| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase I Part: Glioma Maligno recurrente
Phase II Part: Glioblastoma (GBM) recurrente |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065443 |
| E.1.2 | Term | Malignant glioma |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018337 |
| E.1.2 | Term | Glioblastoma multiforme |
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| 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 part:
- To determine the maximum tolerated dose (MTD) and the associated dose-limiting toxicities (DLTs) of PHA-848125AC administered orally once daily for 14 consecutive days followed by 7 days of rest (3-week cycle) in adult patients with recurrent malignant glioma
- To establish the dose recommended for the phase II (RP2D) part of the trial.
Phase II part:
- To evaluate antitumor activity of PHA-848125AC in recurrent glioblastoma multiforme (GBM) patients, assessed as percentage of patients alive and progression-free at 6 months (PFS-6 rate). |
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| E.2.2 | Secondary objectives of the trial |
Phase I part:
- To define the toxicity profile of PHA-848125AC in recurrent malignant glioma patients
- To evaluate the pharmacokinetics of PHA-848125AC in plasma in recurrent malignant glioma patients who are not receiving concomitant enzyme-inducing antiepileptic drugs (EIAEDs)
- Establish the pharmacokinetics of PHA-848125AC in a small cohort of 6 patients receiving EIAEDs and entered at the RP2D level
- To assess biomarker modulation of PHA-848125AC in skin samples of consenting patients.
Phase II part:
- To assess additional measures of tumor control to further characterize the efficacy profile of PHA-848125AC in recurrent GBM patients
- To evaluate the safety profile of repeated administrations of PHA-848125AC in recurrent GBM patients
- To evaluate the pharmacokinetics of PHA-848125AC in plasma in recurrent GBM patients at the RP2D (limited sampling procedure)
- To investigate biomarker modulation of PHA-848125AC in skin samples of consenting patients.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase I part:
1. Signed and dated IRB/IEC-approved Informed Consent
2. Histologically proven supratentorial brain tumor (e.g. anaplastic astrocytoma [WHO grade III], recurrent or progressive low-grade glioma, oligodendroglioma, ependymoma), at recurrence after prior standard therapy. Inclusion of other histologies possible after approval by the Investigator and the Sponsor
3. Recurrence or progression after prior standard treatment with surgery, if feasible, radiotherapy and chemotherapy. Patient may have received more than 1 line of prior chemotherapy
4. Age ≥ 18 years
5. KPS ≥ 70
6. Estimated life expectancy of at least 3 months
7. Negative pregnancy test (if female in reproductive years)
8. Agreement upon the use of effective contraceptive methods (hormonal or barrier method of birth control, or abstinence) prior to study entry and for the duration of study participation, if men and women of child producing potential
9. Adequate liver function:
- Bilirubin ≤ 1.5 upper limit of normal (ULN)
- Albumin ≥ 3.0 g/dL
- AST (SGOT), ALT (SGPT) ≤2.5 ULN
- Alkaline phosphatase ≤ 2.5 ULN
10. Adequate renal function:
- Serum creatinine ≤1.5 mg/dL (or ≤133 µmol/L)
11. Adequate hematologic status:
- ANC ≥1,500 cells/mm3
- Platelet count ≥ 100,000 cells/mm3
- Hemoglobin ≥10.0 g/dL
12. At the time of start of treatment, at least 4 weeks must have elapsed since completion of surgery, radiotherapy and chemotherapy (at least 6 weeks since completion of prior nitrosurea therapy)
13. With the exception of alopecia, resolution of all acute toxic effects of any prior surgery, radiotherapy, radiosurgery or chemotherapy to NCI CTC (Version 3.0) grade ≤ 1 and to the baseline laboratory values as defined in Inclusion Criteria Number 9, 10, 11
14. Concurrent corticosteroids allowed, with dose stable for at least 7 days before treatment
15. Able and willing to comply with scheduled visits, therapy plans, and laboratory tests required in this protocol
16. Capability to swallow capsules intact (without chewing, crushing, or opening)
17. If on treatment with antiepileptic drugs (AEDs), AEDs should be non enzyme-inducing (non-EIAEDs). (Not Applicable to patients enrolled in the EIAEDs subset at the RP2D)
18. Patients on treatment with enzyme-inducing antiepileptic drugs (EIAEDs). (Applicable only to patients enrolled in the EIAEDs subset at the RP2D)
19. Patients should continue on the same anticonvulsant(s) for 2 weeks prior to treatment; patients with tumor-related tremors and/or seizures can be enrolled if well controlled by specific therapy.
