Adenocarcinoma - GEJ, Cancer of Esophagus
Conditions
Keywords
cancer, Oesophagogastric, Oesophagogastric adenocarcinoma,, MGMT deficient,, O6-methylguanine-DNA-methyltransferase, MGMT protein, human, MGMT methylated
Brief summary
An open label single arm phase II trial in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma which is MGMT deficient.
Detailed description
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.
Interventions
DRUGTemozolomide
Metronomic TMZ 50mg/m2/day orally for 3 months then nivolumab 240mg IV +/- TMZ until progression. Patients who don't progress on TMZ will commence with combination treatment; TMZ + Nivolumab at 3 mths. Patients who progress on TMZ will start monotherapy with nivolumab. Patients will remain on monotherapy with nivolumab or combination therapy until progression or up to a maximum of 24mths.
DRUGTemozolomide 50mg/m2/day
Metronomic TMZ 50mg/m2/day orally until progression then nivolumab 240mg IV until progression
DRUGTemozolomide 3 month
Metronomic TMZ 50mg/m2/day orally for 3 months, then nivolumab 240mg IV and TMZ until progression.
DRUGTemozolomide 24month
Metronomic TMZ 50mg/m2/day orally for 3 months, then nivolumab 240mg IV and TMZ until a maximum of 24 months
Sponsors
University of Southampton
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open label
Intervention model description
An open-label, single arm, A'Hern single stage phase II design. Patients will receive TMZ priming followed by nivolumab to establish disease control rates.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumour Response to nivolumab | 24 months | To determine the anti-tumour activity of nivolumab, when given after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma which are MGMT methylated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The percentage of patients who have achieved response | 6 months | The Disease control rate determine the effect of TMZ priming followed by nivolumab on disease control rates of patients with previously treated advanced oesophagogastric adenocarcinoma which is MGMT methylated. Disease control rate, according to RECIST v1.1 and iRECIST, 6 months after starting nivolumab, and 3 months after starting TMZ, respectively. |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORElizabeth Smyth
Cambridge University
Outcome results
None listed