Cilengitide and Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases From Lung Cancer (CIRAB)

Cilengitide (EMD121974) in Combination With Whole Brain Radiotherapy in Patients With Brain Metastases From Lung Cancer - a Single-center, Open-label Phase I Study

RATIONALE: Cilengitide may stop the growth of brain metastases by blocking blood flow to the tumor. Radiation therapy uses high energy X-rays to kill tumor cells. Giving cilengitide together with radiation therapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of cilengitide when given together with whole-brain radiation therapy in treating patients with brain metastases from lung cancer.

Study Overview

• Status: Completed
• Conditions: Lung Cancer; Brain and Central Nervous System Tumors
• Intervention / Treatment: Other: pharmacological study; Radiation: radiation therapy; Drug: cilengitide

Detailed Description

OBJECTIVES:

• Primary

  • To assess the safety and tolerability of daily cilengitide by determining its dose-limiting toxicity and maximum-tolerated dose when combined with concomitant fractionated whole-brain radiation therapy in patients with brain metastases from lung cancer.

• Secondary

  • To collect evidence of the best overall response rate, overall survival, brain-specific progression-free survival, and tumor-specific progression-free survival of these patients.
  • To collect evidence of changes in functional MRI imaging studies at 6 and 12 weeks after initiation of therapy.
  • To collect evidence of early response by functional MRI (ASL technique) on days 1, 4, and 12, immediately before and after the administration of cilengitide.
  • To collect evidence of changes in neurological and neurocognitive function tests at 6 and 12 weeks after initiation of therapy.
  • To further evaluate the safety and toxicity of the combination of cilengitide and whole-brain radiation therapy.
  • To further evaluate the pharmacokinetics of cilengitide administered daily.

OUTLINE:

Patients receive oral cilengitide once daily and undergo whole-brain radiotherapy on the same days. Treatment continues for 2 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection on days 1, 4, 5, and 12 for pharmacokinetic studies.

After completion of study treatment, patients are followed for 10 weeks.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Mannheim, Germany, D-68167
    • University Medical Center, Department of Surgery

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

DISEASE CHARACTERISTICS:

• Histologically confirmed lung cancer (small cell or non-small cell lung cancer)
• Patient must be eligible for whole-brain radiotherapy
• Presence of brain metastasis (single or multiple, synchronous or metachronous) from lung cancer not amenable to surgery or radiosurgery (presence of metastases at any other site is allowed)
• No leptomeningeal metastasis or known subarachnoid spread of tumor

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-1 (ECOG PS 2 allowed if due to the presence of cerebral metastases and not due to a high peripheral-tumor load or other reasons)
• Life expectancy ≥ 3 months
• Adequate hematologic function
• Total bilirubin < 1.5 times upper limit of normal (ULN)
• AST, ALT, and alkaline phosphatase < 2.5 times ULN
• Creatinine clearance > 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after completion of study treatment
• No history of acute or chronic renal disease
• No other malignancies treated within the past 5 years, except adequately treated carcinoma in situ of the cervix or basal cell carcinoma of the skin
• No uncontrolled hypertension
• No history of coagulation disorder associated with bleeding or recurrent thrombotic events
• No peptic ulcer disease within the past 6 months
• No congestive heart failure, high risk for uncontrolled arrhythmia, or history of clinically significant coronary heart disease
• No known alcohol or drug abuse
• No other significant or acute concomitant disease
• No dementia or altered mental status

