A phase IIa study of rituximab and varlilumab in relapsed or refractory B-cell malignancies
| ISRCTN | ISRCTN15025004 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN15025004 |
| EudraCT/CTIS number | 2017-000302-37 |
| ClinicalTrials.gov number | NCT03307746 |
| Secondary identifying numbers | 35676 |
- Submission date
- 14/08/2017
- Registration date
- 16/08/2017
- Last edited
- 08/04/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English summary of protocol
Contact information
Ms Cherish Boxall
Scientific
Scientific
Southampton Clinical Trials Unit
Southampton General Hospital, MP131
Tremona Road
Southampton
SO16 6YD
United Kingdom
| Phone | +44 (0)23 8120 5333 |
|---|---|
| riva@soton.ac.uk |
Study information
| Study design | Randomized; Interventional; Design type: Treatment, Drug, Immunotherapy |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN15025004_PIS_v2_27Jul17.pdf |
| Scientific title | A phase IIa study of Rituximab and Varlilumab in relapsed or refractory B-cell malignancies (RiVa): a randomised controlled trial |
| Study acronym | RiVa |
| Study objectives | Varlilumab enhances rituximab-mediated killing of tumour cells by increasing the number of immune effector cells. |
| Ethics approval(s) | Approved 30/08/2017, South Central - Oxford A Research Ethics Committee (Bristol Research Ethics Committee Centre, Whitefriars, Level 3 Block B, Lewins Mead, Bristol, BS1 2NT, UK; +44 (0)207 1048171, +44 (0)207 104 8141, +44 (0)207 104 8272; oxforda.rec@hra.nhs.uk), ref: 17/SC/0317 |
| Health condition(s) or problem(s) studied | Lymphoma |
| Intervention | 20 patients will be allocated to the high grade group (i.e. patients with DLBCL, follicular lymphoma grade 3b, transformed follicular lymphoma) and 20 patients to the low grade group (i.e. patients with follicular lymphoma grade 1, 2 or 3a, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL)). In the high grade group 10 will be randomised to Arm A and 10 to Arm B. In the low grade group 10 will be randomised to Arm A and 10 to ARM. Patients will receive 6 cycles of treatment, with administration of rituximab on day 1 of each cycle and of varlilumab on day 2 of cycles 1, 3 and 5. Each cycle is 2 weeks long. Patients in Arm A: For Cycle 1 will receive Rituximab 375 mg/m2 IV on Day 1 and Varlilumab 3 mg/kg IV on Day 2. Thereafter every 2 weeks patients will Rituximab 375 mg/m2 IV for 12 weeks in cycle 2 and 6 on Day 1 and Varlilumab 3 mg/kg IV for 12 weeks. Patients in Arm B: For Cycle 1 will receive Rituximab 375 mg/m2 on Day 1 and Varlilumab 3 mg/kg IV on Day 8. Thereafter every 2 weeks patients will receive Rituximab 375 mg/m2 IV for 12 weeks in cycle 2 and 6 on Day 1 and Varlilumab 3 mg/kg IV for 12 weeks. Patients will then be followed up 2 weeks after they complete the trial treatment and every 2 months over a period of 12 months at 2, 4, 6, 8, 10 and 12 months. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Rituximab, varlilumab |
| Primary outcome measure | 1. Safety: DLT and adverse events and grading of severity according to NCI CTCAE Version 4.03). Timepoint(s): during trial treatment and for 12 months after trial treatment 2. Efficacy: response in each case according to the Lugano Revised Response Criteria for Malignant Lymphoma; Timepoint(s): 2 weeks after treatment, and every 2 months after trial treatment up to 12 months |
| Secondary outcome measures | There are no secondary outcome measures |
| Overall study start date | 31/08/2017 |
| Completion date | 21/08/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | Planned Sample Size: 40; UK Sample Size: 40 |
| Total final enrolment | 27 |
| Key inclusion criteria | 1. Relapsed or refractory CD20+ B-cell lymphoma excluding chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL): 1.1. High grade subgroup: Diffuse large B-cell lymphoma, FL grade 3b, transformed FL 1.2. Low grade subgroup: All low grade CD20+ B-cell lymphoma subtypes excluding CLL/SLL (e.g. FL grade 1,2 or 3a, MCL, LPL) 2. Disease must be recurrent or treatment refractory, and received at least one line of treatment. Rituximab-refractory participants are eligible for the entry into the study as long as the tumour expresses CD20 3. At least one measurable lesion by CT scan (defined as >1.5 cm in one axis) that is also easily accessible for biopsy 4. Histological confirmation of relapse within 12 months of treatment 5. 