This is an open-label, multicenter, randomized, parallel, 2-arm, efficacy and safety study.
Patients with GBM after failure of standard first line therapy will be randomized in a 2:1
ratio to receive berubicin or lomustine for the evaluation of OS. Additional endpoints will
include response and progression outcomes evaluated by a blinded central reviewer for each
patient according to RANO criteria.
A pre-planned, non-binding futility analysis will be performed after approximately 30 to 50%
of all planned patients have completed the primary endpoint at 6 months. This review will
include additional evaluation of safety as well as secondary efficacy endpoints. Enrollment
will not be paused during this interim analysis.
Patients will be eligible for the study if they meet all of the following inclusion
criteria and none of the exclusion criteria.
1. Written informed consent prior to any study-related procedure, and willing and able to
comply with the protocol and aware of the investigational nature of this study.
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) 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:
1. Twelve weeks from the completion of radiation (to reduce risk of
pseudoprogression), unless progression is confirmed by biopsy
2. 4 weeks from the end of any previous chemotherapy or 6 weeks after the end of
treatment with nitrosoureas
3. 4 weeks from the end of any TTFields treatment
4. 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.
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:
1. Hematopoietic function: total white blood cell count ≥3000/mm³, absolute
neutrophil count ≥1500/mm³, platelet count ≥75,000/mm³, hemoglobin ≥10 g/dL
2. Hepatic function: bilirubin ≤1.5 × the upper limit of normal (ULN) (excluding
Gilberts Syndrome, for which bilirubin must be ≤4 × ULN); aspartate
aminotransferase and alanine aminotransferase <3 × ULN, and alkaline phosphatase
≤2.5 × ULN
3. Renal function: serum creatinine ≤1.5 × ULN or for patients with creatinine
levels above the ULN, or estimated creatinine clearance of ≥60 mL/min/1.73 m2,
calculated using the Cockcroft-Gault formula
4. Activated partial thromboplastin time ≤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.
1. 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.
2. Women of childbearing potential must have a negative serum or urine pregnancy
3. A highly effective method of birth control is defined as one which results in a
low failure rate (ie, less than 1% per year) when used consistently and
correctly, such as implants, injectables, combined oral contraceptives, some
intrauterine devices, sexual abstinence, or vasectomized partner. For patients
using a hormonal contraceptive method, information regarding all medications
being administered to the patient and their potential effect 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.
1. Unable or not willing to comply with the protocol regulations.
2. Any additional concurrent radiation therapy or chemotherapy (including but not limited
to temozolomide) 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, 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
8. Prior anthracycline cumulative dose more than 550 mg/m2.
9. Heart disease:
1. LVEF <50%
2. Unstable angina
3. Congestive heart failure with New York Heart Association classification of 3 or 4
4. Patients with baseline QT/QTc interval >480 msec, a history of additional risk
factors for torsades de pointes (eg, heart failure, hypokalemia, family history
of long QT syndrome) and using concomitant medications that significantly prolong
the QT/QTc interval
5. History of myocardial infarction within 12 months of enrollment
10. Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg and/or diastolic BP
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. 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.