Condition category
Cancer
Date applied
14/08/2017
Date assigned
16/08/2017
Last edited
16/08/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Lay summary under review with external organisation

Trial website

Contact information

Type

Scientific

Primary contact

Miss Debbie Hamid

ORCID ID

http://orcid.org/0000-0003-2329-805X

Contact details

Southampton Clinical Trials Unit
Southampton General Hospital
MP131
Tremona Road
Southampton
SO16 6YD
United Kingdom

Additional identifiers

EudraCT number

2017-000302-37

ClinicalTrials.gov number

Protocol/serial number

35676

Study information

Scientific title

A phase IIa study of Rituximab and Varlilumab in relapsed or refractory B-cell malignancies (RiVa): a randomised controlled trial

Acronym

Study hypothesis

Varlilumab enhances rituximab-mediated killing of tumour cells by increasing the number of immune effector cells.

Ethics approval

Not provided at time of registration - approval pending

Study design

Randomised; Interventional; Design type: Treatment, Drug, Immunotherapy

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Cancer, Primary sub-specialty: Lymphoma; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissu

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

Other

Phase

Phase II

Drug names

Primary outcome measures

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

No secondary outcome measures

Overall trial start date

31/08/2017

Overall trial end date

30/09/2019

Reason abandoned

Eligibility

Participant 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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 40; UK Sample Size: 40

Participant 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

Recruitment start date

30/09/2017

Recruitment end date

30/03/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Southampton General Hospital
Tremona Road
Southampton
SO16 6YD

Trial participating centre

Churchill Hospital
Old Road Headington
Oxford
OX3 7LE

Trial participating centre

Derriford Hospital
Derriford Road
Plymouth
PL6 8DH

Trial participating centre

The Christie
550 Wilmslow Road Withington
Manchester
MX20 4BX

Sponsor information

Organisation

University Hospital Southampton NHS Foundation Trust

Sponsor details

Mailpoint 18
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

Cancer Research UK; Grant Codes: CRUKD/17/008

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high impact peer review journal 1 year after overall trial end date.

IPD sharing statement
The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Intention to publish date

30/09/2020

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes