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A Study of Berubicin in Adult Subjects With Recurrent Glioblastoma Multiforme

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ClinicalTrials.gov Identifier: NCT04762069
Recruitment Status : Recruiting
First Posted : February 21, 2021
Last Update Posted : November 23, 2021
Sponsor:
Collaborator:
Worldwide Clinical Trials
Information provided by (Responsible Party):
CNS Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE November 11, 2020
First Posted Date  ICMJE February 21, 2021
Last Update Posted Date November 23, 2021
Actual Study Start Date  ICMJE May 18, 2021
Estimated Primary Completion Date October 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 16, 2021)
Overall Survival [ Time Frame: Through study completion an average of 4 years. ]
To assess the effect of berubicin compared with lomustine on overall survival (OS) in adult patients with GBM (WHO Grade IV) that has recurred after standard initial therapy
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 30, 2021)
  • Progression Free Survival [ Time Frame: Through study completion an average of 4 years. ]
    To assess the effect of berubicin on progression free survival per Response Assessment in Neuro-Oncology (RANO) criteria in patients with GBM after failure of standard first line therapy
  • Event Free Survival [ Time Frame: Through study completion an average of 4 years. ]
    To assess the effect of berubicin on event free survival (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)
  • Overall Response Rate [ Time Frame: Through study completion an average of 4 years. ]
    To assess the effect of berubicin on overall response rates (ORR) in adult patients with GBM after failure of standard first line therapy
  • Safety of the Recommended Phase 2 Dose of Berubicin [ Time Frame: From signing of informed consent until until 28 days after the last dose of berubicin and 42 days after the last dose of lomustine, or until the patient receives any additional therapy for their disease (whichever comes first). ]
    To assess the safety of the recommended Phase 2 dose of berubicin 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.
  • Plasma Pharmacokinetics Cmax [ Time Frame: Through study completion an average of 4 years. ]
    Maximum plasma concentration of Berubicin
  • Plasma Pharmacokinetics tmax [ Time Frame: Through study completion an average of 4 years. ]
    Time from each dose to reach the maximum plasma concentration
  • Plasma Pharmacokinetics AUC0-tau [ Time Frame: Through study completion an average of 4 years. ]
    Area under the plasma concentration-time curve from time 0 to Tau, where Tau is the dosing interval, calculated by the linear up/ linear down trapezoidal method
  • Plasma Pharmacokinetics AUC0-last [ Time Frame: Through study completion an average of 4 years. ]
    Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration calculated by the linear up/log linear down trapezoidal method
  • Plasma Pharmacokinetics AUC0-∞ [ Time Frame: Through study completion an average of 4 years. ]
    Area under the plasma concentration-time curve from time 0 to infinite time, calculated as the sum of AUC0-last and Clast/λz, where Clast is the last observed quantifiable concentration
  • Plasma Pharmacokinetics t1/2 [ Time Frame: Through study completion an average of 4 years. ]
    elimination half-life associated with the terminal slope (λz) of the log-linear drug concentration-time curve, calculated as ln(2)/λz
  • Plasma Pharmacokinetics CL [ Time Frame: Through study completion an average of 4 years. ]
    apparent total body clearance
  • Plasma Pharmacokinetics Vz [ Time Frame: Through study completion an average of 4 years. ]
    apparent volume of distribution
  • Plasma Pharmacokinetics Css [ Time Frame: Through study completion an average of 4 years. ]
    Average concentration, calculated as the geometric mean of concentrations over the 72-hour dosing interval
  • Plasma Pharmacokinetics Rac [ Time Frame: Through study completion an average of 4 years. ]
    The accumulation ratio calculated as AUC0-tau (3rd dose) / AUC0-tau (1st dose)
Original Secondary Outcome Measures  ICMJE
 (submitted: February 16, 2021)
  • Progression Free Survival [ Time Frame: 6-month progression free survival from date of initial infusion of Berubicin ]
    To assess the effect of berubicin on progression free survival at 6 months (PFS6) per Response Assessment in Neuro-Oncology (RANO) criteria in patients with GBM after failure of standard first line therapy
  • Event Free Survival [ Time Frame: Through study completion an average of 4 years. ]
    To assess the effect of berubicin on event free survival (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)
  • Overall Response Rate [ Time Frame: Through study completion an average of 4 years. ]
    To assess the effect of berubicin on overall response rates (ORR) in adult patients with GBM after failure of standard first line therapy
  • Compare RANO to mRANO Criteria for Response and Progression Outcomes [ Time Frame: Through study completion an average of 4 years. ]
    To compare RANO to modified RANO (m-RANO) criteria for response and progression outcomes for berubicin versus lomustine (an anthracycline versus an alkylating agent) for the treatment of adult patients with GBM after failure of standard first line therapy
  • Safety of the Recommended Phase 2 Dose of Berubicin [ Time Frame: From signing of informed consent until until 28 days after the last dose of berubicin and 42 days after the last dose of lomustine, or until the patient receives any additional therapy for their disease (whichever comes first). ]
    To assess the safety of the recommended Phase 2 dose of berubicin 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.
  • Plasma Pharmacokinetics Cmax [ Time Frame: Through study completion an average of 4 years. ]
    Maximum plasma concentration of Berubicin
  • Plasma Pharmacokinetics tmax [ Time Frame: Through study completion an average of 4 years. ]
    Time from each dose to reach the maximum plasma concentration
  • Plasma Pharmacokinetics AUC0-tau [ Time Frame: Through study completion an average of 4 years. ]
    Area under the plasma concentration-time curve from time 0 to Tau, where Tau is the dosing interval, calculated by the linear up/ linear down trapezoidal method
  • Plasma Pharmacokinetics AUC0-last [ Time Frame: Through study completion an average of 4 years. ]
    Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration calculated by the linear up/log linear down trapezoidal method
  • Plasma Pharmacokinetics AUC0-∞ [ Time Frame: Through study completion an average of 4 years. ]
    Area under the plasma concentration-time curve from time 0 to infinite time, calculated as the sum of AUC0-last and Clast/λz, where Clast is the last observed quantifiable concentration
  • Plasma Pharmacokinetics t1/2 [ Time Frame: Through study completion an average of 4 years. ]
    elimination half-life associated with the terminal slope (λz) of the log-linear drug concentration-time curve, calculated as ln(2)/λz
  • Plasma Pharmacokinetics CL [ Time Frame: Through study completion an average of 4 years. ]
    apparent total body clearance
  • Plasma Pharmacokinetics Vz [ Time Frame: Through study completion an average of 4 years. ]
    apparent volume of distribution
  • Plasma Pharmacokinetics Css [ Time Frame: Through study completion an average of 4 years. ]
    Average concentration, calculated as the geometric mean of concentrations over the 72-hour dosing interval
  • Plasma Pharmacokinetics Rac [ Time Frame: Through study completion an average of 4 years. ]
    The accumulation ratio calculated as AUC0-tau (3rd dose) / AUC0-tau (1st dose)
Current Other Pre-specified Outcome Measures
 (submitted: July 30, 2021)
Compare RANO to mRANO Criteria for Response and Progression Outcomes [ Time Frame: Through study completion an average of 4 years. ]
To compare RANO to modified RANO (m-RANO) criteria for response and progression outcomes for berubicin versus lomustine (an anthracycline versus an alkylating agent) for the treatment of adult patients with GBM after failure of standard first line therapy
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Berubicin in Adult Subjects With Recurrent Glioblastoma Multiforme
Official Title  ICMJE A Multicenter, Open-Label Study With a Randomized Control Arm of the Efficacy, Safety, and Pharmacokinetics of Intravenously Infused Berubicin in Adult Patients With Recurrent Glioblastoma Multiforme (WHO Grade IV) After Failure of Standard First Line Therapy
Brief Summary

