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A Trial of KB004 in Patients With Glioblastoma

Primary Purpose

Glioblastoma

Status
Completed
Phase
Phase 1
Locations
Australia
Study Type
Interventional
Intervention
KB004
Sponsored by
Olivia Newton-John Cancer Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adults (greater than or equal to 18 years of age) with histologically proven glioblastoma
  • Evidence of progressive glioblastoma (if within 3 months of radiotherapy, then progression outside of radiotherapy field is required)
  • Measurable disease by RANO (Response Assessment in Neuro-Oncology Criteria)
  • ECOG (Eastern Cooperative Oncology Group score) 0 to 1
  • Expected survival more than 3 months
  • Steroid dose less than 2.5 mg per day dexamethasone equivalents and stable or reducing for 1 week prior to day 1
  • Archived (formalin fixed paraffin embedded) tissue or frozen tumour tissue or consent to obtain a fresh tumour biopsy at enrolment is required.
  • Adequate organ function. Out of range values that are not clinically significant will be permitted, except for the following laboratory parameters which must be within the ranges specified
  • Neutrophils greater than or equal to 1.5 x 109 per L
  • Platelets greater than or equal to 100 x 109 per L
  • International Normalised Ratio less than or equal to 1.4
  • Serum Aspartate aminotransferase and Alanine aminotransferase less than or equal to 2.5 x ULN (upper limit of normal)
  • Serum bilirubin less than or equal to 1.5 x ULN (upper limit of normal)

Exclusion Criteria:

  • Evidence of infratentorial, extracranial or leptomeningeal disease
  • More than one prior systemic therapy for progressive disease or prior Steriotactic radiosurgery (SRS) to sites of GB (glioblastoma).
  • Prior treatment with bevacizumab or gliadel wafers
  • Evidence of current or prior intracranial hemorrhage
  • Need for anti-platelet or anti-coagulant drugs
  • Use of anti-cancer therapy including craniotomy, chemotherapy, immunotherapy, radiotherapy, or any investigational therapy within 28 days prior to Study Day 1
  • History of major immunologic reaction to any immunoglobulin G containing agent
  • Medical conditions which place the subject at an unacceptably high risk
  • Subject is pregnant, lactating or unwilling or unable to use adequate contraception

Sites / Locations

  • Royal Brisbane and Women's Hospital
  • Austin Health

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

KB004 dose escalation

Arm Description

Patients will be entered at each KB004 dose level sequentially until 3-6 patients are evaluable for safety. Three sequential cohorts are planned in this study (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg) Additional dose levels may be explored based on the emerging data in the study.

Outcomes

Primary Outcome Measures

Number of Participants With KB004 Treatment-Related Adverse Events as Assessed using CTCAE v4.0. To determine the maximum tolerated dose (MTD).
Three patients are recruited per dose level, 3 dose levels. Dose limiting toxicity (DLT) defined as Grade 4 neutropenia > 7 day duration Grade 3 or 4 febrile neutropenia Grade 3 or 4 thrombocytopenia > 7 day duration Grade 4 anaemia > 7 day duration Grade 3 or 4 non-hematologic adverse events which do not resolve within 48 hours with maximal supportive care. Grade 4 or recurrent Grade 3 infusion reactions despite maximal supportive care and dose reductions Significant intracranial haemorrhage not reasonably attributed to other cause More than 14 days of treatment delay due to attributable toxicity Other toxicities as determined by the investigators. In the absence of any dose limiting toxicity in a cohort, escalate to the next dose level. If one DLT is seen in the first three patients of a cohort, an additional three patients will be recruited to that cohort. If two or more DLT's are seen in any cohort, that cohort will be deemed the maximum tolerated dose.

Secondary Outcome Measures

Biodistribution of 89Zr-KB004
Eligible patients with measurable tumours will receive an initial trace (5mg) dose of zirconium labelled KB004 (89Zr-KB004) on day 1 followed by sequential Positron emission tomography, or PET imaging over 1 week to determine its biodistribution into GBM and normal tissues, frequency of EphA3 (ephrin type-A receptor 3) expression in glioblastoma (GBM) and quantitative tumor antibody uptake.
Response rates following KB004 infusion
Response Assessment in Neuro-Oncology criteria will be used to interpret MRI (magnetic resonance imaging) scans
Plasma concentration versus time (Serum half life) of 89Zr-KB004
Pharmacokinetics (plasma concentration versus time) of 89Zr-KB004 will be determined using gamma well counting of the Zirconium in the samples at various timepoints-Day 1 89Zr-KB004 infusion: pre-infusion, 5min, 1 hour, 2 hours, 4 hours and 24 hours post infusion, then Day 3 or 4, 6 or 7. PK (Pharmacokinetics) timepoints Day 89Zr-KB004 infusion: pre-infusion, 5min, 1 hour, 2 hours, 4 hours and 24 hours post infusion then Day 39 or 40 and Day 42 or 43.
Cmax of 89Zr-KB004
Pharmacokinetics (Cmax) of 89Zr-KB004 will be determined using gamma well counting of the Zirconium in the samples at various timepoints-Day 1 89Zr-KB004 infusion: pre-infusion, 5min, 1 hour, 2 hours, 4 hours and 24 hours post infusion, then Day 3 or 4, 6 or 7. PK (Pharmacokinetics) timepoints Day 89Zr-KB004 infusion: pre-infusion, 5min, 1 hour, 2 hours, 4 hours and 24 hours post infusion then Day 39 or 40 and Day 42 or 43.

