The objectives of this study are to assess the penetration of RO532441 into recurrent GBM by 89Zr-RO5323441 PET imaging and to quantify its uptake, to visualize and quantify 89Zr-RO5323441 organ distribution, and to measure effect of bevacizumab…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
89Zr-RO5323441 tumor uptake and organ distribution will be scored visually and
quantitatively. Standardized uptake value (SUV) and relative uptake value (RUV)
will be determined and compared in the recurrent GBM lesions and in relevant
tissues at baseline and day 15.
Secondary outcome
-
Background summary
Glioblastomas (GBM) account for 70% of all gliomas (80% of all malignant brain
and CNS tumors) and remain the most aggressive sub-type of glioma, with a
particularly poor prognosis (5 y OS 10%). Surgery aimed to complete resection
is the first therapeutic modality, however, the infiltrative nature of the
disease makes a complete resection nearly impossible. Currently, concomitant
temozolomide and radiotherapy followed by 6 cycles of temozolomide remains the
standard of care for newly diagnosed GBM. Almost all GBM patients experience
relapse and there is no one generally agreed standard of care in recurrent GBM.
Vascular endothelial growth factor-A (VEGF-A), a central regulator of
physiological and pathological angiogenesis, is considered to play a major
angiogenic role in GBM. Bevacizumab, a humanized monoclonal antibody against
VEGF-A, has shown RR 28%, 6-month PFS 43% and provided a consistent clinical
benefit both in terms of delayed progression and increased median overall
survival over historical controls. This benefit is limited however, with the
tumor eventually evading treatment by for example compensatory upregulation of
angiogenic factors like placental growth factor (PlGF). Therefore, targeting
PlGF could be a new strategy of tumor angiogenesis inhibition, complementary to
VEGF(R) inhibition. In preclinical setting, inhibiting PlGF has shown to
inhibit growth and metastasis of various tumors. Humanized monoclonal PlGF
antibody RO5323441 was evaluated in phase I trials in healthy volunteers and in
cancer patients; no Dose Limiting Toxicity (DLT) was found, thus no Maximum
Tolerated Dose (MTD) defined. Stable disease was observed in 6/23 patients on
different dose levels. A phase I/II study of bevacizumab in combination with
RO5323441 is currently ongoing in patients with recurrent GBM (NCT01308684).
However, the amount of RO5323441 to reach the recurrent GBM, and how this is
affected by bevacizumab treatment, are yet unknown. This can be determined by
repetitive measurement of RO5323441 tumor uptake with 89Zr-RO5323441 PET.
Study objective
The objectives of this study are to assess the penetration of RO532441 into
recurrent GBM by 89Zr-RO5323441 PET imaging and to quantify its uptake, to
visualize and quantify 89Zr-RO5323441 organ distribution, and to measure effect
of bevacizumab treatment on 89Zr-RO5323441 uptake in recurrent GBM.
Study design
This is a single center, 89Zr-RO5323441 PET imaging and bio- distribution study
in patients with recurrent GBM treated with bevacizumab.
Intervention
Bevacizumab at a dose of 10 mg/kg body weight i.v. in 90 min on day 1 is given
every 2 weeks in cycles of 6 weeks. 89Zr-RO5323441 will be administered i.v. at
a tracer dose of 5 mg (37 MBq) on day -3 and on day 11 of cycle 1 of
bevacizumab treatment. Four PET scans will be performed (2 brain only PET scans
and 2 whole body PET scans). Brain only PET scans will be performed 2 hours
after each 89Zr-RO5323441 administration on day -3 and day 11. Whole body PET
scans will be performed 4 days after each 89Zr-RO5323441 administration (before
dosing with bevacizumab on day 1 and day 15).
Study burden and risks
Bevacizumab is registered in the Netherlands for use in metastasized colon and
breast cancer, in lung cancer and in advanced renal cell carcinoma and has
already been tested in GBM clinical trials. Bevacizumab is expected to have
clinical benefit for patients enrolled in this study and similar safety profile
compared to the other indications. RO5323441 monotherapy was well tolerated in
patients with advanced malignant diseases. In our study, a patient will receive
a low total protein dose of 10 mg RO5323441 (2X5mg) in the tracer and it is
expected that RO5323441 will not enhance bevacizumab related side effects. The
total radiation dose of 89Zr-RO5323441 for a patient participating in this
study would be 36 mSv for women and 30 mSv for men. According to the
investigators this radiation burden is justifiable in this patient group by the
information that can be obtained in this study.
