Temozolomide + Nivolumab in MGMT Methylated Oesophagogastric Cancer

NCT04984733 | Recruiting Phase 2 DMC

• 1 other identifier: 61191
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Adenocarcinoma - GEJ; Cancer of Esophagus

Keywords

cancer; Oesophagogastric; Oesophagogastric adenocarcinoma,; MGMT deficient,; O6-methylguanine-DNA-methyltransferase; MGMT protein, human; MGMT methylated

Outcome Measures

Primary Outcomes (1)

• Tumour Response to nivolumab

  To determine the anti-tumour activity of nivolumab, when given after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma which are MGMT methylated.

  24 months

Secondary Outcomes (1)

• The percentage of patients who have achieved response

  6 months

Study Arms (1)

Treatment

EXPERIMENTAL

Metronomic TMZ 50mg/m2/day orally for 3 months, then nivolumab 240mg IV until progression. Metronomic TMZ 50mg/m2/day orally until progression then nivolumab 240mg IV until progression. Patients who progress on TMZ will start monotherapy with nivolumab. Metronomic TMZ50mg/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 until they progress Metronomic TMZ 50mg/m2/day orally for 3 months, then nivolumab 240mg IV +/- TMZ until 24 months. Patients will remain on combination therapy up to a maximum of 24mths.

Drug: Temozolomide; Drug: Temozolomide 50mg/m2/day; Drug: Temozolomide 3 month; Drug: Temozolomide 24month

Interventions

Temozolomide DRUG

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.

Also known as: Nivolumab

Treatment

Temozolomide 50mg/m2/day DRUG

Metronomic TMZ 50mg/m2/day orally until progression then nivolumab 240mg IV until progression

Also known as: Nivolumab

Treatment

Temozolomide 3 month DRUG

Metronomic TMZ 50mg/m2/day orally for 3 months, then nivolumab 240mg IV and TMZ until progression.

Also known as: Nivolumab

Treatment

Temozolomide 24month DRUG

Metronomic TMZ 50mg/m2/day orally for 3 months, then nivolumab 240mg IV and TMZ until a maximum of 24 months

Also known as: Nivolumab

Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• University of Southampton: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Cambridge University Hospitals NHS Foundation Trust

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

RECRUITING

MeSH Terms

Conditions

Esophageal Neoplasms; Neoplasms

Interventions

Temozolomide; Nivolumab

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Elizabeth Smyth

  Cambridge University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Elizabeth Smyth

CONTACT

023 81205773; elizabeth.smyth2@nhs.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Masking Details: Open label
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 13, 2021
• First Posted: July 30, 2021
• Study Start: September 28, 2021
• Primary Completion: July 1, 2024
• Study Completion (Estimated): July 1, 2026
• Last Updated: November 29, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)