Evaluating alternative treatment regimens for patients who have diffuse large B-cell lymphoma that is unsuitable for standard treatment
| ISRCTN | ISRCTN11542980 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11542980 |
| EudraCT/CTIS number | 2019-000842-36 |
| IRAS number | 261164 |
| Secondary identifying numbers | CPMS 41290, IRAS 261164 |
- Submission date
- 12/11/2020
- Registration date
- 10/12/2020
- Last edited
- 13/03/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Stopped
- Condition category
- Cancer
Plain English Summary
Background and study aims
Diffuse large B-cell lymphoma (DLBCL) is a cancer that starts in white blood cells called B lymphocytes. The standard treatment for DLBCL is a combination of chemotherapy and immunotherapy, referred to as chemo-immunotherapy. Currently, the best results in the treatment of DLBCL are with a chemo-immunotherapy combination called R-CHOP. R-CHOP is not suitable for all patients with DLBCL as one of the drugs can damage the heart. If patients have heart disease or other problems, it may be too risky for them to receive R-CHOP. There have also been some research studies showing that R-CHOP may also be unsuitable for people over the age of 80 years. If this is the case, many patients either receive a reduced dose called mini R-CHOP, or receive one of two alternatives, R-GCVP or R-CEOP. However, outcomes for these treatments are poorer compared to R-CHOP. The aim of this study is to find out whether giving a new drug called polatuzumab vedotin (POLA) in combination with either R-GCP or mini R-CHP is safe and effective. These two combinations are called POLA-R-GCP or POLA-R-mini-CHP.
Who can participate?
Adults who have been diagnosed with DLBCL but their doctors do not think that it would be safe to treat them with R-CHOP because of their age, heart problems, or other significant health problems.
What does the study involve?
Participants will be allocated to one of two different treatment arms based on their age and whether they have other health problems. Patients who are allocated to treatment arm A will receive the following drugs: polatuzumab vedotin, rituximab, gemcitabine, cyclophosphamide, prednisolone. Patients who are allocated to treatment arm B will receive the following drugs: polatuzumab vedotin, rituximab, doxorubicin, cyclophosphamide, prednisolone. Both treatments consist of one period (cycle) of treatment every 21 days (3 weeks) for six cycles. Patients will have initial (screening) tests to confirm they meet all entry criteria, some of these tests will be repeated during the course of the study to assess how the DLBCL is responding to treatment and to check it is safe to continue. Most of the tests are routine. They include a physical examination and blood tests, a biopsy (likely lymph node), a PET-CT scan, tests to assess heart function including an electrocardiogram and either an echocardiogram or MUGA scan.
What are the possible benefits and risks of participating?
It is hoped that the treatments will help patients who take part although that cannot be guaranteed. The information from this study may help to improve the future treatment of patients with DLBCL. Patients are asked to complete questionnaires about their quality of life which may make their hospital appointments longer, but not more frequent. Some of the PET-CT/CT/MUGA scans required for the study are extra. They use ionising radiation which can cause cell damage that may, after many years or decades, turn cancerous. The chance of that happening to participants is extremely small. polatuzumab, vedotin is a new and unlicensed drug, its side effects are not well known. It is unknown if it could reduce the effectiveness of the other drugs, or produce new/worsened side effects.
Where is the study run from?
The Clatterbridge Cancer Centre NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
August 2019 to July 2023
Who is funding the study?
Roche Products Ltd (Switzerland)
Who is the main contact?
