| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Glioblastoma Multiforme (WHO Grade IV) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Glioblastoma multiforme (GBM) |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018337 |
| E.1.2 | Term | Glioblastoma multiforme |
| 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 assess the effect of berubicin compared with lomustine on OS in adult patients with GBM (WHO Grade IV) that has recurred after standard initial therapy. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the effect of berubicin on PFS per RANO criteria in patients with GBM after failure of standard first line therapy, defined as the length of time from the initiation of study drug administration to disease progression based on MRI scan./To assess the effect of berubicin on EFS defined as the length of time from the initiation of study drug administration to disease progression, death, or discontinuation of treatment for any reason./To assess the effect of berubicin on ORR and individual components (ie, CR alone, PR alone) as well as DCR defined as CR or PR or SD per RANO criteria in adult patients with GBM after failure of standard first line therapy./To assess the safety of the RP2D of berubicin given as a 2-hour IV infusion once daily for 3 consecutive days followed by 18 days off study drug (each cycle = 21 days) by the incidence and severity of AEs according to NCI-CTCAE, Version 5.0./To confirm the pharmacokinetics (PK) of berubicin and its metabolite, berubicinol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent [...]
2. At least 18 years of age.
3. A confirmed GBM diagnosis must be based on local review of tumor tissue from the initial biopsy, surgery, or re-resection. A formal pathology report confirming GBM is acceptable. It is not a requirement for slides to be sent to a central reviewer.
4. Recurrent GBM as evaluated by RANO criteria, confirmed by central review, as follows: Measurable disease is required with documented unequivocal evidence of tumor recurrence or progression following prior therapy (ie, 25% increase in the sum of the products of
perpendicular diameters of the contrast-enhancing lesions while on stable or increasing doses of corticosteroids; however, these changes should not be due to changes in the dose of corticosteroids) as documented by the investigator.
5. The tumor is localized supratentorially.
6. The lesion (or sum of lesions) does not exceed 50 cm3 in volume.
7. MGMT methylation status must be available; results of routinely used methods for MGMT methylation testing (eg, methylation-specific polymerase chain reaction or quantitative polymerase chain reaction) are acceptable.
8. No more than 1 prior line of treatment (eg, surgery followed by radiation with concomitant chemotherapy, followed by adjuvant chemotherapy is considered as 1 line of treatment). A second debulking surgery during the first line treatment is acceptable. In addition, treatment with tumor treating fields (TTFields; Optune) is acceptable if provided as first line therapy.
9. Recovery from toxicity/side effects of all prior therapy to Grade 1 or less, subject to the investigator’s discretion, except for alopecia; the following time intervals from previous treatments are required to be eligible:
a. 12 weeks from the completion of radiation (to reduce risk of pseudoprogression), unless progression is confirmed by biopsy
b. 4 weeks from the end of any previous of chemotherapy or 6 weeks after the end of treatment with nitrosoureas
c. 4 weeks from the end of any TTFields treatment
d. 4 weeks from any major surgery (maximal debulking surgery, either gross total resection or partial resection) or significant traumatic injury, and any surgery incisions or wounds must be completely healed
10. A stable or decreasing dose of corticosteroids (or none) for brain edema for at least 5 days prior to baseline MRI and enrollment in the study to document disease progression such that changes in the MRI are not related to the use of corticosteroids.
11. Immunosuppressive therapies allowed include the use of topical, inhalational, ophthalmic or intra-articular glucocorticoids, or the use of physiologic replacement doses of glucocorticoids.
