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.

Phase 1

• Conditions: Relapsed or refractory B-Cell malignancies; MedDRA version: 20.0 Level: PT Classification code 10003903 Term: B-cell lymphoma refractory System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0 Level: PT Classification code 10012821 Term: Diffuse large B-cell lymphoma recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0 Level: PT Classification code 10012822 Term: Diffuse large B-cell lymphoma refractory System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0 Level: PT Classification code 10003902 Term: B-cell lymphoma recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-000302-37-GB
• Lead Sponsor: niversity Hospital Southampton Foundation Trust

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-06-01
• Last Update Posted: 30 June 2019

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Not specified
• Target Recruitment: 40

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.

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).

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified