Clinical Trials /

Rituximab and Hyaluronidase Human in Patients With Advanced Melanoma Undergoing Nivolumab and Ipilimumab Therapy

NCT03719131

Description:

This phase II trial studies how well rituximab and hyaluronidase human (Rituxan Hycela) works in treating participants with stage III-IV melanoma that cannot be removed by surgery who are undergoing nivolumab and ipilimumab therapy. Monoclonal antibodies, such as rituximab and hyaluronidase human, may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Rituximab and Hyaluronidase Human in Patients With Advanced Melanoma Undergoing Nivolumab and Ipilimumab Therapy
  • Official Title: A Randomized Phase 2 Study of Rituxan Hycela in Patients With Advanced Melanoma Undergoing Combination Immune Checkpoint Blockade With Nivolumab and Ipilimumab

Clinical Trial IDs

  • ORG STUDY ID: IRB00105605
  • SECONDARY ID: NCI-2018-01804
  • SECONDARY ID: Winship4457-18
  • NCT ID: NCT03719131

Conditions

  • Cutaneous Melanoma, Stage III
  • Cutaneous Melanoma, Stage IV
  • Stage III Melanoma
  • Stage IIIA Skin Melanoma
  • Stage IIIB Skin Melanoma
  • Stage IIIC Skin Melanoma
  • Stage IV Skin Melanoma
  • Unresectable Melanoma

Interventions

DrugSynonymsArms
NivolumabOpdivoArm A (standard of care)
Rituximab and Hyaluronidase HumanRituxan HycelaArm B (rituximab, hyaluronidase human)
IpilimumabYervoyArm A (standard of care)

Purpose

This phase II trial studies how well rituximab and hyaluronidase human (Rituxan Hycela) works in treating participants with stage III-IV melanoma that cannot be removed by surgery who are undergoing nivolumab and ipilimumab therapy. Monoclonal antibodies, such as rituximab and hyaluronidase human, may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To compare rates for grade 3-4 immune-related adverse event (IRAE)s in the first 6 months
      in patients treated with combination checkpoint blockade (CCB) therapy (anti-CTLA4 and
      anti-PD1) as a part of standard of care for advanced melanoma who are treated with a single
      course of 4 weekly doses of rituximab and hyaluronidase human (Rituxan) therapy versus those
      who are not treated with Rituxan.

      SECONDARY OBJECTIVES:

      I. To evaluate the safety and tolerability (in terms of Rituxan-related adverse events) in
      patients with melanoma receiving CCB.

      II. To compare objective response rate in patients receiving CCB therapy + Rituxan versus CCB
      therapy alone.

      III. To compare 1 year overall and progression-free survival in patients receiving CCB
      therapy + Rituxan versus CCB therapy alone.

      IV. To compare changes in cluster of differentiation 21lo (CD21lo) B cells in patients
      receiving CCB therapy + Rituxan versus CCB therapy alone.

      V. To compare changes in T cells in patients receiving CCB therapy + Rituxan versus CCB
      therapy alone.

      OUTLINE: Participants are randomized to 1 of 2 arms.

      ARM A: Participants receive standard of care ipilimumab and nivolumab therapy.

      ARM B: Participants receive standard of care ipilimumab and nivolumab therapy. On day 2 of
      each cycle, participants also receive rituximab and hyaluronidase human intravenously (IV) or
      subcutaneously (SC) weekly starting week 1 for 4 doses in the absence of disease progression
      or unacceptable toxicity.

      After completion of study treatment, participants are followed up for 4 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (standard of care)Active ComparatorEach cycle is 21 days and includes ipilimumab on day 1 plus nivolumab on day 1. All patients will receive nivolumab every 4 weeks for up to 13 doses (52 weeks) until disease progression or intolerable adverse events. All treatments will have a +/-3 business day window for administration.
  • Nivolumab
  • Ipilimumab
Arm B (rituximab, hyaluronidase human)ExperimentalEach cycle is 21 days and includes ipilimumab on day 1 plus nivolumab on day 1. In addition, patients will receive 4 weekly doses of Rituxan (first dose intravenously and then 3 weekly doses subcutaneously). Rituxan will be administered on day 2 of each cycle after infusion of ipilimumab/nivolumab on weeks 1 and 4. All treatments will have a +/-3 business day window for administration.
  • Nivolumab
  • Rituximab and Hyaluronidase Human
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Clinically eligible to receive Food and Drug Administration (FDA) approved standard of
             care combination immune checkpoint therapy with ipilimumab and nivolumab for
             unresectable stage III or stage IV melanoma.

