GOTHAM
Research type
Research Study
Full title
A phase II trial to assess the activity of Gemtuzumab Ozogamicin Therapy in Haemophagocytic lymphohistiocytosis (HLH) or Macrophage activation syndrome (MAS) or relapsed/refractory solid tumours
IRAS ID
285470
Contact name
Francis Mussai
Contact email
Sponsor organisation
University of Birmingham
Eudract number
2020-002428-36
ISRCTN Number
ISRCTN89158144:
Duration of Study in the UK
3 years, 1 months, 0 days
Research summary
Summary of Research: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are severe and life-threatening activations of the immune system that happen alongside cancer. Current treatment for these conditions is based on chemotherapy but the outlook is extremely poor with 25-50% of patients failing to respond and eventually dying of disease. The current treatment strategy is an untargeted immunesuppressive approach and no effective new therapies have been developed.
Research conduct by the Mussai/De Santo research group at the University of Birmingham has shown that in HLH/MAS there is an expansion of immune cells which drive the disease. A similar effect is also observed by a number of established research groups in a wide range of aggressive cancers where the cells stop the immune system from working effectively against the cancer. These cells can be identified by a marker called CD33 on the cells.
Importantly, an existing drug called gemtuzumab ozogamicin can specifically target CD33 on these immune cells leading to eradication of the cells. The GOTHAM trial is the first to test gemtuzumab ozogamicin specifically in patients with relapsed/refractory HLH/MAS and/or relapsed/refractory solid cancer. The trials aims to see whether gemtuzumab ozogamicin affects the number of CD33 marker cells, and if this treatment is feasible and effective in these patients. It is hoped that by reducing the number of CD33 cells this will in turn allow the patients own immune system to better fight against the patients disease leading to better outcomes.
A minimum of 20 patients will be recruited; 10 patients with relapsed/refractory HLH/MAS and 10 patients with relapsed/refractory solid cancers. Gemtuzumab ozogamicin will be given over a 2 hour period once a week for 3 weeks, and the patients progress will be followed up for 1 year afterwards.Summary of results: GOTHAM Lay Summary of Study Results
V1.0 29-May-2025Name of Chief Investigator: Professor Gary Middleton IRAS ID: 285470 Name of the Research Ethics Committee that issued a Favourable Opinion for the study: South Central – Hampshire A Research Ethics Committee Sponsor Organisation Name: University of Birmingham Study start date: 30-Jun-2021 Study end date: 30-May-2024 Name of Registry: ISRCTN Study Registration Number/Identifier: ISRCTN89158144 Protocol number: HRG_19-271 Trial name:
GOTHAM: A phase II trial to assess the activity of Gemtuzumab Ozogamicin Therapy in HAemophagocytic lymphohistiocytosis (HLH) or Macrophage activation syndrome (MAS) or relapsed/refractory solid tumoursGeneral Information
Who carried out the research?
The University of Birmingham sponsored the study. The Cancer Research UK Clinical Trials Unit (CRCTU) managed the data and delivered the study. Funding was provided by the Little Princess Trust (LPT) research grants programme through the Children’s Cancer and Leukaemia Group (CCLG) and The Eveson Trust. Pfizer provided Gemtuzumab ozogamicin (GO) free of charge for use in the study.
Why was the research needed?
Haemophagocytic lympho-histiocytosis (HLH) and Macrophage Activation Syndrome (MAS) are life-threatening activations of the immune system occurring alongside cancer and infections in children. Current treatment is with untargeted, immunosuppressive chemotherapy but the outlook is extremely poor with 25-50% of patients dying of disease. Our research has shown that in HLH/MAS there is an expansion of immune cells which drive the disease. A similar effect is also observed in a wide range of aggressive cancers where the cells stop the immune system from effectively attacking the cancer. These cells are identified by a marker called CD33. Importantly, an existing drug (GO), already in use for childhood blood cancers, can specifically target CD33 leading to eradication of the cells.
GOTHAM was designed to provide GO for children and adults with HLH/MAS (10 patients) and relapsed/refractory cancer (10 patients). Additionally, samples would be collected from all patients allowing significant laboratory analysis of the effect of GO in patients with HLH/MAS. The quantity of CD33+ cells in the blood would be measured in blood samples from all patients, to provide an indication of if GO was successful in targeting these cells.
Who took part in the study?
Patients were eligible for GOTHAM if they were over 1 year old at the time of trial entry, and split into two groups:
Group 1 – HLH or MAS disease that is relapsing/refractory to treatment at the time of enrolment. No patients were recruited into this group.
Group 2 – Solid cancer with disease progression during or after at least one previous treatment, or any subsequent recurrence.
Patients who had previously been treated with GO were excluded from the study.
The study opened in two hospitals in the UK. In all, seven patients were recruited, with all of these in Group 2.
What treatments did the participants receive?
Three doses of GO were provided to participants across two different dosing schedules.
The original treatment schedule was for patients to receive GO every 7 days, receiving a dose on day 1, 8 and 15. Following recruitment of the first four patients, the trial management group (TMG) under suggestion of the Chief Investigator (CI) decided it would be beneficial to amend the schedule to every three weeks in order to improve feasibility. This meant the participants were scheduled to receive GO on Day 1, Day 22 and Day 43. The remaining three participants were enrolled on this updated schedule.
All patients recruited received at least one dose of GO.
• Three of the four patients treated on the first schedule received two of the planned three doses, with the remaining patient receiving one dose.
• Two of the three patients treated on the updated schedule received all three doses, with the other patient only receiving one dose.Overall:
• Two patients (29%) received all treatment doses
• Three patients (43%) received two treatment doses
• Two patients (29%) received one treatment doseWhat were the results of the study?
Primary Objective
The primary objective was to measure the quantity of CD33+ cells in the patients blood samples. Changes were detected in CD33+ count across the study, with differing responses seen across patients.
In all patients who had samples taken at least a week following GO treatment, a reduction in CD33+ count was seen at least once. This was not maintained in all patients and levels were variable.
Secondary objectives
The secondary objectives were to measure overall and progression free survival. The average overall survival across all patients was 6.53 months. Progression free survival is the length of time from trial entry to the first date of disease progression, where the average across all patients was 2.07 months.
Were there any side effects?
Most patients experienced side effects, with five serious side effects reported in three patients. These included stomach pain, pneumonia and a fever with reduced white blood cells.
Details of any further research planned
The results show that the use on GO in solid cancer patients can potentially be used as a therapy alongside other treatments to enhance the efficacy of anti-cancer immunotherapies although the size of the trial was too small to draw a full conclusion. Therefore, the CI is working on plans to design a future study around this.
REC name
South Central - Hampshire A Research Ethics Committee
REC reference
20/SC/0362
Date of REC Opinion
2 Dec 2020
REC opinion
Further Information Favourable Opinion