A Dose Escalation Phase I Study Of Human- Recombinant Bone Morphogenetic Protein 4 Administrated Via CED In GBM Patients

NCT02869243 | Completed Phase 1 DMC

• 1 other identifier: hrBMP4-001
• Study Type: interventional
• Target: 15
• Locations: 3 countries
• Sites: 4

Brief Summary

The purpose of the study is to evaluate the feasibility and safety of intra-tumor and interstitial therapy with hBMP4 in increasing doses in patients with progressive and/or multiple recurrent Glioblastoma multiforme (GBM).

Conditions

Glioblastoma

Keywords

A malignant growing astrocytoma of central nervous system

Outcome Measures

Primary Outcomes (1)

• DLTs

  Number of patients who experienced Dose-Limiting Toxicities. DLT is collected to determine Maximum-Tolerated Dose (MTD)

  Up to 8 Weeks after each cohort of 3 patients

Secondary Outcomes (8)

• Tumor response

  Within 28 days before resection, intraoperative, up to 24 hours post start infusion, after 4-6 days post start infusion (end of infusion) and 4, 12, 24, 36, 48 and 52 weeks after hospitalization

• EORTC QLQ-C30 Summary Score

  After 4-6 days post start infusion (end of infusion) and during 4,8,12 and 52 weeks after hospitalization

• Maximum observed plasma concentration of BMP4 (Cmax)

  Prior to the infusion, after 4-6 days post start infusion (end of infusion) and 4 weeks after hospitalization

• Lowest concentration of BMP4 in the blood (Ctrough)

  Prior to the infusion, after 4-6 days post start infusion (end of infusion) and 4 weeks after hospitalization

• Area under the curve (AUC∞)

  Prior to the infusion, after 4-6 days post start infusion (end of infusion) and 4 weeks after hospitalization

Study Arms (1)

hrBMP4

EXPERIMENTAL

Intra-tumour and interstitial convection enhanced delivery (CED) as a continuous infusion via intracranial catheters of hrBMP4 solution and gadolinium

Drug: hrBMP4

Interventions

hrBMP4 DRUG

Patients will undergo a resection or biopsy of the tumour, confirmation of viable malignant glioma tumour cells and intratumour/interstitial placement under neuronavigational guidance of 2 or 3 catheters. Catheters will be placed during a second procedure a few days later based upon the patient's condition. Patients will receive intra-tumour and interstitial CED of increasing amounts of hrBMP4 solutions (starting dose of 0.5 mg) and 1:70 gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) in a total of 44-66ml over up to 4-6 days. Gd-DTPA will be co-infused with BMP4 to determine the extent of intra-tumour and interstitial drug delivery. HrBMP4 will be delivered as a continuous infusion via the intracranial catheters.

Also known as: Recombinant Bone Morphogenic Protein-4, Device:Intracranial Catheter

hrBMP4

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Malignant glioma (WHO grade III or IV) who have undergone conventional treatment, including surgery (gross total resection or unintentional partial resection with residual tumour) or biopsy (with residual tumour), and/or radiation therapy, and/or chemotherapy, and/or Temozolomide and have progressive and/or multiple recurrent GBM. Preoperative assessment by clinical presentation and CT/MRI appearance of the lesion will identify suitable candidates.
• Age 18-75 years.
• Karnofsky \>70 (see APPENDIX C: EXAMPLE OF PERFORMANCE STATUS: KARNOFSKY SCALE).
• Stable dose of corticosteroids no longer than 4 weeks prior to enrolment.
• Females of childbearing potential must have a negative serum or urine pregnancy test.
• Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential.
• Females of childbearing potential and males who have not undergone surgical sterilization must agree to practice a form of effective contraception prior to entry into the study and for 1 month after the end of infusion.
• Effective contraception:
• If female, is non-lactating, has a negative urine pregnancy test result, and does not plan on becoming pregnant during the study, or not of childbearing potential (hysterectomy or tubal ligation at least 6 months prior to entry to the study or post-menopausal for 1 year); if of childbearing potential (including peri-menopausal women who have had a menstrual period within one year) must practice or be willing to continue to practice acceptable birth control from screening and until 1 month after the study medication has been discontinued.
• Acceptable birth control includes:
• Combined (oestrogen and progestogen containing) hormonal contraception;
• Associated with inhibition of ovulation; oral OR intravaginal OR transdermal;
• Progestogen-only hormonal contraception associated with inhibition of ovulation: oral OR injectable OR implantable;
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action;
• Intrauterine device (IUD);

You may not qualify if:

• Patients who had chemotherapy, radiotherapy or other anti-neoplastic therapy (within 4 weeks or 5x half-life whichever is shorter) prior to study treatment or those who have not recovered to Grade ≤1 or returned to baseline from any acute treatment-related toxicities of the previous therapy except for alopecia and Grade 2 neuropathy.
• Patients who are receiving any other investigational agents.
• Life expectancy \<3 months
• Haematological dysfunction defined as:
• White blood cell (WBC) count \<3.0 x 109/L;
• Absolute neutrophil count \<1.5 x 109/L;
• Haemoglobin level \<10.0 g/dL;
• Platelet count \<100 x 109/L.
• Liver dysfunction defined as:
• Aspartate transaminase (AST) \>2.5 x the upper limit of normal (ULN) for age and gender;
• Alanine transaminase (ALT) \>2.5 x the ULN for age and gender;
• Bilirubin \>1.5 x the ULN for age and gender.
• Renal dysfunction defined as:
• \- Creatinine clearance \<60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal for age and gender.
• Serology indicating active infection with Hepatitis B or C, or HIV.

Sponsors & Collaborators

• Stemgen: lead
• ORION Clinical Services: collaborator

Study Sites (4)

Tel Aviv Sourasky Medical Center

Tel Aviv, Israel

Location

Istituto Neurologico Carlo Besta

Milan, 20133, Italy

Location

VU University Medical Center

Amsterdam, 1081 HV, Netherlands

Location

Erasmus University Medical Center, Department of Neurosurgery

Rotterdam, 3015 GD, Netherlands

Location

Related Publications (1)

• Bos EM, Binda E, Verploegh ISC, Wembacher E, Hoefnagel D, Balvers RK, Korporaal AL, Conidi A, Warnert EAH, Trivieri N, Visioli A, Zaccarini P, Caiola L, van Wijck R, van der Spek P, Huylebroeck D, Leenstra S, Lamfers MLM, Ram Z, Westphal M, Noske D, Legnani F, DiMeco F, Vescovi AL, Dirven CMF. Local delivery of hrBMP4 as an anticancer therapy in patients with recurrent glioblastoma: a first-in-human phase 1 dose escalation trial. Mol Cancer. 2023 Aug 10;22(1):129. doi: 10.1186/s12943-023-01835-6.

  PMID: 37563568 DERIVED

MeSH Terms

Conditions

Glioblastoma

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Officials

• Francesco DiMeco, PI

  Istituto Neurologico C. Besta Milan Italy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 2, 2016
• First Posted: August 16, 2016
• Study Start: July 18, 2017
• Primary Completion: October 16, 2020
• Study Completion: June 30, 2021
• Last Updated: February 16, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

NL (2); IL (1); IT (1)