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    Summary
    EudraCT Number:2017-000302-37
    Sponsor's Protocol Code Number:RHMCAN1278
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-06-01
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2017-000302-37
    A.3Full title of the trial
    A phase IIa study of Rituximab and Varlilumab in relapsed or refractory B-cell malignancies
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the safety and efficacy of the drugs rituximab and varlilumab in patients with B-cell cancer that did not respond to treatment or has returned.
    A.3.2Name or abbreviated title of the trial where available
    RiVa
    A.4.1Sponsor's protocol code numberRHMCAN1278
    A.5.4Other Identifiers
    Name:EudraCTNumber:2017-000302-37
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity Hospital Southampton Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Southampton NHS Foundation Trust
    B.5.2Functional name of contact pointAilsa Duckworth
    B.5.3 Address:
    B.5.3.1Street AddressR&D office, E level, Southampton Centre for Biomedical Research
    B.5.3.2Town/ citySouthampton General Hospital, Tremona Road
    B.5.3.3Post codeSO16 6YD
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number023 8120 5131
    B.5.6E-mailailsa.duckworth@uhs.nhs.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVarlilumab (as called CDX-1127)
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNvarlilumab
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed or refractory B-Cell malignancies
    E.1.1.1Medical condition in easily understood language
    B-Cell lymphoma in patients who have their disease returning or is resistant to treatment
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10003903
    E.1.2Term B-cell lymphoma refractory
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012821
    E.1.2Term Diffuse large B-cell lymphoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012822
    E.1.2Term Diffuse large B-cell lymphoma refractory
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10003902
    E.1.2Term B-cell lymphoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of this trial is to answer two principal questions:

    - Is it safe to administer varlilumab and rituximab together? (safety and tolerability of combination therapy)

    - Does the combination of varlilumab and rituximab have anti-tumour activity in patients with B-cell lymphoma whose disease did not respond to previous treatment or has returned? (anti-tumour activity of combined rituximab and varlilumab therapy in relapsed or refractory B-cell malignancies)
    E.2.2Secondary objectives of the trial
    The secondary objective of the study is to measure the duration of response to rituximab and varlilumab over a follow-up period of one year (progression-free and overall survival).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Relapsed or refractory CD20+ B-cell lymphoma excluding chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL).
    • High grade subgroup: Diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL) grade 3b, transformed Follicular Lymphoma
    • Low grade subgroup: All low grade CD20+ B-cell lymphoma subtypes excluding CLL/SLL, e.g. Mantle cell lymphoma (MCL), Lymphoplasmacytic lymphoma (LPL) and Follicular Lymphoma (FL) grade 1, 2 and 3a
    2. Disease must be recurrent or treatment refractory, and received at least one line of treatment. Rituximab-refractory patients are eligible for entry into the study.
    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:
    • Haemoglobin (Hb) ≥ 90 g/L (red cell support is permissible)
    • Absolute neutrophil count (ANC) ≥1.0 x 10^9/L (or ≥0.5 x 10^9/L if bone marrow involvement) G-CSF support is not permissible at screening
    • Platelet count ≥75 x 10^9/L (or ≥30 x 10/L if bone marrow involvement)
    • 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
    • Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x (ULN) unless raised due to hepatic involvement
    • Calculated creatinine clearance (Cockroft-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. Women of childbearing potential, must be willing to participate in appropriate pregnancy prevention measures:
    a. Female patients 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 two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom; an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose of varlilumab are considered eligible.
    b. Male patients with partners of child-bearing potential who agree to take measures not to father children by using one form of highly effective contraception (oral, injected or implanted hormonal contraception and condom; an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose of varlilumab are considered eligible. Male subjects must also refrain from donating sperm during this period.
    c. 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.
    E.4Principal 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:
    • 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, and
    • 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.
    • 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.
    • 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).
    E.5 End points
    E.5.1Primary end point(s)
    1. The causality of each adverse event and grading of severity according to NCI CTCAE Version 4.03.

    2. Response in each case according to the Lugano Revised Response Criteria for Malignant Lymphoma.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Adverse events will be recorded at each visit from cycle 1 day 1 until the last follow up visit.

    Response will be assessed two weeks after completion of cycle 6.
    E.5.2Secondary end point(s)
    To measure the duration of response to rituximab and varlilumab over a follow-up period of 1 year.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will have a follow up visit every two months for one year after completion of study treatment.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last visit of last subject.
    The end of the trial is defined as: The patient reaches the final follow up visit, which will be one year after receiving the last study treatment.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days25
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days25
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 2
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The patient will be treated according to standard NHS guidelines and local policy once they have finished the trial. Patients will receive trial drug until treatment completion, if treatment is discontinued as a result of toxicity, patient withdraws consent or the physician decides to withdraw the patient from the study, the patient will be treated according to the standard NHS guidelines in the local hospitals.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-06
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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