A study of Berubicin in Adult Patients with Recurrent Glioblastoma Multiforme

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cns Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Sep 2022 → 28 Apr 2026

Decision date (initial)

2024-10-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-517660-27-00

EudraCT number

2021-003659-40

ClinicalTrials.gov

NCT04762069

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

To assess the effect of Berubicin compared with Lomustine on OS in adult patients with GBM that has recurred or progressed after standard initial therapy

Secondary objectives 5

1. To assess the effect of Berubicin on progression-free survival (PFS) per Response Assessment in Neuro-Oncology (RANO) criteria in patients with GBM after failure of standard first line therapy, defined as the length of time from randomization to objective disease progression or death, whichever occurs first.
2. To assess the effect of Berubicin on event free survival (EFS) defined as the length of time from randomization to disease progression, death, or discontinuation of treatment for any reason (e.g., toxicity, intolerance, disease-related conditions, or failure to respond)
3. To assess the effect of Berubicin on objective response rates (ORR) defined as complete and partial responses (CR + PR, respectively) as well as disease control rates (DCR) defined as CR + PR + SD per RANO criteria in adult patients with GBM after failure of standard first line therapy
4. To assess the safety of the recommended Phase 2 dose (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 adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5.0
5. To confirm the pharmacokinetics (PK) of Berubicin and its metabolite, berubicinol.

Conditions and MedDRA coding

Glioblastoma multiforme (GBM)

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

IPD plan description

Study data will be shared with WPD Pharmaceuticals, INC, sub-licensee of Berubicin

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 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. 13. 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.
3. 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 as well as benign tumors that will not interfere with the treatment plan at the time of screening are allowed.
4. 2. At least 18 years of age.
5. 3. KPS score ≥ 60.
6. 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.
7. 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 (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.
8. 6. 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).
9. 7. (CCI) must be available; results of routinely used methods (CCI) are acceptable.
10. 8. 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.
11. 9. 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
12. 10. 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)
13. 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. Prior bevacizumab is not allowed.
14. 12. 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

Exclusion criteria 14

1. Unable or not willing to comply with the protocol regulations.
2. Any additional chemotherapy (including but not limited to temozolomide 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 isocitrate dehydrogenase (IDH) mutation prior to enrollment
6. 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.
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 . Further information is presented in Appendix 2
10. 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
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, 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).
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 pregnant, lactating or breastfeeding

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. OS defined as the time from randomization until death.

Secondary endpoints 4

1. PFS, defined as the length of time from randomization to disease progression based on MRI scan or death, whichever occurs first.
2. EFS, defined as the length of time from randomization to disease progression, death, or discontinuation of treatment for any reason (e.g., toxicity, intolerance, disease-related conditions, or failure to respond)
3. ORR, defined as CR + PR per RANO criteria
4. DCR, defined as CR + PR + SD per RANO criteria; SD is defined as lack of progression of disease based on MRI scan obtained at least (CCI) weeks after initiation of therapy

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cns Pharmaceuticals Inc.

Sponsor organisation

Cns Pharmaceuticals Inc.

Address

2100 West Loop South Suite 900

City

Houston

Postcode

77027-3522

Country

United States

Scientific contact point

Organisation

Cns Pharmaceuticals Inc.

Contact name

Sandra Silberman, MD, PhD

Public contact point

Organisation

Cns Pharmaceuticals Inc.

Contact name

Zena Muzyczenko

Third parties 5

Locations

3 EU/EEA countries · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications