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

This study has been terminated.
(due to an altered benefit/risk assessment.)
Sponsor:
Collaborator:
Merck KGaA
Information provided by (Responsible Party):
Christof Kramm, Martin-Luther-Universität Halle-Wittenberg
ClinicalTrials.gov Identifier:
NCT01517776
First received: January 11, 2012
Last updated: April 24, 2014
Last verified: April 2014
  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:

  1. To evaluate the safety and toxicity of the study treatment by common toxicity criteria (CTC; version 4.0).
  2. 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.
  3. 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:


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)


Enrollment: 28
Study Start Date: January 2012
Study Completion Date: April 2014
Primary Completion Date: March 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

  Hide Detailed Description

Detailed Description:

Indication:

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

Background and rationale:

Relapsed or refractory high-grade gliomas or diffuse intrinsic pontine gliomas (in the following both addressed as high grade gliomas = HGG) in children and adolescents represent a very bad prognosis group for which a recommended standard salvage therapy is currently not available.

The combination of cilengitide and metronomic temozolomide will be investigated in the present trial as new treatment strategy for these patients.

Metronomic temozolomide was shown to act via inhibition of tumour angiogenesis and as a cytotoxic agent. Cilengitide might act via tumour angiogenesis and also inhibits tumour cell migration.

For both drugs, safe doses with only low toxicity had been defined in phase I trials for paediatric patients with recurrent or refractory brain tumours (Cilengitide: 1800 mg/m² twice weekly; metronomic Temozolomide: 75-80 mg/m²/d in a 6 week schedule followed by one week rest) In a phase II trial for adult patients with relapsed glioblastoma cilengitide as single agent showed a trend towards higher efficacy with 2000 mg twice weekly as compared to 500 mg twice weekly. Furthermore, in a phase II trial of newly diagnosed adult glioblastoma patients, signs of clinical activity of cilengitide in combination with radiotherapy and conventional temozolomide was seen in the methylated MGMT gene promoter subgroup. Based on these findings, a large randomized phase III trial investigating cilengitide in combination with standard therapy (temozolomide and radiation) in this subgroup was started recently.

Metronomic temozolomide was also shown to be still effective in glioma patients suffering from relapse after temozolomide standard therapy. Interestingly, the mode of action appears to be widely independent of the MGMT status, probably due to MGMT depletion by continuous treatment.

In conclusion, for both drugs signs of clinical activity have been shown in relapsed glioblastoma patients, even after failure of temozolomide standard therapy.

Study design:

Prospective, non-randomized phase II trial.

Study population:

Patients 3 years and < 18 years of age with high grade glioma or diffuse intrinsic pontine glioma relapsed after or refractory to standard therapy recruited by approved trial sites

Sample size:

It is planned to include 33 patients.

Therapy:

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.

Biometry:

Statistical analysis and sample size calculation:

The feasibility and efficacy of the HIT-HGG-CilMetro therapy will be assessed by a single stage analysis. Sample size calculation is based on the 6 month overall survival rate. This survival rate was found to be 44% in a historical study population from the HIT-GBM data base. An overall survival rate of 59% in the present study is considered to be of clinical relevance. Based on a one sided one sample χ2-test and a significance level α=5% a sample size of 33 patients is planned. This sample size implies a power of 50%.

Schedule:

The study is scheduled to start on January 1, 2012. The recruitment period for the trial will last 24 months until December 31, 2013. Individual follow-up for at least 1 year after study entry is required for this protocol. The study will be finished 30 days after completion of study treatment of the last patient enrolled, i.e. the expected end of the trial will be January 31, 2015.

Long-term follow-up is strongly recommended and will be organised via the HIT-HGG Study Office.

If the start of the study is delayed, given dates will change accordingly.

Financial support:

Merck KGaA, Darmstadt, Germany, provides a grant for the conduct of the trial, supplies Cilengitide free of charge and agrees to perform the laboratory assessments for pharmacokinetics.

  Eligibility

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

Inclusion Criteria:

  1. 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.
  2. Patient aged 3 years and older but under 18 years at time of relapse diagnosis
  3. Written informed consent of the patient (mandatory from 15 years of age) or the parents (mandatory till 18 years of age).

Exclusion Criteria:

  1. Known hypersensitivity or contraindication to any study drugs
  2. Other (simultaneous) malignancies
  3. Pregnancy and / or lactation
  4. 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)
  5. Current or recent (within 30 days prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial
  6. Severe concomitant diseases (e.g. immune deficiency syndrome) or HIV infection
  7. Severe psychological disease or neurological damage without possibility to communicate
  8. Clinical signs of intracranial pressure
  9. Intracerebral hemorrhage or history of intracerebral hemorrhage
  10. 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

  11. Hereditary Intrinsic Platelet Disorders
  12. Ongoing irradiation or chemotherapy (within the last 4 weeks)
  13. Estimated life expectancy of less than 2 months
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Locations
Germany
University Children´s Hospital
Halle, Saxonia-Anhalt, Germany, 06120
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 (, 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: April 24, 2014
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
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Dacarbazine
Temozolomide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014