| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with recurrent Glioblastoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Specific type of brain tumor called glioblastoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006153 |
| E.1.2 | Term | Brain tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the efficacy of onartuzumab + bevacizumab relative to placebo + bevacizumab as measured by investigator-assessed progression-free survival (PFS)
• To evaluate the efficacy of onartuzumab + bevacizumab relative to placebo + bevacizumab as measured by investigator-assessed PFS in the subgroup of patients with Met-positive (Met+) glioblastoma |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of onartuzumab + bevacizumab relative to placebo + bevacizumab as measured by overall survival (OS) rate at 9 months (OS-9) and OS overall, in all patients and in those with Met+ glioblastoma
• To evaluate the efficacy of onartuzumab + bevacizumab relative to placebo + bevacizumab as measured by PFS rate at 6-months (PFS-6), objective response rate (ORR), and duration of response (DOR) in all patients and in those with Met+ tumors |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed glioblastoma at first recurrence after concurrent or adjuvant chemoradiotherapy
A local pathology report constitutes adequate documentation of histology for study inclusion. Patients with an initial diagnosis of a lower-grade glioma are eligible if a subsequent biopsy was determined to be glioblastoma.
2. Imaging confirmation of first tumor progression or regrowth as defined by the RANO criteria
A minimum of 12 weeks must have elapsed from the completion of
radiotherapy to randomization to minimize the potential for magnetic resonance imaging (MRI) changes related to radiation necrosis that might be misdiagnosed as progression of disease, unless there is a new lesion outside the radiation field or unequivocal evidence of viable tumor on histopathological sampling.
3. Prior treatment with TMZ
4. No more than one prior line of chemotherapy
Concurrent and adjuvant TMZ-based chemotherapy, including the
combination of TMZ with an investigational agent, is considered one line of chemotherapy.
5. No prior treatment with bevacizumab or other VEGF- or
VEGF-receptor-targeted agent
6. No prior exposure to experimental treatment targeting either the HGF or Met pathway
7. Prior therapy with gamma knife or other focal high-dose radiotherapy is allowed, but the patient must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field
8. No prior treatment with prolifeprospan 20 with carmustine wafer
9. No prior intracerebral agent
Recovery from the toxic effects of prior therapy, with a minimum time of:
a) ≥ 28 days elasped from the administration of any investigational agent
b) ≥ 28 days elapsed from the administration of any prior cytotoxic agents, except ≥ 14 days from vincristine, ≥ 21 days from procarbazine, and ≥ 42 days from nitrosureas
c) ≥ 7 days elapsed from administration of any non-cytotoxic agent (e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid)
11. Patients who have undergone recent surgery for recurrent or progressive tumor are eligible provided that:
a) Surgery must have confirmed the recurrence.
b) A minimum of 28 days must have elapsed from the day of surgery to randomization. For core or needle biopsy, a minimum of 7 days must have elapsed prior to randomization.
c) Craniotomy or intracranial biopsy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomization.
12. No evidence of recent hemorrhage on baseline MRI of the brain
However, patients with clinically asymptomatic presence of hemosiderin, resolving hemorrhagic changes related to surgery, or presence of punctuate hemorrhage in the tumor are eligible.
13. No need for urgent palliative intervention for primary disease
(e.g., impending herniation)
14. Availability of formalin-fixed paraffin-embedded tumor tissue representative of glioblastoma
15. Willingness and ability to provide written informed consent and to comply with the study protocol as judged by the investigator
16. Age ≥ 18 years
17. Karnofsky performance status ≥ 70%
18. Stable or decreasing dose of corticosteroids within 5 days prior to randomization
19. For women who are not postmenopausal (i.e., < 2 years after last menstruation) or surgically sterile (absence of ovaries and/or uterus) and who are sexually active: agreement to use an adequate method of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of
contraception in conjunction with spermicidal jelly) during the treatment period and for at least 6 months after the last dose of study drug
20. For male patients who are partners of premenopausal women: agreement to use a barrier method of contraception during the treatment period and for at least 6 months after the last dose of study drug |
|
| E.4 | Principal exclusion criteria |
1. Patients unable to undergo brain MRI scans with IV gadolinium
2. Pregnancy or lactation (or a positive pregnancy test within 7 days before starting any component of study medication)
3. Absolute neutrophil count (ANC) < 1.5 × 109/L; platelet count < 100 × 109/L; or hemoglobin (Hb) < 9.0 g/dL within 7 days prior to enrollment Note: The use of transfusion or other intervention to achieve Hb ≥ 9 g/dL is acceptable.
