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

A Dose Escalation Phase I Study Of Human- Recombinant Bone Morphogenetic Protein 4 Administrated Via Convection-Enhanced Delivery In Patients With Progressive And/Or Multiple Recurrent Glioblastoma Multiforme

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).

Study Overview

• Status: Completed
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: hrBMP4

Detailed Description

This multicentre, open-label, dose escalating, Phase I study will enrol approximately 18 patients with progressive and/or multiple recurrent GBM, who after failure of standard therapies will receive GMP Human- recombinant Bone Morphogenetic Protein 4 via intra-tumour and interstitial delivery by CED.

Patients will undergo a resection or biopsy of the tumour, confirmation of viable malignant glioma tumour cells during frozen section performed by the institutional pathologists, and intra-tumor and interstitial placement under neuronavigational guidance of 2 or 3 catheters. No catheters will be placed at time of resection. After resection, catheters will be placed during a separate procedure several days later based upon the patient's condition as determined by both a clinical examination and routine MRI scan.

Patients will receive intra-tumour and interstitial CED of increasing amounts of hrBMP4 solutions (at a starting dose of 0.5 mg) and 1:70 gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) in a total of 44-66 ml over up to 4-6 days at the discretion of the investigator.

Gd-DTPA will be co-infused with hrBMP4 to determine the extent of intra-tumour and interstitial drug delivery. Patients will be hospitalized from the time of the original surgery until the end of infusion of hrBMP4.

Patients will be followed for the duration of the study. The primary endpoint of the study is monitoring feasibility and patient safety for the incidence of Dose-Limiting Toxicity (DLT) following intra-tumour and interstitial therapy with hrBMP4 and to determine whether there is a Maximum Tolerated Dose (MTD).

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Israel
  • Tel Aviv, Israel
    • Tel Aviv Sourasky Medical Center
• Italy
  • Milano, Italy, 20133
    • Istituto Neurologico Carlo Besta
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus University Medical Center, Department of Neurosurgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

To be eligible for inclusion into this study, each patient must fulfil the following inclusion criteria ≤ 28 days prior to the anticipated surgery date:

1. 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.
2. Age 18-75 years.
3. Karnofsky >70 (see APPENDIX C: EXAMPLE OF PERFORMANCE STATUS: KARNOFSKY SCALE).
4. Stable dose of corticosteroids no longer than 4 weeks prior to enrolment.

5. 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.

6. 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:

   1. Combined (oestrogen and progestogen containing) hormonal contraception;
   2. Associated with inhibition of ovulation; oral OR intravaginal OR transdermal;
   3. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral OR injectable OR implantable;
   4. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action;
   5. Intrauterine device (IUD);
   6. Intrauterine hormone-releasing system (IUS);
   7. Bilateral tubal occlusion;
   8. Vasectomised partner;
   9. Sexual abstinence;
   10. Male or female condom with or without spermicide;
   11. Cap, diaphragm or sponge with spermicide. Complies with The Heads of Medicines Agencies (HMA) Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials (Sept 2014).

   The definition of effective contraception will be based on the judgment of the investigator.

7. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

To be eligible for inclusion into this study, each patient must violate none of the following exclusion criteria ≤ 28 days prior to the anticipated surgery date:

1. 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.
2. Patients who are receiving any other investigational agents.
3. Life expectancy <3 months

4. 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.

5. 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.

6. Renal dysfunction defined as:

   - Creatinine clearance <60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal for age and gender.

7. Serology indicating active infection with Hepatitis B or C, or HIV.
8. Significant co-morbidity, including coagulation disorders.
9. Pregnancy or unwillingness to practice reliable birth control.
10. Presence of another active malignancy less than 2 years previously (exception: non-melanoma skin cancer).
11. Multifocal, bilateral
12. Midline shift more than 5 mm

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

Drug: hrBMP4; 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.; Other Names: Recombinant Bone Morphogenic Protein-4; Device:Intracranial Catheter

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor response	MRI scans with the following variables: volumetric T1, T2, volumetric Fluid Attenuated Inversion Recovery (FLAIR) and volumetric T1 with contrast. Preoperative assessment by clinical presentation and MRI appearance of the tumour burden will be taken and will be used as the reference point to determine the objective tumour response. Objective tumour response: Duplicates of all scans are to be made at the time of each scan and to be retained for the option of a central reading at the end of the trial. Tumour responses must be confirmed by repeat evaluations which should be performed no less than 4 weeks after the criteria of response was first met. Tumor response will be evaluated in accordance to Macdonald criteria	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	The EORTC quality of life questionnaire (QLQ-C30) will be used to assess quality of life. The questionnaires will be available in local languages as per country requirements.	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)	Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method.	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)	Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method.	Prior to the infusion, after 4-6 days post start infusion (end of infusion) and 4 weeks after hospitalization
Area under the curve (AUC∞)	Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method.	Prior to the infusion, after 4-6 days post start infusion (end of infusion) and 4 weeks after hospitalization
Central and peripheral volumes of distribution (Vd)	Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method.	Prior to the infusion, after 4-6 days post start infusion (end of infusion) and 4 weeks after hospitalization
Clearance	Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method.	Prior to the infusion, after 4-6 days post start infusion (end of infusion) and 4 weeks after hospitalization
Half-life (t1/2)	Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method.	Prior to the infusion, after 4-6 days post start infusion (end of infusion) and 4 weeks after hospitalization

Collaborators and Investigators

• Sponsor: Stemgen
• Collaborators: ORION Clinical Services
• Investigators: Principal Investigator: Francesco DiMeco, PI, Istituto Neurologico C. Besta Milan Italy

Study record dates

Study Major Dates

• Study Start (Actual): July 18, 2017
• Primary Completion (Actual): October 16, 2020
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: August 2, 2016
• First Submitted That Met QC Criteria: August 11, 2016
• First Posted (Estimated): August 16, 2016

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: A malignant growing astrocytoma of central nervous system
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: hrBMP4-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No