Table 3 Eligibility Criteria for the ELEVATE Trial
Inclusion Criteria |
1. Participants 18 years of age |
2. Pathologically confirmed advanced unresectable or metastatic OGA |
3. MGMT methylation on archival tissue |
4. Mismatch repair proficient (MSI-normal or MMR intact) |
5. Previously treated with at least 3 months of platinum and fluoropyrimidine based chemotherapy for advanced disease, without evidence of disease progression |
6. Measurable disease per RECIST 1.1 guidelines |
7. ECOG Performance Status of 0 or 1 |
8. Can swallow TMZ capsules |
9. Adequate organ function assessed within 7 days before randomisation: |
∙ White blood cell count (WBC) > 1.5 X 109/L |
∙ Absolute neutrophil count (ANC) > 1.5 X 109/L |
∙ Platelets 100 X 109/L |
∙ Haemoglobin 90 g/l |
∙ Measured/calculated creatinine clearance 60 mL/min (according to Cockroft-Gault formula) |
∙ Total bilirubin within normal limits (if patient has documented Gilbert’s disease 1.5 X ULN or direct bilirubin 1.5 X ULN) |
∙ Aspartate transaminase (AST) and/or alanine transaminase (ALT) 1.5 X ULN |
10. All toxicities (except alopecia, and grade 2 fatigue, neuropathy and lack of appetite/nausea) attributed to prior anti-cancer therapy must have resolved to grade 1 (NCI CTCAE version 5.0) or baseline before administration of study drug |
11. Women of childbearing potential (WOCBP) may be included following a confirmed menstrual period and must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (HCG)). The pregnancy test must be within 24 hours prior to starting treatment |
12. WOCBP should use one highly effective and one effective method of birth control during the study treatment period and for at least 5 months after the last dose of study treatment |
13. Female subjects who are breastfeeding should discontinue nursing prior to the first dose of study treatment and until 5 months after the last dose of study treatment |
14. Men who are sexually active with a WOCBP must adhere to contraception during and for a period of 7 months after the last dose of study treatment |
15. Absence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial |
16. Written informed consent |
Exclusion Criteria |
1. Previous treatment with TMZ |
2. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways |
3. Active central nervous system metastases |
4. Candidate for curative surgery |
5. Previous malignancies are excluded unless a complete remission was achieved at least 5 years prior to study entry. Adequately treated cervical carcinoma in situ, and localised non-melanoma skin cancer are not exclusion criteria, regardless of timepoint diagnosis |
6. Active, known, or suspected infectious or autoimmune disease (except for patients with type 1 diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enrol) |
7. Conditions requiring systemic treatment with either corticosteroids (10 mg daily prednisolone or equivalent) or other immunosuppressive medications within 14 days of study drug administration |
8. Interstitial lung disease |
9. > Grade 1 peripheral neuropathy |
10. Positive test result for HBV or HCV indicating acute or chronic infections |
11. Known history of testing positive for HIV or known AIDS |
12. Known hypersensitivity to the components or excipients of co-trimoxazole, temozolomide or nivolumab |
13. Known hypersensitivity to dacarbazine (DTIC) |
14. Clinically significant abnormal 12-lead ECG. If clinically indicated, cardiac function assessment using either echocardiography or MUGA Scan, if clinically significant the patient is ineligible |
15. In the past 6 months serious cardiac illness or medical condition including but not confined to: |
∙ History of documented CHF |
∙ High-risk uncontrolled arrhythmias |
∙ Angina pectoris requiring antianginal medication |
∙ Clinically significant valvular heart disease |
∙ Evidence of transmural infarction |
∙ Poorly controlled hypertension (e.g. systolic >180mm Hg or diastolic > 100mm Hg) |
16. Patients with severe liver parenchymal damage |
17. Patients with severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed |
18. Patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides |
19. Patients with acute porphyria |
20. Patients with severe myelosuppression |