Full Information

First Posted
September 26, 2017
Last Updated
November 3, 2021
Sponsor
Olivia Newton-John Cancer Research Institute
Collaborators
Humanigen, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03374943
Brief Title
A Trial of KB004 in Patients With Glioblastoma
Official Title
A Phase I Safety and Bioimaging Trial of KB004 in Patients With Glioblastoma
Study Type
Interventional

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Completed
Study Start Date
December 5, 2017 (Actual)
Primary Completion Date
January 25, 2021 (Actual)
Study Completion Date
September 22, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Olivia Newton-John Cancer Research Institute
Collaborators
Humanigen, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a study of drug KB004 in patients with recurrent glioblastoma (GBM). Eligible patients with measurable tumours will receive an initial trace (5mg) dose of zirconium labelled KB004 (89ZrKB004) on day 1 followed by sequential Positron emission tomography (PET) imaging over 1 week to determine its biodistribution into GBM and normal tissues. Safety assessments and pharmacokinetic (movement of drug) sampling will also be undertaken over this time. On Day 8, patients commence weekly KB004 infusions over 2 hours with standard premedications. Three cohorts are planned in this study (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg; additional dose levels may be explored based on toxicity, efficacy and biodistribution data as determined by the safety monitoring committee). On day 36, patients receive both 89ZrKB004 and KB004, allowing assessment of receptor occupancy to guide recommended phase two dose (RPTD) determination. Response rate (RANO) and survival data will be collected and patients benefiting may continue KB004 treatment until disease progression. Primary objective: to determine the toxicity and recommended phase two dose (RPTD) of KB004 in patients with advanced Glioblastoma (GBM). Secondary objectives: to determine the biodistribution and pharmacokinetics of 89ZrKB004; to determine frequency of EphA3 (ephrin receptor A3) positive glioblastoma in archival specimens and by 89ZrKB004 scans, and correlate with known biomarkers; to describe response rates per RANO criteria (Response Assessment in Neuro-Oncology Criteria) and pharmacodynamics following KB004 infusion; Exploratory objectives: to perform exploratory analysis between clinical outcomes and biodistribution/Pharmacokinetics (PK)/pharmacodynamics (PD) data, including from matched biopsies.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Model Description
The study will use a 3+3 methodology for the 3 dose levels proposed. In brief, three patients will be recruited per dose level. In the absence of any Dose Limiting toxicity (DLT) in a cohort, escalation to the next dose level will occur.
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
KB004 dose escalation
Arm Type
Experimental
Arm Description
Patients will be entered at each KB004 dose level sequentially until 3-6 patients are evaluable for safety. Three sequential cohorts are planned in this study (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg) Additional dose levels may be explored based on the emerging data in the study.
Intervention Type
Drug
Intervention Name(s)
KB004
Intervention Description
KB004 is a recombinant, non-fucosylated, IgG1κ (human f-allotype) monoclonal antibody targeting the extracellular ligand binding domain of the EphA3 (ephrin receptor) tyrosine kinase
Primary Outcome Measure Information:
Title
Number of Participants With KB004 Treatment-Related Adverse Events as Assessed using CTCAE v4.0. To determine the maximum tolerated dose (MTD).
Description
Three patients are recruited per dose level, 3 dose levels. Dose limiting toxicity (DLT) defined as Grade 4 neutropenia > 7 day duration Grade 3 or 4 febrile neutropenia Grade 3 or 4 thrombocytopenia > 7 day duration Grade 4 anaemia > 7 day duration Grade 3 or 4 non-hematologic adverse events which do not resolve within 48 hours with maximal supportive care. Grade 4 or recurrent Grade 3 infusion reactions despite maximal supportive care and dose reductions Significant intracranial haemorrhage not reasonably attributed to other cause More than 14 days of treatment delay due to attributable toxicity Other toxicities as determined by the investigators. In the absence of any dose limiting toxicity in a cohort, escalate to the next dose level. If one DLT is seen in the first three patients of a cohort, an additional three patients will be recruited to that cohort. If two or more DLT's are seen in any cohort, that cohort will be deemed the maximum tolerated dose.
Time Frame
0-24 months
Secondary Outcome Measure Information:
Title
Biodistribution of 89Zr-KB004
Description
Eligible patients with measurable tumours will receive an initial trace (5mg) dose of zirconium labelled KB004 (89Zr-KB004) on day 1 followed by sequential Positron emission tomography, or PET imaging over 1 week to determine its biodistribution into GBM and normal tissues, frequency of EphA3 (ephrin type-A receptor 3) expression in glioblastoma (GBM) and quantitative tumor antibody uptake.
Time Frame
0-24 months
Title
Response rates following KB004 infusion
Description
Response Assessment in Neuro-Oncology criteria will be used to interpret MRI (magnetic resonance imaging) scans
Time Frame
0-24 months
Title
Plasma concentration versus time (Serum half life) of 89Zr-KB004
Description
Pharmacokinetics (plasma concentration versus time) of 89Zr-KB004 will be determined using gamma well counting of the Zirconium in the samples at various timepoints-Day 1 89Zr-KB004 infusion: pre-infusion, 5min, 1 hour, 2 hours, 4 hours and 24 hours post infusion, then Day 3 or 4, 6 or 7. PK (Pharmacokinetics) timepoints Day 89Zr-KB004 infusion: pre-infusion, 5min, 1 hour, 2 hours, 4 hours and 24 hours post infusion then Day 39 or 40 and Day 42 or 43.
Time Frame
0-43 days
Title
Cmax of 89Zr-KB004
Description
Pharmacokinetics (Cmax) of 89Zr-KB004 will be determined using gamma well counting of the Zirconium in the samples at various timepoints-Day 1 89Zr-KB004 infusion: pre-infusion, 5min, 1 hour, 2 hours, 4 hours and 24 hours post infusion, then Day 3 or 4, 6 or 7. PK (Pharmacokinetics) timepoints Day 89Zr-KB004 infusion: pre-infusion, 5min, 1 hour, 2 hours, 4 hours and 24 hours post infusion then Day 39 or 40 and Day 42 or 43.
Time Frame
0-43 days
Other Pre-specified Outcome Measures:
Title
clinical outcomes via RANO criteria (Response Assessment in Neuro-Oncology Criteria)
Description
describe response rates using Response Assessment in Neuro-Oncology Criteria to interpret MRI (magnetic resonance imaging) scans
Time Frame
0-24 Months
Title
Biodistribution via PET (Positron-emission tomography)
Description
89Zr-KB004 Positron emission tomography imaging will be used
Time Frame
0-43 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adults (greater than or equal to 18 years of age) with histologically proven glioblastoma Evidence of progressive glioblastoma (if within 3 months of radiotherapy, then progression outside of radiotherapy field is required) Measurable disease by RANO (Response Assessment in Neuro-Oncology Criteria) ECOG (Eastern Cooperative Oncology Group score) 0 to 1 Expected survival more than 3 months Steroid dose less than 2.5 mg per day dexamethasone equivalents and stable or reducing for 1 week prior to day 1 Archived (formalin fixed paraffin embedded) tissue or frozen tumour tissue or consent to obtain a fresh tumour biopsy at enrolment is required. Adequate organ function. Out of range values that are not clinically significant will be permitted, except for the following laboratory parameters which must be within the ranges specified Neutrophils greater than or equal to 1.5 x 109 per L Platelets greater than or equal to 100 x 109 per L International Normalised Ratio less than or equal to 1.4 Serum Aspartate aminotransferase and Alanine aminotransferase less than or equal to 2.5 x ULN (upper limit of normal) Serum bilirubin less than or equal to 1.5 x ULN (upper limit of normal) Exclusion Criteria: Evidence of infratentorial, extracranial or leptomeningeal disease More than one prior systemic therapy for progressive disease or prior Steriotactic radiosurgery (SRS) to sites of GB (glioblastoma). Prior treatment with bevacizumab or gliadel wafers Evidence of current or prior intracranial hemorrhage Need for anti-platelet or anti-coagulant drugs Use of anti-cancer therapy including craniotomy, chemotherapy, immunotherapy, radiotherapy, or any investigational therapy within 28 days prior to Study Day 1 History of major immunologic reaction to any immunoglobulin G containing agent Medical conditions which place the subject at an unacceptably high risk Subject is pregnant, lactating or unwilling or unable to use adequate contraception
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hui Gan
Organizational Affiliation
Austin Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Royal Brisbane and Women's Hospital
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4029
Country
Australia
Facility Name
Austin Health
City
Heidelberg
State/Province
Victoria
ZIP/Postal Code
3078
Country
Australia

12. IPD Sharing Statement

Plan to Share IPD
No

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A Trial of KB004 in Patients With Glioblastoma

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