Cilengitide and Metronomic Temozolomide for Relapsed or Refractory High Grade Gliomas or Diffuse Intrinsic Pontine Gliomas in Children and Adolescents - Full Text View

Purpose

The primary objective of this study is to evaluate the efficacy of a combined treatment with cilengitide and metronomic oral temozolomide as measured by 6 months overall survival (OS) after diagnosis of relapse or tumour progression in children and adolescents with relapsed or refractory high-grade malignant glioma and diffuse intrinsic pontine glioma.

Secondary objectives include:

To evaluate the safety and toxicity of the study treatment by common toxicity criteria (CTC; version 4.0).
To assess
- the response rates at 6 months (continuous complete response = CCR, complete response = CR, partial response = PR, stable disease = SD, progressive disease = PD) and
- progression-free survival (PFS) at 6 months, and
- response rates, OS, and PFS at 12 months after relapse diagnosis or diagnosis of tumor progression. Response will be presented including histopathological variants.
To assess the pharmacokinetics of cilengitide administered as part of the study treatment.

Indication and study population for this trial:

Treatment of relapsed or refractory high grade gliomas and diffuse intrinsic pontine gliomas in paediatric patients ≥ 3 years and < 18 years of age.

Patients included in the study receive

Cilengitide 1800 mg/m² i.v. twice weekly
Temozolomide 75 mg/m²/d p.o. for 6 weeks, followed by 1 week rest with a mandatory platelet-count dependent dose adaptation rule: mandatory blood counts twice weekely: Platelets ≥ 100 000/µl (≥ 100 Gpt/l): 75 mg/m², platelets ≥ 50 000 - < 100 000/µl (≥ 50 - <100 Gpt/l): 50 mg/m², platelets < 50 000/µl (<50 Gpt/l): stop temozolomide until platelet recovery ≥ 100 000/µl (≥100 Gpt/l)
Study treatment in the individual patient is scheduled for 1 year unless tumor progression or excessive toxicity occurs. However, study treatment may be extended beyond 1 year upon individual decision.

Condition	Intervention	Phase
Gliomas	Drug: Cilengitide Drug: Temozolomide	Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Cilengitide and Metronomic Temozolomide for Relapsed or Refractory High Grade Gliomas or Diffuse Intrinsic Pontine Gliomas in Children and Adolescents - A Phase II Study HIT-HGG-CilMetro - A Clinical Phase II Trial of the HIT-HGG Study Group -

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Temozolomide

U.S. FDA Resources

Further study details as provided by Martin-Luther-Universität Halle-Wittenberg:

Primary Outcome Measures:

Efficacy of a combined treatment with cilengitide and temozolomide as measured by 6 months overall survival after diagnosis of relapsed or refractory high grade glioma or diffuse intrinsic pontine glioma in children and adolescents [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Evaluation of overall survival after 6 months

Secondary Outcome Measures:

Safety and toxicity of the study treatment [ Time Frame: Up to 52 weeks of treatment and subsequently 30 days after end of treatment ] [ Designated as safety issue: Yes ]
Evaluation of safety and toxicity of the study treatment by NCI Common Toxicity Criteria (CTC; version 4.0) for up to 30 days after the end of study treatment which may last up to 52 weeks.

Toxic events defined as CTC grade 4 toxicities and deaths caused by therapy (CTC grade 5) excluding haematological toxicities (CTC grade 1-4)will be immediately assessed after documentation, and probability for such a toxic event statistically evaluated to ensure that this probability is within the predefined range (p1=15%).
Response rates (RR) at 6 months, progression-free survival (PFS) at 6 months, and RR, overall survival (OS), and PFS at 12 months after relapse diagnosis or diagnosis of tumor progression [ Time Frame: Response rates and progression-free survival at 6 and 12 months, overall survival at 12 months (Trial subjects will be followed up for at least 1 year and 30 days after study entry) ] [ Designated as safety issue: No ]
Evaluation of RR (continuous complete response = CCR, complete response = CR, partial response = PR, stable disease = SD, progressive disease = PD) by MRI and PFS (defined as survival from date of first progression/relapse to first documented date of second progression/relapse) after 6 and 12 months.

Evaluation of OS after 12 months
Peak plasma levels of cilengitide [ng/ml] on day 1 of week 1 and day 4 of week 6 [ Time Frame: Day 1 of treatment week 1: Immediately before and immediately after as well as 2, 4, and 7 hours after end of cilengitide administration; day 4 of treatment week 6: 2 hours after end of cilengitide adminstration ] [ Designated as safety issue: No ]
Assessment of cilengitide serum levels [ng/ml] by a validated liquid chromatograpy tandem mass spectrometry assay on day 1 of week (before, immediately after, and 2, 4, 7 hours after cilengitide administration) and day 4 of week 6 (2 hours after cilengitide administration)

