Clinical trial NCT02227576: Prevention of Thrombocytopenia in Glioblastoma Patients
Official title: Secondary Prophylaxis Use of Romiplostim for the Prevention of Thrombocytopenia Induced by Temozolomide in Newly Diagnosed Glioblastoma Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Thrombocytopenia
Glioblastoma
Keywords: glioblastoma, thrombocytopenia, temozolomide, chemotherapy
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
First posted: 2014-08-28
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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,
* Adequate haematological, renal, hepatic function at the time of inclusion visit,
* 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,
* Negative pregnancy test at the time of inclusion visit,
* 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).

Exclusion Criteria:

* 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),
* Patients in emergency situations,
* Patients kept in detention.

Primary outcomes:
measure: 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.
timeFrame: one year
Secondary outcomes:
measure: Incidence of serious adverse events according to CTCAE 4.0 criteria.
timeFrame: one year
measure: Incidence of delayed chemotherapy cycles and the incidence of chemotherapy cycles with dose reduction due to severe TP
timeFrame: one year
measure: Number and percentage of patients with TP of grade 3 or grade 4 after receiving Romiplostim.
timeFrame: One year
measure: Number and percentage of patients receiving platelets transfusion for TP
timeFrame: one year
measure: Incidence and type of adverse events linked to TP episodes during Romiplostim and Temozolomide combined treatment.
timeFrame: one year
measure: 6 months Progression Free Survival:
timeFrame: one year
Other outcomes:
Locations:
city: Lille
country: France
facility: CHRU de Lille, Hôpital Roger Salengro,Clinique de Neurochirurgie
city: Lyon
country: France
facility: Hôpital Neurologique Pierre Wertheimer, Lyon,
city: Marseille
country: France
facility: AP-HM,Hôpital La Timone, AP-HM, Marseille
city: Paris
country: France
facility: AH-HP, Hôpital Pitié-Salpêtrière, Service de Neurologie 2
Study officials:
affiliation: CHRU LILLE
name: Emilie Le Rhun, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.