APOLLO Trial co-ordinator
apollo@liverpool.ac.uk
Plain English summary under review with external organization
Contact information
Scientific
APOLLO Trial Co-ordinator
Liverpool Clinical Trials Centre
2nd Floor, Institute in the Park
Alder Hey Children's NHS Foundation Trust
Eaton Road
Liverpool
L12 2AP
United Kingdom
| Phone | +44 (0)151 794 9768 |
|---|---|
| apollo@liverpool.ac.uk |
Study information
| Study design | Non-randomized; Interventional; Design type: Treatment, Drug, Immunotherapy |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A polatuzumab vedotin containing chemo-immunotherapeutic regimen in patients with diffuse large b-cell lymphoma unsuitable for full-dose R-CHOP therapy |
| Study acronym | APOLLO |
| Study hypothesis | The researchers propose that polatuzumab vedotin, a novel and attractive option with demonstrable activity in DLBCL, is safe to combine with otherwise sub-optimal chemo-immunotherapeutic backbones (such as R-GCP or R-mini-CHP) and will likely improve outcomes for patients unsuitable for full-dose R-CHOP. |
| Ethics approval(s) | Approved 07/04/2020, North West - Liverpool Central Research Ethics Committee (3rd Floor, Barlow House, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 (0)207 104 8197, +44 (0)2071048387; liverpoolcentral.rec@hra.nhs.uk), REC ref: 19/NW/0743 |
| Condition | Diffuse large B-cell lymphoma |
| Intervention | This research study is designed to see if adding polatuzumab vedotin to standard anti-cancer drugs (rituximab, gemcitabine, prednisolone or rituximab, doxorubicin, cyclophosphamide and prednisolone) may be effective for treating patients with DLBCL who cannot be treated with standard treatment as they have other conditions. In addition, the study will investigate whether the side effects are manageable. There will be 56 patients recruited in total to the study, split evenly across two arms: Arm A: POLA-R-GCP Arm B: POLA-R-mini-CHP Those patients with cardiac/cardiac co-morbid risk factors will be allocated to arm A. Those without cardiac risk factors will be allocated to arm B. Participants who may be eligible to participate in the study will be identified by the team responsible for their care. The study will be explained by the study doctor and research staff at one of the research sites. Participants will be given time to consider whether to take part in the study before providing informed consent. Participants will attend the clinic for screening, treatment and for regular assessments until 12 months after the last participant has been registered on the study. Screening The screening phase of the study will involve the following investigations: - Written informed consent - Confirmation of histology and diagnosis - Complete medical history - Concomitant medication - Physical examination - WHO performance status - Estimated Glomerular Filtration Rate (eGFR) using MDRD formula - Full Blood Count (Hb, WBC, platelet count, neutrophil count and lymphocyte count) - Serum Urea and Electrolytes (Sodium, Potassium, Urea, Creatinine, Calcium and Phosphate) - Liver Function Tests (albumin, globulins, bilirubin, alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP)) - Serum LDH and Urate - Serology for HIV, HBV and HCV - Whole-body PET scan and CT scan (neck, chest, abdomen and pelvis) - Bone marrow trephine biopsy* - Pregnancy test (in women of childbearing age only) - IPI score - Cumulative Illness Rating Score-Geriatric (CIRS-G), excluding haematological co-morbidities - ECG - Echocardiogram/MUGA scan *The need for a BM trephine biopsy will be assessed by the local investigator and should be considered to verify if neutropenia or thrombocytopenia are thought to be due to marrow involvement. Treatment Participants will receive 6 cycles of treatment, every 21 days. An interim response assessment will be carried out after 3 cycles and will involve a CT scan. If the patient has a partial or complete response, they will receive a further 3 cycles of treatment. An end of treatment FDG-PET/CT scan will determine the final response. Patients will be followed up every 3 months until primary endpoint data collection is complete. Timeline Recruitment is predicted to take 12 months and patients will be followed up for a minimum of 12 months. The final analysis will be ~6 months following the last patient last visit. Sample size Sample size calculations have been made by the trial statistician for each cohort based on single-stage phase 2 design methodology. Interim monitoring and analysis Reviews of study data will be carried out at regular intervals by an Independent Safety and Data Monitoring Committee (ISDMC). The ISDMC will meet after the recruitment of 8 patients to each arm to formally assess adverse events. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Polatuzumab vedotin, rituximab, gemcitabine, prednisolone, rituximab, doxorubicin, cyclophosphamide, prednisolone |
