Patients will be eligible for the study if they meet all of the following inclusion
criteria and none of the exclusion criteria.
Inclusion criteria. 1. Written informed consent from the patient or their legally authorized representative
(LAR) 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. KPS score of ≥ 60. 4. 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.
5. Recurrent or progressive GBM as evaluated by central review applying RANO criteria
on contrast MRI scans of the Baseline/Screening MRI scan obtained up to six weeks
prior to C1D1 and a historical scan taken before the Baseline/Screening scan that
meets at least 1 of the following criteria:
1. In the case of measurable disease, progression will be documented by ≥ 25%
increase in the sum of the perpendicular diameter products (SPDPs) of the
measurable contrast-enhancing (target) lesions or any new measurable lesions.
2. If the SPDPs cannot be reliably estimated due to the lesion's complex
conspicuity, shape, and contrast enhancement pattern, the volume of all
measurable and non-measurable lesions may be used instead, applying the same
threshold (≥ 25% increase) to confirm disease progression.
3. In the case of non-measurable lesions in the historical scan, any
transformation into measurable lesions (≥10 mm in both maximum perpendicular
diameters) in the Baseline/Screening scan will be evidence of progression.
4. If there are only non-measurable (non-target) lesions in the Baseline/Screening
scan, additional lesions/sites will be considered evidence of progression based
on the historical scan. Patients with new cerebrospinal fluid (CSF) seeding
will not be considered eligible.
5. If historical scans are unavailable, a radiology report of a scan taken before
the Baseline/Screening scan documenting the SPDPs from a previous scan of the
enhancing disease or its volume can be used by the central reviewer to assess
eligibility if it demonstrates the quality standards and acquisition guidelines
required.
6. If the scan obtained during standard of care (prior to initiation of formal
clinical screening and patient enrollment) is being used as the
Baseline/Screening scan and does not entirely conform to central reader quality
standards and acquisition guidelines (ie, artifacts or missing sequences), this
can be used for the purpose of inclusion if the central reader in discussion
with the sponsor and PI agree it provides evidence based on standard clinical
practices of recurrence or progression.
7. Patients at first progression who are treated by re-resection or biopsy to
confirm progression do not require measurable disease at their post-operative
screening scan as their Baseline/Screening scan. These patients must be
medically stable after the procedure as assessed by the PI and have the
Baseline/Screening scan available by 7 days before starting treatment.
6. The tumor is localized supratentorially with no leptomeningeal (local or distant),
spinal or CSF metastases, and no ventricular invasion (explicit documentation of the
disease progression that would be problematic in evaluating the efficacy of this
drug).
7. O[6] methylguanine-DNA methyltransferase (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). In addition, treatment with tumor treating fields (TTFields; Optune)
is acceptable if provided as first line therapy prior to progression or recurrence
of disease.
9. A second debulking surgery, additional radiation or gamma knife surgery during the
first line treatment or after progression, and for which the investigator does not
suspect pseudoprogression is acceptable, as long as no chemotherapy or immunotherapy
has been provided.
10. 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. 12 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 of chemotherapy. 3. 2 weeks from tumor biopsy if wound completely healed. 4. 4 weeks from any major surgery (maximal debulking surgery, either gross total
resection or partial resection), gamma knife surgery or significant traumatic
injury. Any surgery incisions or wounds must be completely healed. 11. 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.
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 (WBC) count ≥3 × 103/µL,
absolute neutrophil count (ANC) ≥1.5 × 10³/µL, platelet count ≥75 × 10³/µL,
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 (AST) and alanine aminotransferase (ALT) <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, estimated creatinine clearance of ≥60 mL/min, calculated
using the Cockcroft-Gault equation35. 4. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN. 13. Women 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 6.25 months after the last dose of study drug. Male study patients and their
female sexual partners of childbearing potential must agree to practice a highly
effective method of contraception starting from the time of informed consent until
at least 3.5 months (no less than 104 days) 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
test at Screening.
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 (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. Curatively
treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the
cervix, breast, or bladder; or prostate cancer as well as benign tumors that will
not interfere with the treatment plan at the time of screening are allowed.
Exclusion Criteria. 1. Unable or not willing to comply with the protocol regulations.
2. Any additional chemotherapy (including but not limited to TMZ or immunotherapy) for
recurrent or progressive GBM after a first line treatment.
3. Prior treatment with bevacizumab.
4. Prior treatment with lomustine.
5. Known to have an IDH mutation prior to enrollment. 6. Screening/Baseline MRI showing a mass effect defined as significant compression of
the ventricular system and/or a midline shift with associated clinical symptoms
deemed inappropriate for the patient to enter a clinical trial. If there is
otherwise asymptomatic compression and/or midline shift and the patient fulfills all
other criteria, these patients are considered eligible.
7. 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, adults protected by law or
altered mental status.
8. Presence of poorly controlled seizures, defined as occurring despite SOC or
requiring hospitalization.
9. Prior anthracycline cumulative dose more than 550 mg/m2.
10. Heart disease:
1. LVEF <50%
2. Unstable angina. 3. CHF with New York Heart Association (NYHA) classification of 3 or 4. 4. 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. 5. History of myocardial infarction within 12 months of enrollment. 6. Severe arrhythmia not controlled by medication. 11. Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg and/or diastolic
BP >100 mmHg) sustained over 2 measurements.
12. 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).
13. 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.
14. Women who are lactating or breastfeeding
