E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory B-Cell malignancies |
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E.1.1.1 | Medical condition in easily understood language |
B-Cell lymphoma in patients who have their disease returning or is resistant to treatment |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003903 |
E.1.2 | Term | B-cell lymphoma refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012821 |
E.1.2 | Term | Diffuse large B-cell lymphoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012822 |
E.1.2 | Term | Diffuse large B-cell lymphoma refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003902 |
E.1.2 | Term | B-cell lymphoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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)
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E.2.2 | Secondary 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). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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). |
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E.5 End points |
E.5.1 | Primary 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.
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E.5.1.1 | Timepoint(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. |
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E.5.2 | Secondary end point(s) |
To measure the duration of response to rituximab and varlilumab over a follow-up period of 1 year. |
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E.5.2.1 | Timepoint(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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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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. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 25 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 25 |