| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002224 |
| E.1.2 | Term | Anaplastic astrocytoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to demonstrate superiority in overall survival (OS) and comparable safety when eflornithine is added to lomustine compared to lomustine alone in patients with anaplastic astrocytoma (AA) that progress/recur after irradiation and adjuvant temozolomide chemotherapy.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to determine:
• Progression-free survival (PFS)
• The objective response rate (ORR)
• OS for IDH-1 mutant patients
• OS for IDH-1 wild type patients |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for participation in this study:
1. The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
2. Age ≥ 18 years.
3. Surgical or biopsy-proven diagnosis of WHO grade 3 AA.
4. Received EBRT and temozolomide chemotherapy prior to first tumor progression or recurrence of WHO Grade 3 AA.
5. First AA tumor progression or recurrence ≤ 6 months prior to randomization based on MRI using T2 hyperintensity, gadolinium (Gd)-contrast enhancement, or both. To avoid enrollment of patients with glioblastoma, patients with Gd-contrast enhancing tumors will be eligible if there is no necrosis seen on MRI and any of the following criteria is true:
a. Gd-contrast lesion margins are not clearly defined,
b. Gd-contrast lesions are only measurable in one dimension,
c. Gd-contrast lesion has two perpendicular diameters less than 10 mm,
d. Gd-contrast lesion has two perpendicular diameters greater than 10 mm but less than 20 mm and lesion does not demonstrate central necrosis,
e. Recent histopathological confirmation of WHO grade 3 AA
6. Completion of EBRT ≥ 6 months prior to randomization.
7. Stained, unstained slides or tumor tissue block(s) are available from their most recent tumor surgery are available for central histological confirmation.
8. A patient whose AA tumor has progressed or recurred and has had another surgical resection prior to randomization will be eligible if a) pathology review confirms AA, and b) post-surgical MRI demonstrates measurable tumor on T2 FLAIR.
9. If taking corticosteroids, must be on a stable or decreasing dose for at least 5 days prior to the screening MRI.
10. Karnofsky Performance Status (KPS) score of > 70.
11. Off anticancer therapy for at least 4 weeks and recovered from any significant treatment-related toxicities to Grade ≤ 1 prior to randomization.
12. Adequate recovery from any major surgery is required; at least 4 weeks must have elapsed from the time of any major surgery and must have recovered from all surgery-related toxicities to Grade ≤ 1 prior to randomization.
13. Adequate hematologic function (ANC ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 10.5 gm/dL) within 14 days prior to randomization.
14. Total bilirubin ≤ 1.5x upper limit of normal (ULN) within 14 days prior to randomization.
15. Hepatic transaminases (AST and ALT) ≤ 2x ULN within 14 days prior to randomization.
16. Adequate renal function (serum creatinine ≤ 1.5x ULN) within 14 days prior to randomization.
17. Life expectancy ≥ 6 months.
18. Female patients of childbearing potential must agree to utilize acceptable contraceptive methods from screening throughout the duration of the study period, and for 30 days following the last dose of study drug. Abstinence is an acceptable method of contraception. Otherwise, consistent and current use of 1 of the following methods of birth control is accepted: oral contraceptive, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), tubal sterilization, Essure micro-insert system, or vasectomy in the male partner. Female patients must also refrain from egg donation and in vitro fertilization during treatment and until at least 30 days from the last dose of study drug.
19. Male patients must agree to abstain from sexual intercourse or use an acceptable contraceptive method (e.g. condoms) from screening throughout the duration of the study period, and for 90 days following the last dose of study drug. Male patients must also refrain from sperm donation during treatment and until at least 90 days from the last dose of study drug. |
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| E.4 | Principal exclusion criteria |
Patients who meet any of the following exclusion criteria are not eligible for study participation:
1. MRI defining progression is consistent with a diagnosis of glioblastoma or radiation necrosis.
2. Patients who are considered to be refractory to EBRT and temozolomide but who have not progressed.
3. Prior systemic therapy for recurrence of AA.
4. Presence of extracranial or leptomeningeal disease.
5. Prior lomustine use.
6. History of other invasive malignancy, unless adequately treated with curative intent and with no known active disease present within 2 years prior to the first dose of study drug. Patients with non-melanoma skin cancer, carcinoma in situ (including superficial bladder cancer), cervical intraepithelial neoplasia and organ-confined prostate cancer deemed by the investigator to be at low risk of recurrence are not excluded.
7. Active infection or serious intercurrent medical illness.
8. Known to be HIV positive or to have an AIDS-related illness, active Hepatitis B Virus (HBV), or active Hepatitis C Virus (HCV) positive.
9. Poorly controlled seizures.
10. Unable to undergo an MRI with contrast.
11. Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) Class III or IV congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis.
12. Malabsorption syndrome, history of resection of the stomach or small bowel, active ulcerative colitis or Crohn’s disease, or partial or complete bowel obstruction or other conditions that would be expected to alter the absorption or PK of study drugs.
13. Receipt of any other anticancer therapy while receiving protocol-defined therapy.
14. Concurrent use of any other investigational agent during the study or within 30 days prior to randomization.
15. Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the patient unsuitable for the study.
16. Pregnant or breastfeeding. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the duration of overall survival as measured from the date of randomization.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Measured from the date of randomization until the date of death. The calendar date of the 194th death will serve as the data cut-off date for the primary analysis. |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are PFS, ORR, OS for IDH-1 mutant patients and OS for IDH-1 wild type patients.
Safety:
• Incidence of treatment emergent adverse events
• Incidence of serious adverse events
• Changes and shifts from baseline in hematology and serum chemistry values, ECGs, and vital signs
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of the secondary and exploratory efficacy endpoints and safety will occur at the time of
the primary analysis of overall survival. |
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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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| Database closure, which is one year post last patient last visit. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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