12. Eligible for chemotherapy based on adequate bone marrow function and organ function within 2 weeks of study treatment as defined by the following laboratory guidelines, subject to the investigator’s discretion:
a. Hematopoietic function: total white blood cell (WBC) count ≥3000/mm³, absolute neutrophil count (ANC) ≥1500/mm³, platelet count ≥75,000/mm³, hemoglobin ≥10 g/dL
b. Hepatic function: bilirubin ≤1.5 × × the upper limit of normal (ULN) (excluding Gilberts Syndrome, for which bilirubin must be ≤4 × ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 × ULN, and alkaline phosphatase ≤2.5 × ULN
c. Renal function: serum creatinine ≤1.5 × ULN or for patients with creatinine levels above the ULN, estimated creatinine clearance of ≥60 mL/min, calculated using the Cockcroft- Gault equation35
d. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN
13. Female patients of childbearing potential, and male study patients and their sexual partners of childbearing potential must agree to practice a highly effective method of contraception beginning at least 28 days before the start of treatment until at least 6 months after the last dose of study drug.
a. A woman of childbearing potential is defined as a woman who is not permanently sterilized or postmenopausal. Postmenopausal is defined as 12 months with no menses without an alternative medical cause.
b. Women of childbearing potential must have a negative serum or urine pregnancy test.
c. A highly effective method of birth control is defined as one which results in a low failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or vasectomized partner. For patients using a hormonal contraceptive method, information regarding all medications being administered to the patient and their potential effects on the contraceptive should be addressed.
14. Patients with prior malignancies must be disease-free for ≥5 years. However curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; or prostate cancer curatively treated at the time of screening is allowed. |
|
| E.4 | Principal exclusion criteria |
1. Unable or not willing to comply with the protocol regulations.
2. Any additional concurrent radiation therapy or chemotherapy (including but not limited to TMZ) for recurrent or progressive GBM after a first line treatment.
3. Prior treatment with bevacizumab.
4. Prior treatment with lomustine.
5. Screening MRI showing a mass effect defined as significant compression of the ventricular system and/or a midline shift (≥10 mm)34 confirmed by central MRI review.
6. Any condition (medical, social, psychological) that would prevent adequate information and follow-up, including but not limited to clinically relevant psychiatric disorders, legal incapacity, dementia or altered mental status.
7. Presence of poorly controlled seizures, defined as occurring despite SOC or requiring hospitalization.
8. Prior anthracycline cumulative dose more than 550 mg/m2.
9. Heart disease:
a. LVEF <50%
b. Unstable angina
c. CHF with New York Heart Association (NYHA) classification of 3 or 4
d. Patients with baseline QT/QTc interval >480 msec, a history of additional risk factors for torsades de pointes (TdP) (eg, heart failure, hypokalemia, family history of long QT syndrome) and using concomitant medications that significantly prolong the QT/QTc interval
e. History of myocardial infarction within 12 months of enrollment
10. Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg and/or diastolic BP >100 mmHg).
11. Known to be positive for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV), human immunodeficiency virus (HIV), COVID-19 (currently positive at time of screening), or any other acute viral, bacterial, or fungal infection (testing not required unless symptomatic or suspected disease).
12. Patients with any other uncontrolled intercurrent medical conditions, including but not limited to diabetes mellitus or chronic obstructive pulmonary disease that have not been well controlled by medical management over the prior 3 months are ineligible unless approved by the sponsor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is OS. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| through study completion, an average of 4 years |
|
| E.5.2 | Secondary end point(s) |
•PFS, defined as the length of time from the initiation of study drug administration to disease progression based on MRI scan
• EFS, defined as the length of time from the initiation of study drug administration to disease progression, death, or discontinuation of treatment for any reason (eg, toxicity, intolerance, disease-related conditions, or failure to respond)
• ORR, defined as CR or PR per RANO criteria
• DCR, defined as CR or PR or SD per RANO criteria; SD is defined as lack of progression of disease based on MRI scan obtained at least 6 weeks after initiation of therapy
The PK endpoint of this study is:
• Standard PK parameters for berubicin and its metabolite, berubicinol, as derived from noncompartmental analysis of plasma drug concentration-time data. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| through study completion, an average of 4 years |
|
| 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 | 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) | 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 | 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 | 20 |
| 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 |
| United States |
| France |
| Italy |
| Spain |
| Switzerland |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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