| Primary outcome measure | Progression-free survival defined as disease progression or recurrence, or death from any cause, (defined as days from the date of cohort assignment to event) occurring within 12 months as assessed by the investigator using the revised Lugano response criteria for malignant lymphoma |
| Secondary outcome measures | 1. The frequency of Grade 3-4 adverse events (AEs) will be assessed according to standard National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 following each cycle of treatment and at each subsequent follow-up visit until 12 months after the last dose of treatment 2. The number of patients completing the 6 planned courses of therapy in each cohort, recorded on treatment forms for each of the 6 planned courses of therapy 3. Investigator-assessed end-of-treatment FDG-PET-CT scan assessed using the revised Lugano response criteria for malignant lymphoma (2016) at the end of treatment 4. Overall survival measured as the time from recruitment until death by any cause 5. Time to next treatment recorded on an additional treatment form throughout study participation 6. Quality of life measured using the EQ-5D patient completed questionnaire pre- and post-treatment and at every 3 monthly follow-up visit 7. Co-morbidity/frailty assessed using echocardiography or nuclear medicine examination [MUGA] pre- and post-treatment (excluding haematological comorbidities) |
| Overall study start date | 23/08/2019 |
| Overall study end date | 01/07/2023 |
| Reason abandoned (if study stopped) | Lack of funding/sponsorship |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 56; UK Sample Size: 56 |
| Total final enrolment | 0 |
| Participant inclusion criteria | 1. Male and female subjects ≥16 years of age at the time of enrolment 2. Ability to understand and sign written informed consent 3. Adequate contraceptive precautions if relevant 4. No active malignant disease other than non-melanotic skin cancer or carcinoma in situ of the uterine cervix in the last 3 years 5. ECOG performance status 0-2, at the time of screening 6. Measurable disease 7. Previously untreated histologically proven CD20 and CD79b +ve Diffuse large B cell non-Hodgkin’s lymphoma (DLBCL) according to the current World Health Organisation 2016 classification including all morphological variants: 7.1. DLBCL, not otherwise specified (NOS) including GCB and ABC 7.2. T-cell/histiocyte rich large B lymphoma 7.3. Epstein Barr virus positive DLBCL NOS 7.4. ALK-positive large B cell lymphoma 7.5. HHV8 positive DLBCL, NOS 7.6. High-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double hit or triple hit lymphoma) 7.7. High-grade B cell lymphoma, NOS 8. The B-cell nature of the proliferation must be verified by the positivity with anti-CD20 and anti-CD79b antibodies before entry to the study. A central pathology panel will review all histology 9. At least one bi-dimensionally measurable lesion, defined as >1.5 cm in its longest dimension as measured by CT or MRI 10. Availability of archival or freshly obtained tumour tissue 11. No previous chemotherapy, radiotherapy, or other investigational drug for this indication 12. Patients with a cardiac status that does not allow the administration of 6 courses of R-CHOP as defined by an ejection fraction of < = 50% either assessed by echocardiography or nuclear medicine examination [MUGA] or New York Heart Association classification Grade III or IV. If the ejection fraction is > 50% but there is evidence of other significant co-morbid cardiac risk factors (i.e. Hypertension, Diabetes Mellitus, previous history of Ischaemic heart disease, previous cardiac dysfunction, renal impairment etc.) that may preclude full dose anthracycline use, these patients