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A Multicenter, Study of the Safety and Pharmacokinetics of Intravenously Infused Berubicin in Pediatric Patients With Progressive, Refractory, or Recurrent High Grade Gliomas

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ClinicalTrials.gov Identifier: NCT05082493
Recruitment Status : Not yet recruiting
First Posted : October 19, 2021
Last Update Posted : July 15, 2022
Sponsor:
Collaborator:
Worldwide Clinical Trials
Information provided by (Responsible Party):
WPD Pharmaceuticals Sp. z o.o.

Brief Summary:
This is a Phase 1, multicenter, open-label, dose escalation study of intravenous Berubicin in pediatric patients. The purpose of this first-in-pediatrics study is to examine the safety, tolerability, and PK of Berubicin and to estimate its MTD and/or RP2D when administered to pediatric patients with progressive, refractory, or recurrent HGG who have completed at least 1 standard line of therapy. This study will also make a preliminary assessment of the antitumor activity of Berubicin in this patient population. An exploratory evaluation of quality of life will also be performed

Condition or disease Intervention/treatment Phase
High Grade Glioma Drug: Berubicin Hydrochloride Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This is a Phase 1, multicenter, open-label, dose escalation study of intravenous Berubicin in pediatric patients. The purpose of this first-in-pediatrics study is to examine the safety, tolerability, and PK of Berubicin and to estimate its MTD and/or RP2D when administered to pediatric patients with progressive, refractory, or recurrent HGG who have completed at least 1 standard line of therapy. This study will also make a preliminary assessment of the antitumor activity of Berubicin in this patient population. An exploratory evaluation of quality of life will also be performed
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Multicenter, Open-label, Dose Escalation Study of the Safety and Pharmacokinetics of Intravenously Infused Berubicin in Pediatric Patients With Progressive, Refractory, or Recurrent High Grade Gliomas
Estimated Study Start Date : September 2022
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Berubicin HCL - MTD phase
Berubicin will be administered as 1-hour infusions each day for 3 consecutive days followed by 18 days off drug (ie, 21-day cycles). The starting dose is based on population PK modeling of data from adult studies and will be 1.20 mg/m2 (Dose Level 1). During the study, PK data will be incorporated into a PK model on an ongoing basis and may be used to inform dose escalation decisions
Drug: Berubicin Hydrochloride
Berubicin will be administered as 1-hour infusions each day for 3 consecutive days followed by 18 days off drug (ie, 21-day cycles). The starting dose is based on population PK modeling of data from adult studies and will be 1.20 mg/m2 (Dose Level 1). During the study, PK data will be incorporated into a PK model on an ongoing basis and may be used to inform dose escalation decisions




Primary Outcome Measures :
  1. • Dose Escalation Cohorts first outcome [ Time Frame: 6 months ]

    To estimate the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of single-agent Berubicin administered after at least 1 prior line of therapy in pediatric patients with progressive, refractory, or recurrent HGG.

    To completely document the assessment of response, the measurements of the longest tumor dimension, and its perpendicular, of all target lesions should be recorded for the baseline and all subsequent follow-up exams. Changes in nontarget lesions and newly occurring lesions should also be described. The same method of assessment and the same technique should be used at baseline and during follow-up.


  2. • Dose Escalation Cohorts second outcome [ Time Frame: 6 months ]

    To estimate the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of single-agent Berubicin administered after at least 1 prior line of therapy in pediatric patients with progressive, refractory, or recurrent HGG.

    Tumor response criteria are determined by changes in size using the longest tumor dimension and its perpendicular. If multiple measurable lesions are present, a minimum of the 2 largest lesions should be measured; a maximum of 5 should be selected as target lesions. Target lesions should be selected on the basis of size and suitability for accurate repeated measurements. All other lesions will be followed as nontarget lesions. Only solid components of cystic/necrotic tumors should be measured.


  3. • Expansion Cohort first outcome [ Time Frame: 6 months ]
    To evaluate the safety of Berubicin administered at the MTD or RP2D to pediatric patients with progressive, refractory, or recurrent HGG who have completed at least 1 prior line of therapy The MTD is empirically defined as the highest dose level at which 6 patients have been treated with at most 1 patient experiencing a DLT and the next higher dose level has been determined to be not tolerated (≥2 out of 6 patients experience a DLT). The MTD estimation will be limited to evaluable patients and toxicity assessments from the first cycle of Berubicin treatment (21 days).

  4. • Expansion Cohort second outcome [ Time Frame: 6 months ]
    To evaluate the safety of Berubicin administered at the MTD or RP2D to pediatric patients with progressive, refractory, or recurrent HGG who have completed at least 1 prior line of therapy The RP2D is a multifactorial endpoint that considers toxicity as well as additional determinants (eg, efficacy, pharmacodynamics) to define the optimal Phase 2 dose on the basis of available clinical safety and efficacy data. It is usually a dose in which there is ≤20% dose-limiting toxicity; however, it can be further defined by exploration of doses that maximize efficacy in the presence of minimal safety concerns.