Phase II part:
1. Signed and dated IRB/IEC-approved Informed Consent
2. Histologically proven (at diagnosis) glioblastoma (GBM)
3. Patients in first relapse, following 1st line chemotherapy (maximum 1 line of prior chemotherapy, either administered at initial diagnosis or at a recurrence)
4. Presence of at least one ≥1.5 cm2 bi-dimensionally measurable lesion by gadolinium (Gd)-enhanced MRI scan, indicating progressive or recurrent disease, obtained at least 12 weeks after standard external-beam radiotherapy and within 14 days prior to treatment
5. Age ≥ 18 years
6. KPS ≥ 70
7. Estimated life expectancy of at least 3 months
8. Negative pregnancy test (if female in reproductive years)
9. Agreement upon the use of effective contraceptive methods (hormonal or barrier method of birth control, or abstinence) prior to study entry and for the duration of study participation, if men and women of child-producing potential
10. Adequate liver function:
- Bilirubin ≤1.5 upper limit of normal (ULN)
- Albumin ≥ 3.0 g/dL
- AST (SGOT), ALT (SGPT) ≤ 2.5 ULN
- Alkaline phosphatase ≤ 2.5 ULN
11. Adequate renal function:
- Serum creatinine ≤1.5 mg/dL (or ≤133 µmol/L)
12. Adequate hematologic status:
- ANC ≥ 1,500 cells/mm3
- Platelet count ≥100,000 cells/mm3
- Hemoglobin ≥ 10.0 g/dL
13. At the time of start of treatment, at least 4 weeks must have elapsed since completion of surgery, radiotherapy and chemotherapy (at least 6 weeks since completion of prior nitrosurea therapy)
14. With the exception of alopecia, resolution of all acute toxic effects of any prior surgery, radiotherapy, radiosurgery or chemotherapy to NCI CTC (Version 3.0) grade ≤ 1 and to the baseline laboratory values as defined in Inclusion Criteria Number 10, 11, 12
15. Concurrent corticosteroids allowed, with dose stable for at least 7 days before treatment
16. Able and willing to comply with scheduled visits, therapy plans, and laboratory tests required in this protocol
17. Capability to swallow capsules intact (without chewing, crushing, or opening)
18. If on treatment with antiepileptic drugs (AEDs), AEDs should be non enzyme-inducing (non-EIAEDs)
19. Patients should continue on the same anticonvulsant(s) for 2 weeks prior to treatment; patients with tumor-related tremors and/or seizures can be enrolled if well controlled by specific therapy
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| E.4 | Principal exclusion criteria |
Phase I and Phase II parts:
The presence of any of the following will exclude a subject from study enrollment:
1. Grade >1 retinopathy
2. Any of the following in the past 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis
3. Major surgery, other than diagnostic surgery, within 4 weeks prior to treatment
4. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
5. Pregnant or breast feeding women
6. Known infection with HIV, active hepatitis B or hepatitis C
7. Prior high-dose chemotherapy with bone marrow or stem cell support
8. Previous (within the last 5 years) or current malignancies at other sites, except for adequately treated basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri
9. Patients with extra-brain metastases
10. Current enrollment in or participation in another therapeutic clinical trial within 4 weeks preceeding treatment start
11. Diabetes mellitus uncontrolled, or with clinical evidence of diabetic retinopathy, severe peripheral vascular disease or diabetic ulcers
12. Patients who have exhibited allergic reactions to a similar structural compound, biological agent, or formulation or to the contrast medium
13. Gastrointestinal disease (e.g. Crohn’s disease, ulcerative colitis, or short gut syndrome) that would impact on drug absorption
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgement of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
15. Patients under treatment with anticoagulants or with coagulation disorders or with signs of hemorrhage at the baseline MRI
16. Patients treated with drugs which might inhibit CYP3A4
17. Patients treated with drugs which might induce CYP3A4 (except for patients taking EIAEDs and enrolled in the EIAEDs subset at the RP2D).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I part:
- First-cycle DLTs
Phase II part:
- Progression Free Survival rate at 6 months (PFS-6 rate) (i.e., the proportion of patients known to be alive and progression-free at ≥ 6 months out of the total number of treated patients [supportive analysis on the evaluable patients population will also be performed]. The progression free survival time is defined as the time from the date of start of treatment to the date of disease progression or death).
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| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Additional Phase I study to determine the MTD in recurrent malignant glioma patients |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 24 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
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