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Concurrent corticosteroids allowed if the dosing regimen has ben stable ≥ 5 days
• Concurrent anticonvulsants allowed if the dosing regimen has been stable for the past week
• More than 30 days since prior participation in another clinical trial
• No concurrent anticoagulation with vitamin K antagonists, therapeutic-dose anticoagulation with heparin resulting in prolonged PTT, or therapeutic-dose anticoagulation with low molecular weight heparin (low-dose [i.e. prophylactic], low molecular weight heparins allowed)
• No prior whole-brain radiation or radiosurgery
• No prior antiangiogenic therapy
• No other concurrent anticancer therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cilengitide	Other: pharmacological study; Radiation: radiation therapy; Drug: cilengitide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicity	(i) Any grade III-IV non-hematological toxicity as defined by CTCAE, version 3.0, with the exclusion ofalopecia, nausea, vomiting, and fever that can be rapidly contolled with appropriate measures; (ii) absolute neutrophil count (ANC)<0.5x10'/L lasting for >7days; (iii) febrile neutropenia defined as ANC <1.0x10'/L and fever >38.5°C; (iv) platelets <25x10'/L or thrombocytopenic bleeding requiring transfusion; and (v) severe hypotension requiring dopamine administration.	12 days
Maximum-tolerated dose	5 planned steps to be tested: 100, 250, 500, 750, to 1000mg; the highest dose at which one or no DLT will have been observed among 6 patients	12 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	Any response to treatment	12 weeks
Overall survival	Death as event, Kaplan-Meier (KM)	1 year
Brain-specific progression-free survival (PFS)	Every recurrence within the brain or death is an event, Kaplan-Meier (KM)	1 year
Tumor-specific PFS	Every tumor related event or death will be counted, Kaplan-Meier (KM)	1 year
Changes in functional MRI imaging (time to peak) at 6 and 12 weeks	time-to-peak measurements	12 weeks
Changes in functional MRI imaging (blood flow) at 6 and 12 weeks	blood flow measurements	12 weeks
Changes in functional MRI imaging (blood volume changes) at 6 and 12 weeks	blood volume changes during functional MRI	12 weeks
Evidence of early response by functional MRI on days 1, 4, and 12	(ASL technique) on day 1,4 and 12, immediately before and after the administration of cilengitide.	12 days
Changes of neurocognitive function tests (intelligence) at 6 and 12 weeks	Intelligence was measured with a multiple-choice test of vocabulary knowledge.	12 weeks
Changes of neurocognitive function tests (memory figures) at 6 and 12 weeks	Memory was tested by aims of "Medical College of Georgia Complex Figures"	12 weeks
Changes of neurocognitive function tests (memory verbal) at 6 and 12 weeks	Memory was tested by aims of "Rea Auditory Verbal Learning Test - German Version"	12 weeks
Changes of neurocognitive function tests (perception) at 6 and 12 weeks	Perception was assessed by the "Digit Symbol Substitution Test"	12 weeks
Changes of neurocognitive function tests (attention/alertness) at 6 and 12 weeks	Attention was tested by "Alertness"	12 weeks
Changes of neurocognitive function tests (attention) at 6 and 12 weeks	Attention was tested by "Divided Attention"	12 weeks
Changes of neurocognitive function tests (attention speaking) at 6 and 12 weeks	Attention was tested by "Go,A.lo-Go".	12 weeks
Fatigue at 6 and 12 weeks	"Functional Assessment of Cancer Therapy - Fatigue Subscale" measured in points (range 0-52)	12 weeks
Anxiety/depression at 6 and 12 weeks	"Hospital Anxiety and Depression Scale - German Version"	12 weeks
Activities of daily living (Barthel) at 6 and 12 weeks	"Barthel Activities of Daily Living Index" measured in points (range 0-100)	12 weeks
Activities of daily living (instrumental) at 6 and 12 weeks	"lnstrumental Activities of Daily Living Scale" measured in points (range 0-8)	12 weeks

Collaborators and Investigators

• Sponsor: Universitätsmedizin Mannheim
• Collaborators: Heidelberg University
• Investigators: Principal Investigator: Christian Manegold, MD, University Medical Center Mannheim

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2008
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: April 18, 2009
• First Submitted That Met QC Criteria: April 18, 2009
• First Posted (Estimated): April 21, 2009

Study Record Updates

• Last Update Posted (Actual): May 10, 2024
• Last Update Submitted That Met QC Criteria: May 7, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: extensive stage small cell lung cancer; stage IV non-small cell lung cancer; adult tumors metastatic to brain
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Brain Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms
• Other Study ID Numbers: CDR0000636508; HUMCM-CIRAB; EUDRACT-2008-004573-17