An open label single arm phase II trial in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma which is MGMT deficient.

The aim of the ELEVATE trial is to determine the activity and safety of maintenance TMZ dosing followed by nivolumab treatment to evaluate the potential for a future randomised trial against a standard of care control arm. The rationale to continue TMZ for 3 months or until PD is to evaluate the emergence of mismatch repair deficiency both with and without radiological PD, as clinically relevant MMRd may emerge before radiological progression. This will also reduce the number of patients who drop out due to symptomatic progressive disease.

INCLUSION CRITERIA

• Patients ≥ 18 years of age

• Pathologically confirmed advanced unresectable or metastatic OGA

• MGMT methylation on archival tissue

• Mismatch repair proficient (MSI-normal or MMR intact)

• Previously treated with at least 3 months of platinum and fluoropyrimidine based chemotherapy for advanced disease and without evidence of disease progression.

• Measurable disease per RECIST 1.1.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Can swallow TMZ capsules

• Adequate organ function assessed within 7 days before randomization:

  • 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 the 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

• All toxicities (exception 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.

• 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)). Pregnancy test must be within 24 hours prior to starting treatment. (A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient).

• 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 the study treatment.

• Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 5 months after the last dose of the study treatment.

• 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 the study treatment.

• 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.

• Written informed consent

EXCLUSION CRITERIA

• Previous treatment with TMZ

• 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

• Active central nervous system metastases

• Candidate for curative surgery

• 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 localized non-melanoma skin cancer are not exclusion criteria, regardless of timepoint of diagnosis.

• Active, known, or suspected infectious or autoimmune disease (except for patients with Type I 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)

• Conditions requiring systemic treatment with either corticosteroids (≥ 10 mg daily prednisolone or equivalent) or other immunosuppressive medications within 14 days of study drug administration

• Interstitial lung disease

• > Grade 1 peripheral neuropathy

• Positive test result for HBV or HCV indicating acute or chronic infection

• Known history of testing positive for HIV or known AIDS

• Known hypersensitivity to the components or excipients of co-trimoxazole, temozolomide or nivolumab. (Please refer to nivolumab IB and SmPC for TMZ and co-trimoxazole).

• Known hypersensitivity to dacarbazine (DTIC)

• 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.

• In the past 6 months serious cardiac illness or medical condition including but not confined to:

  • History of documented congestive heart failure (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 greater than 100mm Hg)

• Patients with severe liver parenchymal damage

• Patients with severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed

• Patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides.

• Patients with acute porphyria

• Patients with severe myelosuppression

Open label