may be considered for trial entry 13. Adequate bone marrow function as defined by: 14. Platelets >100 x 10e9 /l; WBC >3 x 109 /l; neutrophils >1.0 x 10e9 /l at the time of study entry - unless attributed to bone marrow infiltration by lymphoma 15. Serum bilirubin < 50 µmol/l and transaminases < 2.5 x upper limit of institutional normal range unless elevated levels attributed to lymphoma 16. Glomerular filtration rate >30 ml/min as assessed by urinary creatinine clearance or Cockcroft-Gault Formula 17. No concurrent uncontrolled medical condition 18. Life expectancy >3 months 19. Bulky stage IA (defined as lymph node or lymph node mass greater than 10 cm in diameter), stage IB, stage II, stage III and stage IV 20. Patients receiving corticosteroid treatment with ≤20 mg/day of prednisolone or equivalent must be documented to be on a stable dose of at least 4 weeks duration prior to the start of Cycle 1 21. If glucocorticoid treatment is urgently required for lymphoma symptom control prior to the start of treatment, prednisolone 1 mg/kg or equivalent is permitted to a maximum of 14 days as a pre-phase treatment |
| Participant exclusion criteria | 1. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products 2. Patients with central nervous system or meningeal involvement by the lymphoma 3. Contraindication to any of the individual components of mini-CHP or GCP including prior administration of anthracyclines. 4. Prior organ transplantation 5. Demyelinating Charcot-Marie-Tooth disease 6. Burkitt lymphoma 7. Primary mediastinal B-cell lymphoma 8. Prior treatment with cytotoxic drugs within 5 years of screening for any condition (e.g. cancer, rheumatoid arthritis) or prior use of any anti-CD20 antibody. 9. Patients with a previous diagnosis of low-grade lymphoma (NB: a concurrent finding of low-grade NHL in the BM at presentation is allowed) and patients with non-bulky stage IA disease 10. Patients with positive serology for HIV, HTVL-1, HCV, HepBcAb, HepBsAg 11. Patients with suspected active Tuberculosis or latent Tuberculosis 12. Pregnancy or lactation or intending to become pregnant during the study 13. Peripheral neuropathy >Grade 1 14. Known active bacterial, viral, fungal or parasitic infections 15. Illicit drug or alcohol abuse; active viral or other hepatitis or cirrhosis 16. Prolonged corticosteroid use >20 mg/day of prednisolone or equivalent for purposes other than lymphoma symptom control |
| Recruitment start date | 01/05/2022 |
| Recruitment end date | 30/05/2022 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Clatterbridge Road
Bebington
CH63 4JY
United Kingdom
Great Maze Pond
London
SE1 9RT
United Kingdom
235 Euston Road
London
NW1 2BU
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
550 Wilmslow Road
Withington
Manchester
M20 4BX
United Kingdom
Glasgow
G12 0YN
United Kingdom
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Sponsor information
Hospital/treatment centre
c/o Maria Maguire
Clatterbridge Road
Bebington
Wirral
CH63 4JY
England
United Kingdom
| Phone | +44 (0)1515565321 |
|---|---|
| maria.maguire2@nhs.net | |
| Website | http://www.clatterbridgecc.nhs.uk/ |
"ROR" |
https://ror.org/05gcq4j10 |
Funders
Funder type
Industry
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- Hoffman-La Roche, F. Hoffmann-La Roche Ltd.
- Location
- Switzerland
Results and Publications
| Intention to publish date | 31/12/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Planned publication in a high-impact peer-reviewed journal 2. Additional files aren’t currently available |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
13/03/2023: The trial was stopped on 23/01/2023 before any participants had been enrolled.
11/03/2022: The recruitment start date has been changed from 31/01/2022 to 01/05/2022.
28/09/2021: The following changes have been made:
1. The recruitment start date has been changed from 01/09/2021 to 31/01/2022.
2. The recruitment end date has been changed from 31/01/2022 to 31/05/2022.
16/06/2021: The recruitment start date has been changed from 01/06/2021 to 01/09/2021.
03/03/2021: The recruitment start date has been changed from 01/03/2021 to 01/06/2021.
05/01/2021: The recruitment start date was changed from 30/01/2021 to 01/03/2021.
11/12/2020: Internal review.
12/11/2020: Trial's existence confirmed by the NIHR.
