Carbon Ion Radiotherapy for Primary Glioblastoma (CLEOPATRA)

Randomized Phase II Study Evaluating a Carbon Ion Boost Applied After Combined Radiochemotherapy With Temozolomide Versus a Proton Boost After Radiochemotherapy With Temozolomide in Patients With Primary Glioblastoma

Treatment standard for patients with primary glioblastoma (GBM) is combined radiochemotherapy with temozolomide (TMZ). Radiation is delivered up to a total dose of 60 Gy using photons. Using this treatment regimen, overall survival could be extended significantly however, median overall survival is still only about 15 months.

Carbon ions offer physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increase relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons.

First Japanese Data on the evaluation of carbon ion radiation therapy showed promising results in a small and heterogeneous patient collective.

In the current Phase II-CLEOPATRA-Study a carbon ion boost will be compared to a proton boost applied to the macroscopic tumor after surgery at primary diagnosis in patients with GBM applied after standard radiochemotherapy with TMZ up to 50 Gy. In the experimental arm, a carbon ion boost will be applied to the macroscopic tumor up to a total dose of 18 Gy E in 6 fractions at a single dose of 3 Gy E. In the standard arm, a proton boost will be applied up to a total dose 10 Gy E in 5 single fractions of 2 Gy E.

Primary endpoint is overall survival, secondary objectives are progression-free survival, toxicity and safety.

Study Overview

• Status: Completed
• Conditions: Primary Glioblastoma
• Intervention / Treatment: Radiation: Carbon Ion Radiotherapy; Radiation: Proton Radiotherapy

Detailed Description

Study design

The purpose of the trial is to compare a carbon ion boost to a proton boost delivered to the macroscopic tumor in combination with combined radiochemotherapy with TMZ in patients with primary GBM.

The aim of the study is to compare overall survival as a primary endpoint, and progression free survival, toxicity and safety as secondary endpoints.

Focus of the analysis is to evaluate the change in overall survival and local control by carbon ion radiotherapy. Therefore, the aim of the trial is to evaluate the improvement in outcome due to effect of the altered biology of carbon ions on GBM. Chemotherapy with TMZ is considered standard treatment and is administered continuously as it would be applied in standard patient care outside any trial.

Trial Design The trial will be performed as a single-center two-armed randomized Phase II study.

Patients fulfilling the inclusion criteria will be randomized into two arms:

Arm A - Experimental Arm Carbon Ion Radiation Therapy as a Boost to the macroscopic tumor Total Dose 18 Gy E, 6 fractions, 3 Gy E single dose

Arm B - Standard Arm Proton Radiation Therapy as a Boost to the macroscopic tumor Total Dose 10 Gy E, 5 fractions, 2 Gy E single dose

Standard chemotherapy with TMZ will be continued during the experimental and standard arm in conventional dosing of 75 mg/m2 per day.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Heidelberg, Germany, 69120
    • University Hospital of Heidelberg, Department of Radiation Oncology

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• histologically confirmed unifocal, supratentorial primary glioblastoma
• macroscopic tumor after biopsy or subtotal resection
• indication for combined radiochemotherapy with temozolomide
• prior photon irradiation of 48-52 Gy to the T2-hyperintense area, resection cavity, areas of contrast enhancement adding 2-3cm safety margin in combination with standard temozolomide
• registration prior to photon RT or within photon RT allowing the beginning of particle therapy ≤ 4 days after completion of photon irradiation
• beginning of study treatment (proton or carbon ion RT) no later than 12 weeks after primary diagnosis
• age ≥ 18 years
• Karnofsky Performance Score ≥ 60
• adequate contraception.
• Ability of subject to understand character and individual consequences of the clinical trial
• Written informed consent (must be available before enrolment in the trial)

Exclusion Criteria:

• refusal of the patients to take part in the study
• previous radiotherapy of the brain or chemotherapy with DTIC or TMZ other than during the radiochemotherapy stated in the inclusion criteria
• more than 52 Gy applied via photon-RT prior to particle therapy
• time interval of > 12 weeks after primary diagnosis (neurosurgical intervention) and beginning of study treatment (proton or carbon ion RT)
• Patients who have not yet recovered from acute toxicities of prior therapies
• Clinically active kidney, liver or cardiac disease
• Known carcinoma < 5 years ago (excluding Carcinoma in situ of the cervix, basal cell carcinoma, squamous cell carcinoma of the skin) requiring immediate treatment interfering with study therapy
• Pregnant or lactating women
• Participation in another clinical study or observation period of competing trials, respectively.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm; Carbon Ion Radiotherapy to the Macroscopic Tumor 6 x 3 Gy E up to 18 Gy E	Radiation: Carbon Ion Radiotherapy; Carbon ion Radiotherapy up to 18 Gy E in 3 Gy E fractions to the macroscopic tumor
Active Comparator: Standard Arm; Proton Radiotherapy to the Macroscopic Tumor 5 x 2 Gy E up to 10 Gy E (Standard dose) applied after 48-52 Gy photon radiotherapy	Radiation: Proton Radiotherapy; Proton Radiotherapy up to 10 Gy E in 2 Gy E fractions to the macroscopic tumor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival		within 12 months
Toxicity	CTCAC 5.0	within 12 months

Collaborators and Investigators

• Sponsor: University Hospital Heidelberg

Publications and helpful links

General Publications

• Combs SE, Kieser M, Rieken S, Habermehl D, Jakel O, Haberer T, Nikoghosyan A, Haselmann R, Unterberg A, Wick W, Debus J. Randomized phase II study evaluating a carbon ion boost applied after combined radiochemotherapy with temozolomide versus a proton boost after radiochemotherapy with temozolomide in patients with primary glioblastoma: the CLEOPATRA trial. BMC Cancer. 2010 Sep 6;10:478. doi: 10.1186/1471-2407-10-478.

Helpful Links

• Homepage Department of Radiation Oncology

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2010
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: July 13, 2010
• First Submitted That Met QC Criteria: July 19, 2010
• First Posted (Estimate): July 20, 2010

Study Record Updates

• Last Update Posted (Actual): April 3, 2020
• Last Update Submitted That Met QC Criteria: April 2, 2020
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Primary Glioblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: CLEOPATRA; 2009-014668-21 (EudraCT Number); ISRCTN37428883 (Registry Identifier: BMC Study Registry)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No