16 years of age or older 6. Haematological and biochemical indices with the ranges shown below: 6.1. Haemoglobin (Hb) ≥ 90 g/L (red cell support is permissible) 6.2. Absolute neutrophil count (ANC) ≥1.0 x 109/L (or ≥0.5 x 109/L if bone marrow involvement) G-CSF support is not permissible at screening 6.3. Platelet count ≥75 x 109/L (or ≥30 x 109/L if bone marrow involvement) 6.4. Serum bilirubin ≤1.5 x upper limit of normal (ULN) unless raised due to Gilbert’s syndrome in which case up to 3 x ULN is permissible 6.5. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN unless raised due to hepatic involvement 6.6. Calculated creatinine clearance (Cockcroft-Gault formula) ≥30 ml/min (uncorrected value) 7. Ability to understand the purpose and risks of the study and provide written informed consent 8. Willing and able to participate in all required evaluations and procedures in this study protocol 9. Participants must be willing to participate in appropriate pregnancy prevention measures 9.1. Women of childbearing potential who have a negative serum or urine pregnancy test during screening (within 14 days prior to the start of trial treatment) and agree to use one highly effective form of contraception combined with an effective form of contraception (see below) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose all study drugs are considered eligible 9.2. Male participants with partners of child-bearing potential who agree to take measures not to father children by using one form of highly effective contraception from the first administration of all study drugs, throughout the trial and for 12 months after last dose of all study drugs are considered eligible. Male subjects must also refrain from donating sperm during this period. Contraception that is considered highly effective includes oral, injected or implanted progesterone-only hormonal contraception (with inhibition of ovulation); oral, intravaginal, or transdermal combined (oestrogen and progesterone containing) hormonal contraception (with inhibition of ovulation); an intra-uterine device (IUD); an intrauterine hormone releasing system (IUS); bilateral tubal occlusion; vasectomised partner or abstinence. Contraceptive methods considered to be effective include progesterone-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action; condom; cap, diaphragm or sponge with spermicidal gel 9.3. Men with pregnant or lactating partners must be advised to use barrier method contraception (for example: condom plus spermicidal gel) to prevent exposure to the foetus or neonate 10. Life expectancy ≥ 12 weeks 11. ECOG performance status 0-2 |
| Key exclusion criteria | 1. Known central nervous system involvement by lymphoma, that is not in remission, are excluded from the study 2. History of other malignancy within the last 2 years except for: 2.1. Noninvasive malignancies such as adequately treated ductal carcinoma in situ of the breast, non-melanoma skin cancer or lentigo maligna, cervical carcinoma in situ and urothelial papillary noninvasive carcinoma or carcinoma in situ 2.2. Prostate intraepithelial neoplasia without evidence of prostate cancer 3. Receiving treatment (or within a month of) with chemotherapy, immunotherapy or immunosuppressive agents. This includes any systemic steroids at dose exceeding 10 mg prednisolone (or other steroid equivalent) within 2 weeks prior to first dose of varlilumab 4. Significant concurrent, uncontrolled medical condition that in the opinion of the investigator contraindicates participation in this study 5. Active and documented autoimmune disease (including, but not limited to, inflammatory bowel disease, coeliac disease, haemolytic anaemia, or immune thrombocytopenic purpura) prior to first dose of varlilumab 6. Active infection requiring systemic therapy 7. Women who are pregnant or lactating 8. Serological positivity for Hepatitis B, C, or known HIV infection. As per standard of care, the results of hepatitis serology should be known prior to commencement of immunochemotherapy 8.1. Positive test results for chronic HBV infection (defined as positive HBsAg serology and positive HBcAb) will not be eligible. Patients with occult or prior HBV infection (defined as negative HBsAg and positive HBcAb) will not be eligible. Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible 8.2. Positive test results for hepatitis C (HCV antibody serology testing) will not be eligible 9. Previous recipient of an allogeneic bone marrow transplant at any time 10. Autologous bone marrow transplant within 100 days of first dosing 11. Systemic radiation therapy within 4 weeks or prior focal radiotherapy within 2 weeks prior to first dosing 12. Subjects known or suspected of being unable to comply with the protocol 13. Ongoing toxic manifestations of previous treatments. Exceptions are to this are alopecia or certain Grade 1-toxicities, which in the opinion of the Investigator should not exclude the patient 14. Uncontrolled congestive cardiac failure, cardiac ischaemia or cardiac arrhythmia. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to registration, congestive heart failure (NYHA III-IV) 15. Subjects with a known hypersensitivity to rituximab (≥Grade 3) or murine proteins, or any other excipients used in the formulation of rituximab |
| Date of first enrolment | 30/09/2017 |
| Date of final enrolment | 31/12/2020 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
Southampton
SO16 6YD
United Kingdom
Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
United Kingdom
Headington
Oxford
OX3 7LE
United Kingdom
Derriford Hospital
Derriford Road
Plymouth
PL6 8DH
United Kingdom
Plymouth
PL6 8DH
United Kingdom
The Christie
550 Wilmslow Road
Withington
Manchester
MX20 4BX
United Kingdom
Withington
Manchester
MX20 4BX
United Kingdom
The Beatson West of Scotland Cancer Centre
1053 Great Western Rd
Glasgow
G12 0YN
United Kingdom
Glasgow
G12 0YN
United Kingdom
Newcastle Freeman Hospital
Freeman Rd
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Sponsor information
University Hospital Southampton NHS Foundation Trust
Hospital/treatment centre
Hospital/treatment centre
Mailpoint 18, Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
England
United Kingdom
"ROR" |
https://ror.org/0485axj58 |
|---|
Funders
Funder type
Charity
Cancer Research UK; Grant Codes: CRUKD/17/008
Private sector organisation / Other non-profit organizations
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, CRUK
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/01/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Planned publication in a high impact peer review journal 1 year after overall trial end date. |
| IPD sharing plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 09/11/2018 | Yes | No | |
| Participant information sheet | version v2 | 27/07/2017 | 01/04/2019 | No | Yes |
Additional files
- ISRCTN15025004_PIS_v2_27Jul17.pdf
- Uploaded 01/04/2019
Editorial Notes
08/04/2025: The overall end date was changed from 31/12/2023 to 21/08/2024.
04/09/2023: The following changes were made to the study record:
1. Total final enrolment and ethics approval details added.
2. The overall study end date was changed from 31/07/2022 to 31/12/2023.
3. The intention to publish date was changed from 31/03/2022 to 31/01/2024.
22/09/2020: The overall end date was changed from 30/11/2021 to 31/07/2022.
15/09/2020: The following changes have been made:
1. Recruitment has resumed.
2. The recruitment end date has been changed from 31/08/2020 to 31/12/2020.
04/05/2020: Due to current public health guidance, recruitment for this study has been paused.
13/01/2020: The following changes have been made:
1. The recruitment end date has been changed from 31/12/2019 to 31/08/2020.
2. The overall trial end date has been changed from 31/03/2021to 30/11/2021.
3. The trial participating centre Newcastle Freeman Hospital was added.
08/05/2019: The following changes have been made:
1. The overall trial end date has been changed from 30/09/2019 to 31/03/2021.
2. The intention to publish date has been changed from 30/09/2020 to 31/03/2022.
3. The Beatson West of Scotland Cancer Centre was added to the trial participating centres.
29/04/2019: The following changes have been made:
1. Debbie Hamid has been replaced by Cherish Boxall as the scientific contact.
2. The recruitment end date has been changed from 30/03/2019 to 31/12/2019.
24/04/2019: The clinicaltrials.gov number has been added.
03/04/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Lymphoma; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue" to "Lymphoma" following a request from the NIHR.
01/04/2019: The participant information sheet has been uploaded
12/11/2018: Publication reference added.
13/06/2018: Cancer Research UK lay summary link added to plain English summary field
14/05/2018: Internal review.
16/01/2018: Internal review.
16/10/2017: Internal review.
