89Zr-RO5323441 PET Imaging in Patients With Recurrent Glioblastoma Treated With Bevacizumab
18 Years
N/A
Both
Glioblastoma
Trial Information
89Zr-RO5323441 PET Imaging in Patients With Recurrent Glioblastoma Treated With Bevacizumab
Rationale: 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. Surgery aimed to complete resection is the first therapeutic modality, however,
the infiltrative nature of the disease makes a complete resection nearly impossible. In a
randomized, phase III EORTC-NCIC trial, overall survival in newly diagnosed glioblastoma
patients treated with concomitant temozolomide and radiotherapy followed by 6 cycles of
temozolomide was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1%
(8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years, treatment which is now standard of
care. 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, showed
a 28%RR,a 43% 6-month PFS and provided a consistent clinical benefit in terms of both
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.
Objectives: 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 non-tumor organ distribution, and to measure the effect of
bevacizumab treatment on 89Zr-RO5323441 uptake in recurrent GBM.
Study design: This is a single center, investigator driven, 89Zr-RO5323441 PET imaging and
bio-distribution study in patients with recurrent GBM treated with bevacizumab. 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. The treatment with bevacizumab will continue until documented disease
progression, unacceptable toxicity, patient refusal or patient's best interest.
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, and will take 10 minutes/ scan.
Whole body PET scans will be performed 4 days after each 89Zr-RO5323441 administration
(before dosing with bevacizumab on day 1 and day 15), and will take 50 minutes/ scan.
89Zr-RO5323441 uptake values in recurrent GBM lesions at baseline and day 15 will be
compared to assess bevacizumab effect on tracer tumor uptake. The purpose of the two early
brain-only PET scans after each 89Zr-RO5323441 injection is to identify whether changes in
89Zr-RO5323441 uptake in recurrent GBM lesions following treatment with bevacizumab can be
solely attributed to an effect on blood volume/ vascular permeability, or rather indicate a
possible modulation of placental growth factor (PlGF) level in the tumor tissue. The
rationale for the whole body 89Zr-RO5323441 PET scans is to assess 89Zr-RO5323441 non-tumor
organs distribution at baseline, as well as to evaluate the influence bevacizumab treatment
could exert on 89Zr-RO5323441 non-tumor organs uptake. For 89Zr-RO5323441 pharmacokinetics,
blood samples will be taken 1 hour after 89Zr-RO5323441 tracer injection on d-3 and d11,
respectively together with the blood samples for hematology on d1 and d15 during the 1st
cycle of bevacizumab treatment. The rationale for this is that performing both the
89Zr-RO5323441 PET scan data quantification and the assessment of the tracer's blood
pharmacokinetics would enable us to better understand the specificity of 89Zr-RO5323441
uptake in recurrent GBM lesions. Patients will be assessed for bevacizumab treatment
response by brain MRI every 6 weeks (i.e. every cycle) in the first 6 month and every 12
weeks thereafter, until documented progression using the updated RANO criteria. Treatment
and tracer injection related side effects will be assessed according to the National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE; version 4.0) for
toxicity and adverse event reporting.
Main study parameters/ endpoints: 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.
Nature and extent of the burden and risk associated with participation, benefit and group
relatedness: 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
this study, one 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. Risk: exposure to 89Zr-RO5323441 PET scan-related radiation,
possibility of allergic reaction to the protein in the tracer, possible side-effects of
bevacizumab.
Inclusion Criteria:
- Age more or at least equal to 18 years
- WHO Performance Status between 0 and 2
- Histologically proven glioblastoma multiforme at recurrence, including patients with
anaplastic oligoastrocytomas with necrosis
- Patients treated with one line of systemic treatment (combined treatment with
temozolomide and RT followed by 6 cycles of temozolomide is considered as one line of
systemic treatment)
- No prior treatment with bevacizumab or other PlGF,VEGF,VEGF-R targeted agents,
cilengitide or enzastaurin
- No radiotherapy within 4 weeks prior to the diagnosis of progression
- No chemotherapy within 4 weeks prior to study enrollment
- Adequate bone marrow function
- Adequate liver function
- Adequate renal function
- 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
- Written informed consent
Exclusion Criteria:
- Invasive procedures (major surgical procedure, open biopsy or significant traumatic
injury) within 28 days prior to start study treatment, or anticipation of the need
for major surgery during the course of the study treatment. Placement of a vascular
access device is not considered as a major surgical procedure if performed more than
24 hours prior to bevacizumab administration.
- Arterial or venous thrombosis less or equal than 6 months prior to study registration
- Prior history of hypertensive crisis or hypertensive encephalopathy
- History of myocardial infarction (less or equal than 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) more than 140 mm
Hg and or diastolic pressure more than 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
- History or evidence of inherited bleeding diathesis or coagulopathy with risk of
bleeding
- Current or recent (within 10 days of first dose of bevacizumab) use of aspirin more
than 325 mg per day) or other NSAID with anti-platelet activity or treatment with
dipyramidole, ticlopidine, clopidogrel and cilostazol
- 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
- Current or recent (within 4 weeks of enrollment) treatment with another
investigational drug or participation in another investigational study
- Known hypersensitivity to any part of the bevacizumab formulation
- Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or
humanized antibody
- Other diseases, interfering with the follow-up
- 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)
Type of Study:
Interventional
Study Design:
Intervention Model: Single Group Assignment, Masking: Open Label
Outcome Measure:
Assess the penetration of RO5323441 into recurrent GBM by 89Zr-RO5323441 PET imaging and to quantify its uptake
Outcome Description:
Calculations of specific 89Zr-RO5323441 uptake in recurrent GBM lesions will be determined for all patients who underwent tracer injection(s) and 89Zr-RO5323441 PET. 89Zr-RO5323441 tumor uptake will be scored visually and quantitatively. The visual analysis of the PET scans will be performed by a qualified nuclear medicine physician. Quantification of 89Zr-RO5323441 uptake will be performed using AMIDE software (Stanford University, Palo Alto, CA). Standardized uptake value (SUV) and relative uptake value (RUV)of 89Zr-RO5323441 will be determined.
Outcome Time Frame:
Patients will be assessed up to 19 days after the first 89Zr-RO5323441 tracer injection (D-3)
Safety Issue:
No
Principal Investigator
Annemiek M. Walenkamp, MD, PhD
Investigator Role:
Principal Investigator
Investigator Affiliation:
University Medical Centre Groningen
Authority:
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Study ID:
BP28015
NCT ID:
NCT01622764
Start Date:
September 2012
Completion Date:
September 2014
Related Keywords:
- Glioblastoma
- RO5323441
- bevacizumab
- PET imaging
- recurrent glioblastoma
- Glioblastoma
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