Evaluation of Berubicin Hydrochloride Versus Lomustine in Adult Patients with Recurrent Glioblastoma Multiforme Post-Standard Therapy Failure

Trial ID: 2024-517660-27-00
Protocol: CNS-201
Sponsor: Cns Pharmaceuticals Inc.

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Diseases & Conditions

Glioblastoma multiforme

Objectives

The primary objective of this study is to evaluate the effect of **Berubicin** compared with Lomustine on overall survival (OS) in adult patients with recurrent or progressive **glioblastoma multiforme (GBM)** after standard initial therapy. This is clinically relevant as it aims to determine the potential of Berubicin to improve survival outcomes in a patient population with limited treatment options following the failure of first-line therapy.

Secondary objectives include:

Assessing the effect of Berubicin on progression-free survival (PFS) according to Response Assessment in Neuro-Oncology (RANO) criteria, which is defined as the time from randomization to disease progression or death.
Evaluating the effect of Berubicin on event-free survival (EFS), defined as the time from randomization to disease progression, death, or treatment discontinuation for any reason.
Determining the effect of Berubicin on objective response rates (ORR) and disease control rates (DCR) per RANO criteria in adult patients with GBM.
Assessing the safety of the recommended Phase 2 dose (RP2D) of Berubicin, focusing on the incidence and severity of adverse events (AEs) as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5.0.
Confirming the pharmacokinetics (PK) of Berubicin and its metabolite, berubicinol.

Participants

The clinical trial involves a total of **202 participants** diagnosed with **glioblastoma multiforme (GBM)**, a highly aggressive brain tumor. The study population includes both male and female adults, aged 18 years and older, who have experienced recurrence or progression of GBM following standard initial therapy. Participants were selected based on specific criteria, including a confirmed diagnosis of GBM and a Karnofsky Performance Status (KPS) score of 60 or higher, indicating they are capable of self-care and able to carry out normal activities. The trial does not exclude based on gender, and both male and female subjects are included. Participants are required to have adequate bone marrow and organ function, and must not have received more than one prior line of treatment. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial population includes individuals who are considered vulnerable, reflecting the serious nature of the disease being studied.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy, safety, and pharmacokinetics of **Berubicin hydrochloride** in adult patients with recurrent **glioblastoma multiforme** (GBM) following the failure of standard first-line therapy. This is a multicenter, open-label study with a randomized control arm, comparing the effects of Berubicin with **Lomustine**. The trial is expected to run from June 9, 2023, to December 4, 2024, with recruitment having started on June 15, 2023, and ending on January 16, 2024. The estimated end date for the trial is January 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, prior treatment history, and current health status. The primary endpoint is overall survival (OS), defined as the time from randomization until death. Secondary endpoints include progression-free survival (PFS), event-free survival (EFS), overall response rate (ORR), and disease control rate (DCR), all assessed using MRI scans and RANO criteria.

Study visits will include regular follow-up assessments to monitor the patient's response to treatment and any adverse effects. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants are expected to be involved in the study for a maximum treatment period of 13 to 18 months, depending on the assigned treatment arm. Conditions that may lead to early termination from the study include significant adverse reactions, disease progression, or withdrawal of consent.

The trial employs a rigorous methodology to ensure the reliability of results, with randomization and control measures in place to minimize bias. The study is not classified as low intervention and is categorized as a Phase II trial. Participants will receive either Berubicin via intravenous infusion or Lomustine orally, with dosages and treatment schedules tailored to maximize therapeutic outcomes while minimizing risks.

Treatment

The clinical trial involves the administration of **Berubicin hydrochloride**, an experimental medication, in the form of a **solution for infusion**. This pharmaceutical product is developed by CNS Pharmaceuticals, Inc. and is identified by the sponsor product code WP 744. The active substance, **berubicin hydrochloride**, is of chemical origin. The medication is administered via **intravenous use**. The dosing regimen specifies a maximum daily dose of 7.1 mg/m², with a total maximum dose of 21.3 mg/m² over a treatment period of up to 13 weeks. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The comparator treatment in this study is **Cecenu® 40 mg Kapsel**, which contains the active substance **lomustine**. This medication is provided in the form of a **hard capsule** and is manufactured by MEDAC Gesellschaft für klinische Spezialpräparate mbH (Wedel). **Lomustine** is also of chemical origin and is administered orally. The dosing schedule for lomustine involves a maximum daily dose of 130 mg/m², with a total maximum dose of 130 mg/m² over a treatment period of up to 18 weeks. As with the experimental treatment, participant adherence to the dosing regimen is closely monitored to ensure protocol compliance.

Efficacy

Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoint is overall survival (OS), defined as the time from randomization until death. Secondary endpoints include progression-free survival (PFS), event-free survival (EFS), overall response rate (ORR), and disease control rate (DCR). PFS is defined as the length of time from randomization to disease progression based on MRI scan or death, whichever occurs first. EFS is defined as the time from randomization to disease progression, death, or discontinuation of treatment for any reason, such as toxicity or intolerance. ORR is defined as the sum of complete response (CR) and partial response (PR) according to the RANO criteria. DCR includes CR, PR, and stable disease (SD), with SD defined as the lack of progression based on MRI scans obtained at specified intervals after therapy initiation.