4. Total bilirubin ≥ 1.5 × ULN (except in patients diagnosed with Gilbert’s disease)
5. AST (SGOT), ALT (SGPT), or alkaline phosphatase (ALP) ≥ 2.5 ×ULN
6. Serum creatinine > 1.5 × ULN or calculated creatinine clearance
(CrCl) < 60 mL/min (Cockcroft and Gault)
7. Urine dipstick test for proteinuria ≥ 2+ Patients found to have ≥ 2+ proteinuria should undergo a 24-hour urine collection and must demonstrate ≤ 1.0 g of protein in 24 hours)
8. International normalized ratio (INR), protohrombin time (PT), or activated partial thromboplastin time (APTT) as follows:
In the absence of therapeutic intent to anticoagulate the patient:
INR > 1.5 or PT > 1.5 × ULN or aPTT > 1.5 ×ULN OR
In the presence of therapeutic intent to anticoagulate the patient: INR or PT and aPTT not within therapeutic limits (according to the medical standard in the institution) or patient has not been on a stable dose of anticoagulants for at least 2 weeks before randomization. (Note: Per ASCO guidelines, low-molecular-weight heparin [LMWH] should be the preferred approach.)
9. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg while on antihypertensive medication)
10. Uncontrolled diabetes, as evidenced by fasting serum glucose level > 200 mg/dL
11. Prior history of hypertensive crisis or hypertensive encephalopathy
12. New York Heart Association (NYHA) Grade II or greater congestive cardiac failure
13. History of myocardial infarction (within 12 months) or unstable angina (within 6 months) prior to randomization
14. History of stroke or transient ischemic attacks within 6 months prior to randomization
15. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to randomization
16. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
17. History of abdominal fistula or gastrointestinal perforation within 6 months prior to randomization
18. History of intracranial abscess within 6 months prior to randomization
19. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization
20. Anticipation of need for major surgical procedure during the course of the trial
21. Serious non-healing wound, active ulcer, or untreated bone fracture
22. History of another malignancy in the previous 3 years, with a disease-free interval of < 3 years
Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.
23. Evidence of any active infection requiring hospitalization or IV antibiotics within 2 weeks prior to randomization
24. Known hypersensitivity to any excipients of onartuzumab or bevacizumab
25. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibody |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Patients will be followed until the point at which approximately 84 investigator-assessed PFS events are observed |
|
| E.5.2 | Secondary end point(s) |
Overall Survival (OS)
OS-9
PFS-6
Objective Response Rate (ORR)
Duration of Objective Response (DOR) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Follow-up for survival will continue until all patients have either died, or are lost to follow-up, or the Sponsor decides to end the trial, whichever occurs first. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Tolerability, QoL, Serum levels and incidence of anti-therapeutic
antibodies (ATAs) against MetMAb |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Germany |
| Italy |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The efficacy analysis will occur when 48 investigator-assessed PFS events in patients with Met diagnostic-positive tumors and 96 PFS events in the ITT population have occurred. Follow-up for survival will continue until all patients have either died, or are lost to follow-up, or the Sponsor decides to end the trial, whichever occurs first. Depending on study outcome, patients may be allowed to continue treatment if they are deriving benefit, with continued safety follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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