-Outpatient clinic visit with physical examination, ECG, blood and urine
sample prior to start the study
- Injection with 89Zr-RO5323441 intravenously on day-3 and day 11 of cycle 1
of bevacizumab treatment, with 2 hrs observation afterwards
- 89Zr-RO5323441 PET scans on the day of tracer injection and 4 days after
- Bevacizumab infusion every 2 wks till progression, unacceptable toxicity or
patients best interest
- Clinical visit, physical examination, blood and urine samples at 2-6 wks
during bevacizumab treatment
- MRI scans every 6 weeks in the first 6 months of treatment (4 cycles) and
every 3 months thereafter during bevacizumab treatment
Number of extra visits: 5 in the first 2 weeks + therafter 1 at every 2 wks for
bevacizumab treatment
Number of extra blood samples: in the first 2 weeks 6 bloodsamples, and then at
every 2 wks 1 bloodsample, not more than 25 ml/sample
Risk: radiation of 89Zr-RO5323441 PET scan, possibility of allergic recation to
protein in the tracer, possible side-effect of bevacizumab tretament.
Hanzeplein 1
9713 GZ Groningen
NL
Hanzeplein 1
9713 GZ Groningen
NL
Listed location countries
Age
Inclusion criteria
• Age >= 18 years;• WHO Performance status 0 - 2;• Histologically or biopsy proven glioblastoma at recurrence;• Patients treated with one line of systemic chemotherapy (combined treatment with temozolomide/ RT followed by 6 cycles of temozolomide is considered as one line of systemic chemotherapy).;• Adequate hematological functions: Neutrophils >= 1.5 x 109 cells/L, platelets >= 100 x 109 cells/L, Hb >= 6.2 mmol/L;• Adequate liver function: Bilirubin < 1.5 x upper limit of the normal range (ULN), alkaline phosphatase and transaminases (ASAT/ALAT) < 2.5 x ULN, INR < 1.5;• Adequate renal function:;- Serum creatinine increased * 3x ULN or/and Calculated (Cockcroft-Gault) or measured creatinine clearance > 30 mL/min;- Urine dipstick for proteinuria < 2+. Patients with >= 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hrs urine collection and must demonstrate <= 1 g of protein/24 hr;• Women of reproductive potential, female patients within one year of entering the menopause as well as males must agree to use an effective non-hormonal method of contraception during the treatment period and for at least 6 months after the last dose of bevacizumab;• Patients must be able to give written informed consent to participate.
Exclusion criteria
• Last surgical procedure (including biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) < 28 days prior to start study treatment;• Current or recent (within 4 weeks of enrolment) treatment with another investigational drug or participation in another investigational study;• No radiotherapy within the 1 months prior to the diagnosis of progression;• No chemotherapy in the past 4 weeks;• Arterial or venous thrombosis <= 6 months prior to registration;• History of myocardial infarction (<= 6 months prior to inclusion), unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring digoxin treatment;• Uncontrolled hypertension defined by a systolic blood pressure (BP) > 140 mm Hg and/or diastolic pressure > 100 mm Hg, with or without anti-hypertensive medication. Patients with initial blood pressure elevation are eligible if initiation or adjustment of anti-hypertensive medication lowers pressure to meet the entry criteria;• Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325 mg/day) or other NSAID with anti-platelet activity or treatment with dipyramidole, ticlopidine, clopidogrel and cilostaz;• Use of therapeutic-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic (as opposed to prophylactic) purposes;• Clinically serious (as judged by the investigator) non-healing wounds, active skin ulcers or incompletely healed bone fracture;• Evidence of any active infection requiring hospitalization or antibiotics, within 2 weeks prior to day 1 of cycle 1;• Known hypersensitivity to any part of the bevacizumab formulation;• No geographical, psychological or other non-medical conditions interfering with follow-up;• Pregnant or lactating females. Serum pregnancy test to be assessed before entry in the trial
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-004974-27-NL |
| Other | het onderzoek wordt op clinicaltrials.gov gezet, NCT nummer is nog niet bekend. |
| CCMO | NL38507.042.11 |