Diffuse Hemispheric Glioma, H3 G34-Mutant, Glioblastoma Multiforme (GBM), Glioblastoma Multiform (Grade IV Astrocytoma), Malignant Primary Gliomas
Conditions
Brief summary
The purpose of this clinical trial is to evaluate the safety and tolerability of amivantamab and to determine the preliminary antitumour activity of amivantamab administered at the recommended Phase 2 dose (RP2D). In the Phase 1b of this study a biomarker defined arm will be opened, initially in the relapsed GMB setting, enrolling 12 patients. These patients will be treated with amivantamab monotherapy. Amivantamab will be administered intravenously (IV) weekly for the first 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. The first dose will be given as a split infusion, 350 mg IV over 4 hours on cycle 1 day 1 and 1400 mg IV over 6 hours on cycle 1 day 2. Subsequent infusions are given at a dose of 1750 mg IV over 2-5 hours in cycle 1 and between 2-3 hours from cycle 2 onwards if the first dose was well-tolerated with no significant toxicity. Progression to Phase 2 is dependent on emergent data and funding.
Detailed description
The clinical trial will start in Phase 1b (proof of concept of hypothesis-driven biomarker-guided therapies). This is a study within Minderoo 5G: A Next Generation AGile Genomically Guided Glioma Modular Platform for proof-of-concept molecular hypothesis testing in patients with high grade malignant brain tumours. 5G-EMERALD is a Bayesian multi-centre, multi-arm, open-label, adaptive, seamless Phase 1 trial of amivantamab for patients with high grade malignant brain tumours. 5G-EMERALD will recruit patients with glioblastoma (GBM) into one molecularly-defined biomarker arm of patients who have tumours that harbour: • EGFR amplification (high copy number) The above mentioned arm, within Phase 1, will have robust GO/ADAPT decision points, reviewed by the Safety Review Committee (SRC) to allow for both agility and clear direction for next steps. A 2-stage Bayesian adaptive design will be performed to assess preliminary efficacy. In the Phase 1b of this study a biomarker defined arm will be opened, initially in the relapsed GBM setting, enrolling 12 patients onto each arm. These patients will be treated with amivantamab. Amivantamab will be administered intravenously (IV) weekly for the first 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.
Interventions
DRUGAmivantamab
Amivantamab will be supplied in single-use 350 mg injectable solution, provided as a 7 ml per glass vial (50mg/ml), intended for IV infusion.
Sponsors
Institute of Cancer Research, United Kingdom
Royal Marsden NHS Foundation Trust
Cambridge University Hospitals NHS Foundation Trust
Janssen Pharmaceutica N.V., Belgium
Cancer Research UK
Minderoo Foundation
University of Cambridge
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for Phase 1b: 1. Patients with histologically confirmed advanced WHO Stage IV glioblastoma (per fourth edition 2016). Per the new 2021 fifth edition of WHO Classification of Tumours of the Central Nervous System, this will include: * Glioblastoma, IDH-wildtype Grade 4 * Astrocytoma, IDH-mutant, Grade 4 (lower Grade 2/3 are not included) * Diffuse hemispheric glioma, H3 G34 mutant Grade 4 2. Patients for Phase 1 will need to have consented to the Minderoo Precision Brain Tumour Programme and have available whole genome, and transcriptome data available. 3. Patients for the relapsed cohorts will be eligible at first relapse following completion of optimal surgery, and Stupp based adjuvant chemo-radiotherapy (or equivalent). They will need to have measurable disease per Response Assessment in Neuro-Oncology (RANO) or evaluable disease. 4. Patients for the front line minimal residual disease (MRD) cohort will be eligible following completion of optimal surgery and Stupp based adjuvant chemoradiotherapy as long as they meet all other inclusion/
Exclusion criteria
. 5. 16 years or over. 6. Life expectancy of at least 12 weeks. 7. World Health Organisation (WHO) performance status of 0-1. 8. Neurologically stable (e.g., without a progression of neurological symptoms or requiring escalating doses of systemic steroid therapy within the last week). 9. Written (signed or dated) informed consent and be capable of co-operating with treatment and follow up. 10. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week prior to the first dose of either IMP: Haemoglobin (Hb): ≥ 10.0 g/dL Absolute neutrophil count: ≥ 1.5 x 10\^9/L Platelet count: ≥ 75 x 10\^9/L Coagulation: INR \<1.5 and APTT \<1.5x if not anticoagulated INR stable \> 7 days within intended therapeutic range if anticoagulated Bilirubin: ≤ 1.5 x ULN; subjects with Gilbert's syndrome can enrol if conjugated bilirubin is within normal limits. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): \< 3 x ULN Albumin: ≥ 28 g/L Creatinine: \<1.5 x ULN and creatinine clearance \> 45 ml/min as measured or calculated based on Cockcroft-Gault formula Sodium: ≥ 130 mmol/L Potassium, Calcium, Magnesium, phosphate: Within institution normal ranges (replacement is permitted) Urinary protein: \< 1+ on dipstick 11. Female patients with reproductive potential must have a negative serum, or urine, pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study. 12. A participant must be either of the following: a. not of childbearing potential, b. of child-bearing potential and practicing true abstinence during the entire period of the study, including up to 6 months after the last dose of the study treatment is given, or c. of childbearing potential and practicing 2 methods of contraception, including 1 highly effective user independent method and a second method, to avoid impregnating a partner or becoming pregnant, respectively. A participant must agree to continue contraception throughout the study, and for at least 6 months after the last dose of study treatment. Please, refer to section 4.1 of CTFG guidance "Recommendations related to contraception and pregnancy testing in clinical trials" and to section 9.6 of the Master Protocol for further details. Note: If the childbearing potential changes after start of the study (eg, participant of childbearing potential who is not heterosexually active becomes active, premenarchal participant experiences menarche) the participant must begin birth control, as described above. 13. A participant must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study treatment. 14. A participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for 6 months after receiving the last dose of study treatment. A participant who is sexually active with a partner of childbearing potential must agree to use a condom with spermicidal foam/gel/film/cream/suppository and their partner must also be practicing a highly effective method of contraception (ie, established use of oral, injected, or implanted hormonal methods of contraception; placement of an intrauterine device \[IUD\] or intrauterine hormone-releasing system \[IUS\]). If the participant is vasectomized, they must still use a condom (with or without spermicide) for prevention of passage of exposure through ejaculation, but their partner is not required to use contraception. 15. A participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 6 months after receiving the last dose of study treatment. 16. A participant must be willing and able to adhere to the lifestyle restrictions specified in this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b - To determine the preliminary antitumour activity of the investigational agent administered at the RP2D in patients with molecularly defined malignant brain tumours | 18 months | Antitumour activity will be defined on the basis of the following outcomes. If any of the following occur, patients will be considered to have clinically benefitted: For relapsed GBM: Achievement of overall response of CR or PR per Response Assessment in Neuro-Oncology (RANO) within 6 months or Free of disease progression or death at 6 months For front line unmethylated GBM (MRD): • Progression-free survival (PFS) |
| Phase 1b - To evaluate the safety and tolerability of investigational agent in patients with malignant brain tumours | 18 months | To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b - To identify molecular determinants of response and antitumour activity of the investigational agent in patients with molecularly selected brain tumours | 18 months | Determination of biomarkers of response, including but not limited to changes in genomic, transcriptomic or immunological signatures from responders and non-responders using tumour sequencing analysis. |
Countries
United Kingdom
Contacts
STUDY_DIRECTORJuanita Lopez, MD, PhD
National Health Service, UK
Outcome results
None listed