5G-EMERALD: Amivantamab in Malignant Brain Tumours

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.
• •1. Receipt of treatment before the first dose of study drug (Cycle 1 Day 1) within an interval shorter than the following, as applicable:
• •* Cytotoxic chemotherapy during the prior 2 weeks or 6 weeks for nitrosoureas
• •* Bevacizumab during the prior 6 weeks
• •* Five half-lives of any small molecule investigational or licensed medicinal product.
• •2. Prior immune checkpoint inhibitor therapy or vaccine therapy is not permitted. Prior EGFR-targeting therapy is not permitted. Prior use of any other immune-modulatory investigational agent must be discussed with sponsor team and CI.
• •3. Ongoing Grade 2 or greater toxicities from pre-existing conditions or from previous treatments.
• •4. Patients with carcinomatous meningitis, leptomeningeal spread of tumour, spread of tumour to the brain stem or spinal cord.
• •5. Has evidence of recent intratumoural or peritumoural haemorrhage on baseline MRI. Patients with radiological findings that are stable on at least 2 consecutive MRI scans at least 3 weeks apart will be eligible.
• •6. History of clinically relevant bleeding disorders, including significant gastrointestinal (GI) bleeding within last 6 months.
• •7. Participant has active cardiovascular disease including, but not limited to:
• •* A medical history of deep venous thrombosis or pulmonary embolism within 1 month prior to first dose of study drug or any of the following within 6 months prior to first dose of study drug: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis such as non-obstructive catheter-associated thrombus, incidental or asymptomatic pulmonary embolism, are not exclusionary. Patients on Warfarin will need to be converted onto low-molecular weight-based heparin therapy.
• •* Participant has a significant genetic predisposition to venous thromboembolic (VTE) events such as Factor V Leiden.
• •* Participant has a prior history of VTE and is not on appropriate therapeutic anticoagulation as per National Comprehensive Cancer Network (NCCN) or local guidelines.
• •* Uncontrolled (persistent) hypertension: systolic blood pressure \> 160 mm Hg; diastolic blood pressure \> 100 mm Hg.
• •* Congestive heart failure (CHF), defined as New York Heart Association (NYHA) class III-IV or hospitalization for CHF (any NYHA class) within 6 months of first dose of the study drug.
• •* Concurrent and clinically significant abnormalities on ECG at Screening, including a corrected QT interval (QTcF \> 460ms).
• •8. History of malabsorption syndrome or other conditions that may interfere with enteral absorption. Patients with a history of or active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis). Patients with acute or chronic pancreatitis. History of GI perforation or fistulae.
• •9. Has urine protein \> 1g/24 hours. Participants with \> 1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria.
• •10. Has significant lung disease including pneumonitis, interstitial lung disease (including drug-induced or radiation ILD/pneumonitis), idiopathic pulmonary fibrosis, cystic fibrosis, active tuberculosis, or history of opportunistic infections (including PCP or Cytomegalovirus (CMV) pneumonia).