Estimated Enrollment:	33
Study Start Date:	January 2012
Estimated Study Completion Date:	January 2015
Estimated Primary Completion Date:	June 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Cilengitide and metronomic temozolomide Cilengitide 1800 mg/m² i.v. twice weekly and Temozolomide 75 mg/m²/d p.o. for 6 weeks, followed by 1 week rest with a mandatory platelet-count dependent dose adaptation rule	Drug: Cilengitide Cilengitide 1800 mg/m² i.v. twice weekly with a mandatory platelet-count dependent dose adaptation rule Other Name: EMD 121974 Drug: Temozolomide Temozolomide 75 mg/m²/d p.o. for 6 weeks, followed by 1 week rest with a mandatory platelet-count dependent dose adaptation rule Other Name: Temodal

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Eligibility

Ages Eligible for Study:	3 Years to 17 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Diagnosis of high-grade malignant glioma confirmed by central neuropathological review (last MRI diagnosis not older than 4 weeks) - including glioblastoma multiforme (WHO IV), anaplastic astrocytoma (WHO III), anaplastic oligodendroglioma (WHO III), anaplastic oligoastrocytoma (WHO III), anaplastic pilocytic astrocytoma (WHO III), anaplastic ganglioglioma (WHO III), anaplastic pleomorphic xanthoastrocytoma (analogous to WHO III), giant cell glioblastoma (WHO IV), and gliosarcoma (WHO IV) - or diagnosis of diffuse intrinsic pontine glioma confirmed by central neuroradiological review - refractory to standard treatment, or relapsed or progressive after first-line therapy.
Patient aged 3 years and older but under 18 years at time of relapse diagnosis
Written informed consent of the patient (mandatory from 15 years of age) or the parents (mandatory till 18 years of age).

Exclusion Criteria:

Known hypersensitivity or contraindication to any study drugs
Other (simultaneous) malignancies
Pregnancy and / or lactation
Patients who are sexually active refusing to use effective contraception (oral contraception, intrauterine devices, barrier method of contraception in conjunction with spermicidal jelly or surgical sterile)
Current or recent (within 30 days prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial
Severe concomitant diseases (e.g. immune deficiency syndrome) or HIV infection
Severe psychological disease or neurological damage without possibility to communicate
Clinical signs of intracranial pressure
Intracerebral hemorrhage or history of intracerebral hemorrhage
Requirements for laboratory test results not older than 2 weeks before patient´s inclusion:

Platelets < 100 000/µl (< 100 Gpt/l) PT, INR and PTT above normal range Absulute neutrophil count ≤ 1 500/µl (< 1,5 Gpt/l) Hemoglobin < 10g/dl (< 6,4 mmol/L) Serum creatinine ≥ 1,5 x upper limit of normal range or creatinine clearance rate ≤ 60 ml/min/m2 (corrected for body surface area) Total bilirubin ≥ 1,5 x upper limit of normal range SGOT (ASAT) and SGPT (ALAT) ≥ 2,5 x upper limit of normal range Alkaline phosphatase ≥ 2,5 x upper limit of normal range
Hereditary Intrinsic Platelet Disorders
Ongoing irradiation or chemotherapy (within the last 4 weeks)
Estimated life expectancy of less than 2 months

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01517776

Contacts

Contact: Christof M Kramm, MD

+49 345 557 ext 2503

hit-hgg-studie@uk-halle.de

Locations

Germany
University Children´s Hospital	Recruiting
Halle, Saxonia-Anhalt, Germany, 06120
Contact: Christof M Kramm, MD +49 345 557 ext 2388 christof.kramm@uk-halle.de
Principal Investigator: Christof M Kramm, MD

Sponsors and Collaborators

Martin-Luther-Universität Halle-Wittenberg

Merck KGaA

Investigators

Study Chair:

Christof M. Kramm, MD

University Children´s Hospital, Halle, Germany

More Information

No publications provided

Responsible Party:	Christof Kramm, Principal investigator ("Leiter Klinische Prüfung"), Martin-Luther-Universität Halle-Wittenberg
ClinicalTrials.gov Identifier:	NCT01517776 History of Changes
Other Study ID Numbers:	HIT-HGG-CilMetro, 2009-011898-33
Study First Received:	January 11, 2012
Last Updated:	January 20, 2012
Health Authority:	United States: Food and Drug Administration Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Martin-Luther-Universität Halle-Wittenberg:

High grade glioma
Glioblastoma multiforme
Anaplastic astrocytoma
Diffuse intrinsic pontine glioma

Relapse
refractory tumour disease
Relapsed or refractory high grade gliomas and diffuse intrinsic pontine gliomas

Additional relevant MeSH terms:

Glioma
Pontine Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue

Astrocytoma
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 16, 2013

Cilengitide and Metronomic Temozolomide for Relapsed or Refractory High Grade Gliomas or Diffuse Intrinsic Pontine Gliomas in Children and Adolescents (HGG-CilMetro)