Clinical Trials /

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

NCT03307746

Description:

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.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Combination of Rituximab and Varlilumab Immunotherapy in Patients With B-cell Lymphoma
  • Official Title: A Phase IIa Study of RItuximab and VArlilumab in Relapsed or Refractory B-cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: RHMCAN1278
  • NCT ID: NCT03307746

Conditions

  • B Cell Lymphoma

Interventions

DrugSynonymsArms
VarlilumabRituximabARM A- Rituximab and Varlilumab

Purpose

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.

Detailed Description

      A multicentre, randomised, phase IIa study in participants with relapsed or refractory CD20+
      B-cell malignancies. The study will be conducted in 2 stages as follows:

      Stage 1 - Safety During the safety phase, 6 participants (3 from each Arm and from any
      subtype) will be treated as detailed in section 6.1. The number of dose limiting toxicities
      (DLTs) experienced by these participants in each arm after having completed the first cycle
      will dictate whether the trial will proceed to the second stage.

        1. In each arm, if out of these 3 participants 0 experience a DLT, then that arm will
           proceed to stage 2.

        2. In each arm, if out of these 3 participants 1 or 2 experience a DLT, then that arm will
           be expanded to 3 more participants.

             1. If 1 or 2 out of 6 participants experience a dose limiting toxicity, the arm will
                proceed to Stage 2.

             2. If 3 or more out of 6 participants experience a DLT, recruitment for that arm will
                be stopped.

        3. If out of these 3 participants, 3 experience a dose limiting toxicity, recruitment for
           that arm will be stopped.

      Initially, the first patient will be entered into the trial. Providing there are no serious
      or unexplained safety issues during the first 2 weeks, as determined by the Safety Review
      Committee (SRC), then dosing of subsequent participants will continue as they are identified.
      Should toxicity findings of concern occur, the SRC may choose to stagger the start of dosing
      for subsequent participants and/or cohorts.

      The objective of Stage 2 is to obtain some further information on the safety of the
      intervention in a larger sample, information on activity (response rate overall and per
      lymphoma subtype) and feasibility of administrating rituximab and varlilumab together. During
      Stage 2, recruitment will continue so (including those in Stage 1), there is a total of 10
      participants per arm and per disease category (a total of 20 participants per disease
      category, 40 participants in the trial in total).
    

Trial Arms

NameTypeDescriptionInterventions
ARM A- Rituximab and VarlilumabActive ComparatorPatients 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
  • Varlilumab
ARM B - Rituximab and VarlilumabActive ComparatorPatients 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
  • Varlilumab

Eligibility Criteria

        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, 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)

          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:

               -  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)

          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:

               -  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.

               -  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

             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.

               -  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. 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.

          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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Toxicity
Time Frame:From date of consent, up to max. 15 months
Safety Issue:
Description:Causality of each adverse event and grading of severity according to NCI CTCAE version 4.03

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:Time from randomisation until death from any cause up to a max. of 15 months after randomisation
Safety Issue:
Description:Survival status will be assessed every 2 months
Measure:Progression-Free Survival
Time Frame:Time from randomisation until disease progression or death from any cause up to a max. of 15 months after randomisation
Safety Issue:
Description:Length of time that patients are free from disease

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Hospital Southampton NHS Foundation Trust

Last Updated

February 2, 2018