A Combination of Rituximab and Varlilumab Immunotherapy in Patients with B-cell Lymphoma

NCT03307746 | Completed Phase 1 DMC

• 1 other identifier: RHMCAN1278
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 4

Brief Summary

A total of 40 participants will be recruited, with 20 participants in each of the following subcategories: A) High grade lymphoma (DLBCL, FL grade 3b, transformed FL) (n=20) B) Low grade lymphoma (e.g. FL grade 1, 2 or 3a, MZL, MCL) (n=20) The main purpose for having two experimental treatment arms is to provide a comparator for the translational endpoints, i.e. to assess whether the differences observed are due to the addition of varlilumab to rituximab. The only difference between Arm A and Arm B is the delay in administration of varlilumab in cycle 1, which is on Day 2 in Arm A and Day 8 in Arm B. As the post-treatment tissue collection occurs on Day 7/8, prior to administration of varlilumab in Arm B, samples will be obtained from participants that have either been treated with rituximab alone, or both rituximab and varlilumab. To minimise any potential risks to the patient as a result of a repeat biopsy on Day 7/8, a prerequisite for entry to the trial is that the participants must have accessible sites for biopsy. Difference in response rates between Arm A and Arm B are not expected.

Conditions

B Cell Lymphoma

Outcome Measures

Primary Outcomes (2)

• Causality and severity of each adverse event

  Causality of each adverse event and grading of severity according to NCI CTCAE version 4.03

  From date of consent, up to max. 15 months

• Activity - Lugano response criteria

  Response of disease to treatment assessed at the end of treatment via contrast enhanced CT scan and classified according to the Lugano Revised Response Criteria for Malignant Lymphoma

  4 months

Secondary Outcomes (2)

• Overall Survival

  Time from randomisation until death from any cause up to a max. of 15 months after randomisation

• Progression-Free Survival

  Time from randomisation until disease progression or death from any cause up to a max. of 15 months after randomisation

Study Arms (2)

ARM A- Rituximab and Varlilumab

ACTIVE COMPARATOR

Patients in ARM A willl receive Cycle1 Day 1: rituximab 375 mg/m2 IV Cycle 1 Day 2: varlilumab 3 mg/kg IV Cycles 2 Day 1: rituximab 375 mg/m2 IV Cycle 3 Day 1: rituximab 375 mg/m2 IV Cycle 3 Day 2: varlilumab 3 mg/kg IV Cycle 4 Day 1: rituximab 375 mg/m2 IV Cycle 5 Day 1: rituximab 375 mg/m2 IV Cycle 5 Day 2: varlilumab 3 mg/kg IV Cycle 6 Day 1: rituximab 375 mg/m2 IV

Drug: Varlilumab

ARM B - Rituximab and Varlilumab

ACTIVE COMPARATOR

Patients in ARM B will receive Cycle 1 Day 1: rituximab 375 mg/m2 IV Cycle 1 Day 8: varlilumab 3 mg/kg IV Cycle 2 Day 1: rituximab 375 mg/m2 IV Cycle 3 Day 1: rituximab 375 mg/m2 IV Cycle 3 Day 2: varlilumab 3 mg/kg IV Cycle 4 Day 1: rituximab 375 mg/m2 IV Cycle 5 Day 1: rituximab 375 mg/m2 IV Cycle 5 Day 2: varlilumab 3 mg/kg IV Cycle 6 Day 1: rituximab 375 mg/m2 IV

Drug: Varlilumab

Interventions

Varlilumab DRUG

Rituximab is a so-called direct-targeting mAb, which binds to the CD20 molecule on the surface of normal and malignant B cells. The mAb then engages immune effectors cells, such as macrophages, through Fc:Fc gamma receptor interaction, leading to tumour cell killing by antibody directed cellular cytotoxicity and/or phagocytosis (ADCC/ADCP). Varlilumab (1F5, CDX-1127) is a recombinant and fully human IgG1kappa mAb that binds to human CD27 with high affinity (62). As far as we are aware, it is the only anti-CD27 mAb in clinical development. Once bound, varlilumab blocks CD70 binding to CD27.

Also known as: Rituximab

ARM A- Rituximab and Varlilumab; ARM B - Rituximab and Varlilumab

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Relapsed or refractory CD20+ B-cell lymphoma excluding chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL).
• High grade subgroup: Diffuse large B-cell lymphoma, FL grade 3b, transformed FL
• Low grade subgroup: All low grade CD20+ B-cell lymphoma subtypes excluding CLL/SLL (e.g. FL grade 1,2 or 3a, MCL, LPL)
• 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.
• At least one measurable lesion by CT scan (defined as \>1.5 cm in one axis) that is also easily accessible for biopsy.
• Histological confirmation of relapse within 12 months of treatment.
• years of age or older.
• Haematological and biochemical indices with the ranges shown below:
• Laboratory Test Value required
• Haemoglobin (Hb) ≥ 90 g/L (red cell support is permissible)
• 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.
• Platelet count ≥75 x 109/L (or ≥30 x 109/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 (Cockcroft-Gault formula) ≥30 ml/min (uncorrected value)

You may not qualify if:

• Known central nervous system involvement by lymphoma, that is not in remission, are excluded from the study.
• 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.
• 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.
• Significant concurrent, uncontrolled medical condition that in the opinion of the Investigator contraindicates participation in this study.
• 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.
• Active infection requiring systemic therapy.
• Women who are pregnant or lactating.
• 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. Participants with occult or prior HBV infection (defined as negative HBsAg and positive HBcAb) will not be eligible. Participants 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.
• Previous recipient of an allogeneic bone marrow transplant at any time.
• Autologous bone marrow transplant within 100 days of first dosing.
• Systemic radiation therapy within 4 weeks or prior focal radiotherapy within 2 weeks prior to first dosing.

Sponsors & Collaborators

• University Hospital Southampton NHS Foundation Trust: lead
• University Hospital Plymouth NHS Trust: collaborator
• The Christie NHS Foundation Trust: collaborator
• Oxford University Hospitals NHS Trust: collaborator
• Celldex Therapeutics: collaborator
• Cancer Research UK: collaborator

Study Sites (4)

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

Oxford University Hospitals NHS Foundation Trust

Oxford, United Kingdom

Location

Plymouth Hospitals NHS Trust

Plymouth, United Kingdom

Location

University Hospital Southampton NHS Foundation Trust

Southampton, United Kingdom

Location

MeSH Terms

Conditions

Lymphoma, B-Cell

Interventions

varlilumab; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patient will be randomised into Arm A (20 patients) or Arm B (20 Patients)

Study Record Dates

• First Submitted: August 7, 2017
• First Posted: October 12, 2017
• Study Start: November 23, 2017
• Primary Completion: February 18, 2021
• Study Completion: August 21, 2024
• Last Updated: December 2, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

GB (4)