The efficacy parameters will be measured and collected at various timepoints throughout the trial. MRI scans will be utilized to assess disease progression and response to treatment, following the RANO criteria. The analysis of these endpoints will provide insights into the efficacy of Berubicin compared to Lomustine in adult patients with recurrent **Glioblastoma Multiforme** after the failure of standard first-line therapy. The trial is designed to ensure rigorous evaluation of the treatment's impact on survival and disease progression, contributing to the understanding of its potential benefits in this patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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
Women of childbearing potential must consent to practicing a highly effective method of contraception beginning from the time of consent or 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 must consent 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. 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 at screening. c. A highly effective method of birth control is defined as one which results in a low failure rate (i.e., 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.
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 as well as benign tumors that will not interfere with the treatment plan at the time of screening are allowed.
At least 18 years of age.
KPS score ≥ 60.
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.
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 (CCI) weeks prior to C(CCI) D(CCI) and a historical scan taken before the baseline/screening scan that meets at least 1 of the following criteria (except in the case of re-resection or recent biopsy, see #5g below)a. 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. b. 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 lesion´s may be used instead, applying the same threshold (≥ 25% increase) to confirm disease progression. c. 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.d. 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. e.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 and the patient agrees to its proposed use for the study. f. If the scan obtained during standard of care (SOC, prior to initiation of formal clinical screening and patient enrollment) or radiology report is being used as the baseline/screening and/or historical scan and does not entirely conform to central reader quality standards and acquisition guidelines (i.e., artifacts or missing sequences), this can be used for the purpose of inclusion if the central reader in discussion with the Sponsor and Principal Investigator (PI) agree it provides evidence based on standard clinical practices of recurrence or progression and the patient consents to its proposed use for the study. g. Patients at first progression who are treated by re-resection or biopsy require 3 scans submitted for central review for eligibility: one from a previous (historical) scan before progression, one scan performed after the historical scan but immediately prior to any invasive procedure showing progression (after progression and before the procedure) in which it is clearly documented that there is progression of disease, and 1 after the procedure within (CCI) days and available by 7 days prior to C(CCI) D(CCI) (baseline). All lesions must be considered maximally recovered and the patient must be medically stable after the procedure as assessed by the PI.
The tumor is localized supratentorially with no clinical evidence of 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).
(CCI) must be available; results of routinely used methods (CCI) are acceptable.
No more than 1 prior line of treatment (e.g., surgery followed by radiation with concomitant chemotherapy, followed by adjuvant chemotherapy is considered as 1 line of treatment). In addition, treatment with TumorTreating Fields (TTFields; Optune) is acceptable if provided as first line therapy prior to progression or recurrence of disease.
A second debulking surgery, additional radiation or gamma knife surgery during the first line of 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
Recovery from toxicity/side effects of all prior therapy to Grade 1 or less except for alopecia; The following time intervals from previous treatments are approximate and subject to the investigator’s discretion: a. 12 weeks from the completion of radiation (to reduce the risk of pseudoprogression unless progression is confirmed by biopsy)
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. Prior bevacizumab is not allowed.
Eligible for chemotherapy based on adequate bone marrow function and organ function as defined by the following laboratory guidelines within the screening period, subject to the investigator’s discretion a. 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 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 (ALP) ≤ 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 equation d. Activated partial thromboplastin (aPTT) time ≤ 1.5 × ULN

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Exclusion Criteria

Unable or not willing to comply with the protocol regulations.
Any additional chemotherapy (including but not limited to temozolomide or immunotherapy) for recurrent or progressive GBM after a first line treatment.
Prior treatment with bevacizumab
Prior treatment with Lomustine.
Known to have an isocitrate dehydrogenase (IDH) mutation prior to enrollment
Screening/baseline MRI showing a mass effect defined as significant compression of the ventricular system and/or 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.
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
Presence of poorly controlled seizures, defined as occurring despite SOC or requiring hospitalization
Prior anthracycline cumulative dose more than 550 mg/m2 . Further information is presented in Appendix 2
Heart disease: a. Left ventricular ejection fraction (LVEF) < 50% b. Unstable angina c. Congestive heart failure with New York Heart Association classification of 3 or 4 d. Patients with baseline QT/QTc interval > 480 msec, a history of additional risk factors for torsades de pointes (e.g., 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 f. Severe arrhythmia not controlled by medication
Uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg and/or diastolic BP > 100 mmHg) sustained over 2 measurements.
Known to be positive for hepatitis B virus surface antigen, hepatitis C virus, human immunodeficiency virus, coronavirus disease-2019 (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).
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.
Women who are pregnant, lactating or breastfeeding