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Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1. Written informed consent of the patient's LAR, and assent when appropriate based on the patient's age and institutional guidelines, prior to any study-related procedure.

    2. Patients must have progressive, refractory, or recurrent HGG (WHO Grade III or IV).

    3. Age ≥2 to <18 years at the time of the first Berubicin dose. 4. Performance status score ≥50 (Lansky for research patients aged ≤16 years and Karnofsky for patients ˃16 years). Patients who are unable to walk because of paralysis but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score.

    5. Patients must have completed at least 1 line of prior therapy. 6. Before the projected start of scheduled study treatment, the following time periods must have elapsed:

    1. 5 half-lives from any investigational agent.
    2. 4 weeks from cytotoxic therapy (except 23 days from temozolomide and 6 weeks from nitrosoureas).
    3. 6 weeks from antibody therapies.
    4. 4 weeks (or 5 half-lives, whichever is shorter) from other antitumor therapies.
    5. Patients who have received radiation therapy must be ≥6 weeks post the completion of local palliative radiation therapy (re-irradiation for progressive disease or upfront radiation therapy at initial diagnosis).

      7. Adequate organ function defined as:

    a. Bone marrow: i. Peripheral absolute neutrophil count ≥1000/mm3 ii. Hemoglobin ≥8 g/dL (may have received packed red blood cell transfusion) iii. Platelet count ≥100,000/mm3 (transfusion-independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) b. Renal function: i. Creatinine clearance or radioisotope glomerular filtration rate ≥70 mL/min/1.73 m2 or normal serum creatinine based on age c. Hepatic function: i. Total bilirubin (sum of conjugated + unconjugated) ≤1.5 × the upper limit of normal (ULN) for the institution ii. Alanine aminotransferase ≤3 × ULN for the institution iii. Serum albumin ≥2 g/dL d. Neurologic function: i. Patients with seizure disorder may be enrolled if the seizure disorder is well controlled, as determined by the investigator.

    e. Cardiac function (left ventricular ejection fraction [LVEF]): i. Fractional shortening ≥27% or LVEF ≥50% by echocardiogram or multigated radionuclide study (MUGA) 8. All adverse events (AEs) Grade >1 related to prior therapies (chemotherapy, radiation therapy, and/or surgery) must be resolved to Grade 1 or baseline level, except for alopecia and sensory neuropathy Grade ≤2 or other Grade ≤2 AEs not constituting a safety risk based on the investigator's judgment.

    9. For postpubertal patients: Female patients must agree to use highly effective contraception during the period of the study and for at least 90 days after completion of treatment. Male patients must be surgically sterile or must agree to use highly effective contraception during the period of the study and for at least 3,5 months (no less than 104 days) after completion of treatment. Details are provided in the full protocol.

    10. Female patients of childbearing potential aged 10 years or older must have a negative serum or urine pregnancy test.

    11. MRI of the brain and entire spine (including all sites of disease), within 10 days prior to start of study drug.

    12. Corticosteroid dose must be stable or decreasing for at least 5 days prior to the baseline MRI scan.

Exclusion Criteria:

  • 1. Evidence of diffuse leptomeningeal disease or evidence of cerebrospinal fluid (CSF) dissemination.

    2. Known additional malignancy that is progressing or has required active treatment within 3 years of start of study drug.

    3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Berubicin or its excipients.

    4. Patients with any clinically significant, unrelated systemic illness (eg, significant pulmonary, hepatic [including Gilbert's syndrome], or other organ dysfunction) or psychiatric illness/social situations that would compromise the patient's ability to tolerate the study drug or study procedures or would likely interfere with the study procedures or results.

    5. Any known clinically significant active bacterial, fungal, or viral infection including hepatitis B or hepatitis C, or any underlying disease in the recent past that could compromise enrollment and the safety of the patient.

    6. Patient with a history of clinically significant, uncontrolled heart disease and/or repolarization abnormalities as documented by a standard 12 lead electrocardiogram (ECG).

    7. Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias, or bradycardia, unless arrhythmia is controlled and after a cardiology consultation has cleared the patient to receive Berubicin. Patients receiving therapeutic agents known to prolong QT interval will be excluded; however, the use of ondansetron is permitted. Patients with a history of congestive heart failure, myocardial infarction, or stroke in the last 3 months will be excluded.

    8. Congenital long QT syndrome or QTc >460 ms. 9. Patients receiving any other anticancer or investigational drug therapy. 10. Prior treatment with bevacizumab. 11. Current or planned participation in a study of another investigational agent or using an investigational device.

    12. Requirement for cytochrome P450 3A4 (CYP3A4)-inducing or inhibiting agents, with the exception of corticosteroids.

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Responsible Party: WPD Pharmaceuticals Sp. z o.o.
ClinicalTrials.gov Identifier: NCT05082493    
Other Study ID Numbers: WPD-201P
First Posted: October 19, 2021    Key Record Dates
Last Update Posted: July 15, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue