| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relaped Malignant Glioma = patients with anaplastic astrocytoma, anaplastic oligodendroglioma, mixed anaplastic oligoastrocytoma, glioblastoma multiforme or gliosarcoma at recurrence |
|
| MedDRA Classification |
| 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 |
Phase I
• To determine the safety and tolerability of pazopanib and lapatinib when
administered in combination with EIAC in patients with recurrent Grade III or IV
malignant gliomas.
• To determine the OTR of pazopanib and lapatinib when administered in combination
with EIAC.
Phase II
• To determine PFS at 6 months in patients with recurrent Grade IV malignant gliomas who are receiving pazopanib and lapatinib. Patients will be enrolled into 1 of 2 strata. One stratum will consist of patients with tumors that express EGFRvIII
and/or PTEN, and the other stratum will consist of patients with tumors that express
neither molecular marker.
• To determine the safety and tolerability of pazopanib and lapatinib when
administered to patients with recurrent Grade IV malignant gliomas.
|
|
| E.2.2 | Secondary objectives of the trial |
Phase I
• To determine the pharmacokinetics of pazopanib and lapatinib when administered
together in the presence of EIAC.
Phase II
• To determine overall PFS for each stratum of patients with tumors of different
EGFRvIII and PTEN expression profiles.
• To determine the pharmacokinetics of pazopanib and lapatinib when administered
together in the absence of EIAC.
• Assess the relationship between pazopanib and lapatinib exposure at steady-state
[area under the concentration-time curve from 0 to 24 hours (AUC (0-24)) or area
under the concentration-time curve from 0 to 12 hours (AUC(0-12)), Cmax, C24]
and the levels of relevant circulating biomarkers (e.g. VEGF, sVEGFR-1, and
sVEGFR-2).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase I
1. Patients are on Enzyme-inducing anticonvulsant (EIAC) for a minimum of 15 days. Patients may be on more than one AC. At least one of the ACs must be an EIAC.
2. Patients with anaplastic astrocytoma, anaplastic oligodendroglioma, mixed anaplastic
oligoastrocytoma, glioblastoma multiforme, or gliosarcoma at recurrence
3. Patients whose diagnostic pathology confirmed these pathologies will not need rebiopsy
4. Patients with prior low-grade glioma are eligible if histologic assessment demonstrates transformation to Grade IV malignant glioma
Phase II
1. Patients must have histologically confirmed glioblastoma multiforme or gliosarcoma in first or second recurrence.
2. Patients may not have received more than two prior cytotoxic chemotherapy containing regimen.
3. Patients must not have received prior treatment with VEGFR, ErbB1, ErbB2 inhibitors as defined in the protocol. Prior Avastin therapy is permitted as defined in the protocol
4. Tumor tissue must be analyzed for PTEN and EGFRvIII prior to dosing.
5. Patients with prior low-grade glioma are eligible if histologic assessment
demonstrates transformation to Grade III or IV malignant glioma.
6. Patients must not be on an EIAC.
Phase I and II:
7. An evaluable patient for either the Phase I or Phase II studies must meet additional inclusion criteria relating to laboratory tests, population and child-bearing potential – please refer to the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Poorly controlled hypertension (SBP > 140 mmHg, or DBP > 90 mmHg).
2. Concurrent severe and/or uncontrolled medical disease
3. History of myocardial infarction, admission for unstable angina, cardiac angioplasty or stenting as defined in the protocol.
4. Has Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
5. QTc prolongation defined as a QTc interval greater than or equal to 470milliseconds.
6. Current use of therapeutic warfarin.
7. Excessive risk of bleeding as defined by stroke within the prior 6 months, history of CNS or intraocular bleed, or septic endocarditis.
8. Evidence of intratumor hemorrhage on pretreatment diagnostic imaging, except for stable post-operative Grade 1 hemorrhage.
9. Active systemic bleeding, such as gastrointestinal bleeding or gross hematuria. Hemoptysis within 6 weeks of Day 1, Treatment Period 1.
10. Female patients who are pregnant or breast feeding.
11. Acute or chronic liver disease (i.e., hepatitis, cirrhosis).
12. Patients who received investigational drugs <21days prior to Day 1, Treatment Period 1, or who have not recovered from the toxic effects of such therapy.
13. Patients who received chemotherapy <21days prior (6 weeks for prior nitrosourea or mitomycin C) to Day 1, Treatment Period 1, or who have not recovered from the toxic effects of such therapy.
14. Patients who received radiation therapy <12 weeks prior to Day 1, Treatment Period 1, or who have not recovered from the toxic effects of such therapy.
15. Patients who received biologic, immunotherapeutic or cytostatic agents <14 days prior to Day 1, Treatment Period 1, or who have not recovered from the toxic effects of such therapy.
16. Patient is <3 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant or requiring active intervention.
Patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
17. Surgical resection of brain tumor or any other surgery < 21 days prior to Day 1,Treatment Period 1, or who have not recovered from side effects of such a procedure.
18. Patients with any Grade of intraparenchymal CNS hemorrhage. Exceptions are detailed in the protocol.
19. Patients unwilling to or unable to comply with the protocol.
20. History of malabsorption syndrome, disease significantly affecting gastrointestinal function or major resection of the stomach or small bowel that could affect absorption, distribution, metabolism or excretion of study drugs. Has any unresolved bowel obstruction or diarrhea. Other clinically significant gastrointestinal abnormalities that may increase the risk of GI bleeding or perforation including, but not limited to: active peptic ulcer, inflammatory bowel disease such as ulcerative colitis, or other GI conditions with increased risk of perforation, history of abdonimal fistula, GI perforation, or intra-abdominal abcess within 28 days prior to Day 1, Treatment Period 1.
21. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
22. Is on any specifically prohibited medication or requires any of these medications during treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I
• The safety and tolerability endpoints will consist of the evaluation of AEs, and
changes in vital signs and laboratory values.
• A dose regimen where no more than 1 out of 6 patients experiences a dose limiting
toxicity (DLT) will define the OTR.
Phase II
• Disease progression using MacDonald Criteria (Appendix 12).
• PFS rate at 6 months defined as the proportion of evaluable patients who experience
PFS at 6 months. PFS is defined as the interval between the date of enrollment and
the earliest date of disease progression or death due to any cause. For patients who
do not progress or die, PFS will be censored at the time of initiation of alternative
anti-cancer therapy, date of last radiologic assessment, or time of last contact, if
sooner.
• The safety and tolerability endpoints will consist of the evaluation of AEs, and
changes in vital signs and laboratory values.
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarkers, drug interaction, proteomics |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
Phase I - when OTR has been determined for pazopanib, lapatinib and EIACs.
Phase II - Stopping rules are defined in the protocol |
|
| 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 | 0 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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