Prevention of Thrombocytopenia in Glioblastoma Patients

NCT02227576 | Terminated Phase 2 DMC

• 2 other identifiers: 2011_292012-001751-38
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 4

Brief Summary

Chemotherapy used in the treatment of primitive tumors of the central nervous system has a particularly important platelet toxicity compared to chemotherapy used for treatment of other tumors. Chemotherapy postponed for toxicity is often due to thrombocytopenia (TP). The TP and/or the other anomalies of coagulation, which can be spontaneous (Rogers, 2004) or induced (Gerber, 2006) can have dramatic consequences:

• specifically neurological (intratumoral bleeding with particularly important neovascularization) with a functional aggravation and sometimes involvement of vital prognosis,
• digestive (Garcia-Rodiguez, 2001) in patients receiving long term treatment with corticoids (potential gastric toxicity). The encouraging results from the EORTC/NCIC trial by Stupp (median survival among patients with newly diagnosed glioblastoma is 14.6 months with an estimated 5-year survival of 9, 8%), has changed the standard of care of these patients (Stupp et al., 2009). Patients with newly diagnosed, histologically confirmed glioblastoma receive radiotherapy (2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) plus continuous daily Temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant Temozolomide (TMZ) (150 to 200 mg per square meter for 5 days during each 28-day cycle). The Stupp regimen is currently the treatment of reference for glioblastoma and is used as a basis in various clinical studies with new agents. This study aims to evaluate Romiplostim for the treatment of TP secondary to initial TMZ chemotherapy of glioblastomas.

Conditions

Thrombocytopenia; Glioblastoma

Keywords

glioblastoma, thrombocytopenia, temozolomide, chemotherapy

Outcome Measures

Primary Outcomes (1)

• Proportion of patients receiving 100% of the planned TMZ dosage in the whole Stupp protocol. The primary endpoint will consider dose reduction and dose delay.

  one year

Secondary Outcomes (6)

• Incidence of serious adverse events according to CTCAE 4.0 criteria.

  one year

• Incidence of delayed chemotherapy cycles and the incidence of chemotherapy cycles with dose reduction due to severe TP

  one year

• Number and percentage of patients with TP of grade 3 or grade 4 after receiving Romiplostim.

  One year

• Number and percentage of patients receiving platelets transfusion for TP

  one year

• Incidence and type of adverse events linked to TP episodes during Romiplostim and Temozolomide combined treatment.

  one year

Study Arms (1)

Romiplostim

EXPERIMENTAL

Romiplostim lyophilized formulation is a white, solide cake that is reconstituted with sterile water for injection.

Drug: Romiplostim

Interventions

Romiplostim DRUG

Romiplostim

Eligibility Criteria

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

You may qualify if:

• Histological proof of newly diagnosed glioblastoma,
• Age: 18 and older,
• Information to patient and signed consent form,
• Indication for a " Stupp " protocol (cerebral focal radiotherapy and concomitant TMZ followed by adjuvant TMZ - 6 cycles),
• Patient with grade 3 or 4 TP during Temozolomide chemotherapy, regardless of when the onset of TP was: after completion of concomitant RT/CT, before adjuvant CT or during adjuvant CT and only if a minimum of 2 cycles are still planned,
• Normal initial platelets count (\> 100 000/mm3) before the start of Temozolomide during the RT/CT concomitant phase,
• ECOG PS 0-2 (patients unable to walk because of a paralysis and who are up in a wheel chair will be considered as ambulatory for the evaluation of the ECOG performance status),
• Life expectancy \> 2 months,
• Patients covered by the French Health Insurance System,
• If required, effective contraception respecting criteria of CPMP/ICH/286/95 (such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner).

You may not qualify if:

• Concomitant radiotherapy (Romiplostim will be started after the completion of the RT/CT concomitant phase),
• Other malignancies (prior hx malignancies),
• Any anterior systemic chemotherapy,
• Any known coagulation disease or known haematological disease even if resolved. Known hypercoagulate state (e.g., factor V Leiden, protein C defiency, protein S deficiency, PT 20201, antiphospholipid antibody syndrome…),
• Prior Romiplostim exposure or prior exposure to other TPO mimetics,
• History of thromboembolic disease \< 6 months. Treatment with anticoagulant such as Heparin or antivitamin K (LMWH as prophylactic treatment is authorized),
• Any other hemato-toxicity (anemia, neutropenia) requiring EPO or GCSF,
• Other causes of Temozolomide interruption (non haematological toxicities),
• Known hypersensitivity to any E-coli derived product,
• Participation to any other study during the last 30 days,
• Refusal to give written informed consent,
• Pregnancy or nursing,
• For all men and women of childbearing potential: Refusal or inability to use effective means of contraception,
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial,
• Persons protected by a legal regime (guardianship, trusteeship),