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.

Detailed Description Berubicin is one of the first anthracyclines that crosses the blood brain barrier and overcomes drug resistance (i.e. it is not a substrate for multi-drug resistant/breast cancer resistant transporters). A Phase 1 clinical trial of berubicin in patients with primary CNS malignancies demonstrated a durable response (one subject alive 13+ years) as well as stable disease in heavily pretreated patients. Therefore, this phase 2 study is designed to further evaluate Berubicin's activity in patients with rGBM after treatment with standard of care.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Open-Label Study with a Randomized Control Arm
Masking: Single (Outcomes Assessor)
Masking Description:
Response and progression outcomes are evaluated by a blinded central reviewer for each patient according to RANO criteria
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma Multiforme, Adult
Intervention  ICMJE
  • Drug: Berubicin
    Berubicin HCl is a novel synthetic anthracycline with a chemical structure similar to doxorubicin HCl, a cytotoxic anthracycline topoisomerase II inhibitor isolated from cultures of Streptomyces peucetius var. caesius.
    Other Name: Berubicin Hydrochloride
  • Drug: Lomustine
    Lomustine is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. This medication is classified as an "alkylating agent.
    Other Names:
    • Lomustine Capsules
    • CCNU
    • CeeNU
    • Gleostine
Study Arms  ICMJE
  • Experimental: Berubicin

    Berubicin intravenously infused will be administered at a dose of 7.1 mg/m2 as free base as a 2 hour intravenous (IV) infusion once daily for 3 consecutive days followed by 18 days off study drug (each cycle = 21 days)

    Each treatment cycle is 21 days. Subjects will be allowed to continue on treatment at the discretion of the Investigator if there is no evidence of disease progression and the subject is not experiencing unacceptable toxicity as well as if both the subject and Investigator agree that further therapy is in the subject's best interest.

    Intervention: Drug: Berubicin
  • Active Comparator: Lomustine (CCNU, CeeNU®, or Gleostine®) capsules
    Lomustine (CCNU, CeeNU®, or Gleostine®) capsules will be administered at the institutionally-approved dose and regimen or per the full prescribing information/summary of product characteristics.
    Intervention: Drug: Lomustine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 16, 2021)
210
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2025
Estimated Primary Completion Date October 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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 test.
    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.

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 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 hospitalization.
  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 >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. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Zena Muzyczenko 800-946-9185 clinicaltrials@cnspharma.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04762069
Other Study ID Numbers  ICMJE CNS-201
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Study data will be shared with WPD Pharmaceuticals, Inc., sub-licensee of Berubicin.
Responsible Party CNS Pharmaceuticals, Inc.
Study Sponsor  ICMJE CNS Pharmaceuticals, Inc.
Collaborators  ICMJE Worldwide Clinical Trials
Investigators  ICMJE
Study Chair: Sandra Silberman, MD, PhD CNS Pharmaceuticals, Inc.
PRS Account CNS Pharmaceuticals, Inc.
Verification Date November 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP