting
    • Hematology, Klinikum Frankfurt/Oder
    • Contact: Michael Kiel, MD; Phone Number: +4933-55484604; Email: melanie.binsker@klinikum-ffo.de
    • Contact: Melanie Binsker; Phone Number: +4933-55484604; Email: melanie.binsker@klinikum-ffo.de
  • Heidelberg, Germany, 69120
    • Not yet recruiting
    • Hematology, University Hospital Heidelberg
    • Contact: Gerlinde Egerer, MD; Phone Number: +49-6221568029; Email: martina.gronkowski@med.uni-heidelberg.de
    • Contact: Martina Gronkowski; Phone Number: +49-6221568029; Email: martina.gronkowski@med.uni-heidelberg.de
  • Munich, Germany, 81377
    • Recruiting
    • Klinikum Grosshadern, University Hospital Munich
    • Contact: Martin Dreyling, MD; Phone Number: +498970955202; Email: carmen.carlucci@med.uni-muenchen.de
    • Contact: Carmen Carlucci; Phone Number: +498970955202; Email: carmen.carlucci@med.uni-muenchen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Primary CNS lymphoma diagnosed histologically or by cerebrospinal fluid cytology; absence of systemic lymphoma manifestations
• Relapse or lymphoma progression after/during high-dose methotrexate containing first-line chemotherapy or alternative therapy in the case of contraindications against high-dose methotrexate
• ECOG performance score ≤ 2
• Age ≥18 years and ≤ 75 years
• Life expectancy of at least 3 months
• Absence of active infection
• Negative HIV serology
• Adequate renal function (GFR >30ml/h)
• Adequate bone marrow reserve (neutrophils > 1500/µl, platelets > 80,000/µl)
• Bilirubin <1.5x upper limit of normal (ULN), ALT and AST <3x ULN
• At least 3 weeks interval from prior cytostatic treatment
• Negative pregnancy test
• Patient accessible for treatment and follow-up
• Patient compliance
• Signed informed consent

Exclusion Criteria:

• Secondary CNS lymphoma
• Primary intraocular lymphoma
• Patient eligible for high-dose chemotherapy and autologous stem-cell transplantation
• Concurrent treatment within another clinical trial
• Concurrent other malignant disease
• Symptomatic congestive heart failure (≥NYHA II)
• Active or uncontrolled chronic infection
• Severe concomitant disease incompatible with study conduct
• History of cerebral bleeding
• Concomitant treatment with strong CYP3A4/5-inductors or -inhibitors
• Premenopausal women without highly effective contraception (defined as Pearl index <1)
• Pregnant or lactating women
• Refusal to record and pass on pseudonymized disease and treatment related data as part of the treatment protocol
• Concurrent admission to a psychiatric institution by public order

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Temsirolimus; Weekly IV temsirolimus	Drug: temsirolimus; Weekly infusion of 25mg Temsirolimus (first 3 patients) or 75mg Temsirolimus (all other patients) up to a maximum of 12 months in the case of continuing response to treatment; Other Names: Torisel; CCI-770

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall response rate	Weeks 4, 12, every 12 weeks thereafter

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety	continuous
Time to progression of disease	Weeks 4, 12, every 12 weeks thereafter or upon clinical suspicion of disease progression
Penetration of temsirolimus into cerebrospinal fluid	Weeks 1, 4 and 12

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: Pfizer
• Investigators: Principal Investigator: Agnieszka Korfel, MD, Charite University, Berlin, Germany

Publications and helpful links

General Publications

• Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, Ansell SM, Luyun R, Flynn PJ, Morton RF, Dakhil SR, Gross H, Kaufmann SH. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005 Aug 10;23(23):5347-56. doi: 10.1200/JCO.2005.13.466. Epub 2005 Jun 27.
• Kuhn JG, Chang SM, Wen PY, Cloughesy TF, Greenberg H, Schiff D, Conrad C, Fink KL, Robins HI, Mehta M, DeAngelis L, Raizer J, Hess K, Lamborn KR, Dancey J, Prados MD; North American Brain Tumor Consortium and the National Cancer Institute. Pharmacokinetic and tumor distribution characteristics of temsirolimus in patients with recurrent malignant glioma. Clin Cancer Res. 2007 Dec 15;13(24):7401-6. doi: 10.1158/1078-0432.CCR-07-0781.
• Smith SM, van Besien K, Karrison T, Dancey J, McLaughlin P, Younes A, Smith S, Stiff P, Lester E, Modi S, Doyle LA, Vokes EE, Pro B. Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol. 2010 Nov 1;28(31):4740-6. doi: 10.1200/JCO.2010.29.2813. Epub 2010 Sep 13.
• Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A, Hanushevsky O, Clancy J, Hewes B, Moore L, Coiffier B. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009 Aug 10;27(23):3822-9. doi: 10.1200/JCO.2008.20.7977. Epub 2009 Jul 6.
• Ansell SM, Inwards DJ, Rowland KM Jr, Flynn PJ, Morton RF, Moore DF Jr, Kaufmann SH, Ghobrial I, Kurtin PJ, Maurer M, Allmer C, Witzig TE. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer. 2008 Aug 1;113(3):508-14. doi: 10.1002/cncr.23580.
• Costa LJ. Aspects of mTOR biology and the use of mTOR inhibitors in non-Hodgkin's lymphoma. Cancer Treat Rev. 2007 Feb;33(1):78-84. doi: 10.1016/j.ctrv.2006.10.004. Epub 2006 Dec 11.
• Korfel A, Schlegel U, Herrlinger U, Dreyling M, Schmidt C, von Baumgarten L, Pezzutto A, Grobosch T, Kebir S, Thiel E, Martus P, Kiewe P. Phase II Trial of Temsirolimus for Relapsed/Refractory Primary CNS Lymphoma. J Clin Oncol. 2016 May 20;34(15):1757-63. doi: 10.1200/JCO.2015.64.9897. Epub 2016 Mar 14.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Anticipated): December 1, 2013
• Study Completion (Anticipated): June 1, 2014

Study Registration Dates

• First Submitted: July 20, 2009
• First Submitted That Met QC Criteria: July 20, 2009
• First Posted (Estimate): July 21, 2009

Study Record Updates

• Last Update Posted (Estimate): April 17, 2013
• Last Update Submitted That Met QC Criteria: April 15, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: temsirolimus, primary CNS lymphoma, PCNSL, salvage treatment
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Lymphoma; Recurrence; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: TemPCNSL; EudraCT 2009-011277-33