Sponsors & Collaborators

• University Hospital, Lille: lead

Study Sites (4)

CHRU de Lille, Hôpital Roger Salengro,Clinique de Neurochirurgie

Lille, 59037 Cedex, France

Location

Hôpital Neurologique Pierre Wertheimer, Lyon,

Lyon, France

Location

AP-HM,Hôpital La Timone, AP-HM, Marseille

Marseille, France

Location

AH-HP, Hôpital Pitié-Salpêtrière, Service de Neurologie 2

Paris, 75013, France

Location

Related Publications (9)

• Armstrong TS, Cao Y, Scheurer ME, Vera-Bolanos E, Manning R, Okcu MF, Bondy M, Zhou R, Gilbert MR. Risk analysis of severe myelotoxicity with temozolomide: the effects of clinical and genetic factors. Neuro Oncol. 2009 Dec;11(6):825-32. doi: 10.1215/15228517-2008-120.

  PMID: 19179423 BACKGROUND

• Gerber DE, Grossman SA, Zeltzman M, Parisi MA, Kleinberg L. The impact of thrombocytopenia from temozolomide and radiation in newly diagnosed adults with high-grade gliomas. Neuro Oncol. 2007 Jan;9(1):47-52. doi: 10.1215/15228517-2006-024. Epub 2006 Nov 15.

  PMID: 17108062 BACKGROUND

• George JN, Raskob GE, Shah SR, Rizvi MA, Hamilton SA, Osborne S, Vondracek T. Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med. 1998 Dec 1;129(11):886-90. doi: 10.7326/0003-4819-129-11_part_1-199812010-00009.

  PMID: 9867731 BACKGROUND

• Kuter DJ, Rummel M, Boccia R, Macik BG, Pabinger I, Selleslag D, Rodeghiero F, Chong BH, Wang X, Berger DP. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010 Nov 11;363(20):1889-99. doi: 10.1056/NEJMoa1002625.

  PMID: 21067381 BACKGROUND

• Molineux G. The development of romiplostim for patients with immune thrombocytopenia. Ann N Y Acad Sci. 2011 Mar;1222:55-63. doi: 10.1111/j.1749-6632.2011.05975.x.

  PMID: 21434943 BACKGROUND

• Sure D, Dunn I, Norden A, Anderson WS. Intracerebral hemorrhage secondary to thrombocytopenia in a patient treated with temozolomide. Clin Neurol Neurosurg. 2010 Oct;112(8):741-2. doi: 10.1016/j.clineuro.2010.04.005.

  PMID: 20434832 BACKGROUND

• Mutter N, Stupp R. Temozolomide: a milestone in neuro-oncology and beyond? Expert Rev Anticancer Ther. 2006 Aug;6(8):1187-204. doi: 10.1586/14737140.6.8.1187.

  PMID: 16925485 BACKGROUND

• Oh J, Kutas GJ, Davey P, Morrison M, Perry JR. Aplastic anemia with concurrent temozolomide treatment in a patient with glioblastoma multiforme. Curr Oncol. 2010 Aug;17(4):124-6. doi: 10.3747/co.v17i4.526.

  PMID: 20697524 BACKGROUND

• Le Rhun E, Devos P, Houillier C, Cartalat S, Chinot O, Di Stefano AL, Lepage C, Reyns N, Dubois F, Weller M. Romiplostim for temozolomide-induced thrombocytopenia in glioblastoma: The PLATUM trial. Neurology. 2019 Nov 5;93(19):e1799-e1806. doi: 10.1212/WNL.0000000000008440. Epub 2019 Oct 4.

  PMID: 31586022 DERIVED

MeSH Terms

Conditions

Thrombocytopenia; Glioblastoma

Interventions

romiplostim

Condition Hierarchy (Ancestors)

Blood Platelet Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cytopenia; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Officials

• Emilie Le Rhun, MD

  CHRU LILLE

  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

Study Record Dates

• First Submitted: August 26, 2014
• First Posted: August 28, 2014
• Study Start: July 10, 2014
• Primary Completion: December 14, 2017
• Study Completion: December 14, 2017
• Last Updated: April 25, 2018

Record last verified: 2018-04

Data Sharing

• IPD Sharing: Will not share

Locations

FR (4)