          -  No therapy with immune checkpoint inhibitors within 1 year prior to starting
             combination checkpoint therapy. Prior adjuvant ipilimumab, nivolumab, or pembrolizumab
             as single agent is allowed if greater than 1 year since last treatment and patient had
             no grade 3 or 4 toxicities from the checkpoint inhibitors. History of adjuvant
             interferon is allowed.

          -  Obtained within one week prior to randomization:

               -  White blood count ≥ 3,000/µL

               -  Absolute neutrophil count (ANC) ≥ 1,500/µL

               -  Platelet count ≥ 100,000/µL

               -  Hemoglobin ≥ 9 g/dL

               -  Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) or serum
                  creatinine clearance (CrCl) ≥ 40 ml/min

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (≤
                  5 x ULN for patients with documented liver metastases)

               -  Alkaline phosphatase ≤ 2 X ULN (≤ 5 X ULN for those with bone metastasis)

               -  Total bilirubin ≤ 1.5 X ULN except those with direct bilirubin or Gilbert's
                  syndrome

               -  Serum lactate dehydrogenase (LDH) ≤ 10 X ULN

        Exclusion Criteria:

          -  Allergy to rituximab, or any of the ingredients in rituximab injection or rituximab
             and hyaluronidase human injection.

          -  Patients with active central nervous system (CNS) metastatic disease or leptomeningeal
             disease. Patients with CNS metastatic disease that has been treated with surgical
             resection or stereotactic radiosurgery are eligible if lesions are stable for at least
             4 weeks following therapy as determined by magnetic resonance imaging (MRI) scan done
             within one week of randomization.

          -  Prior therapy with immune checkpoint blocking antibodies (unless monotherapy given at
             least 1 year prior to starting combination therapy and no grade 3-4 toxicities while
             on monotherapy), vaccines or interleukin-2 (IL-2).

          -  Patients may have had prior systemic therapy in the adjuvant setting (e.g. interferon,
             proto-oncogene B-Raf [BRAF], or mitogen-activated protein-extracellular
             signal-regulated kinase [MEK] agents). Adjuvant ipilimumab, nivolumab, or
             pembrolizumab as single agent is allowed if greater than 1 year since last treatment
             and patient had no grade 3 or 4 toxicities from the checkpoint inhibitors.

          -  Women must not be pregnant or lactating. Must have negative urine or blood pregnancy
             test within 1 week of starting therapy.

          -  Patients with known human immunodeficiency virus (HIV) are ineligible.

          -  Patients with active hepatitis B virus (HBV) or hepatitis C virus (HCV) are
             ineligible.

          -  Patients with active, known or suspected autoimmune disorders including lupus and type
             I diabetes are ineligible. Patients with history of vitiligo, thyroiditis are
             eligible.

          -  Patients with active disease or history of inflammatory bowel disease are ineligible.

          -  Patients cannot be on corticosteroid therapy except as physiologic replacement
             therapy.

          -  Patients receiving ongoing corticosteroid therapy for autoimmune disorders are
             ineligible. Occasional steroid inhaler use or nasal spray are allowed. Patients
             receiving replacement doses of steroids for adrenal insufficiency are eligible.

          -  Patients must not have any serious underlying medical conditions or take medications
             that in the investigators opinion may interfere with compliance or interpretation of
             Immune-related adverse events (IRAEs).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of Common Terminology Criteria (CTC) (version [v]5.0) grade 3 or greater immune-related adverse events
Time Frame:At 6 months after study start
Safety Issue:
Description:All patients will be evaluable for toxicity from the time of their first treatment with ipilimumab/nivolumab. Investigators will review the toxicities, grade, and attribute each toxicity.

Secondary Outcome Measures

Measure:Rate of CTC (v5.0) toxicity related to rituximab and hyaluronidase human
Time Frame:Up to 4 weeks after study start
Safety Issue:
Description:All patients will be evaluable for toxicity from the time of their first treatment with ipilimumab/nivolumab. Investigators will review the toxicities, grade, and attribute each toxicity.
Measure:Objective tumor response
Time Frame:At 12 weeks and every 12 weeks thereafter up to 1 year
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune-related (ir)RECIST. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.
Measure:Rate of overall survival
Time Frame:From start of treatment up to 1 year
Safety Issue:
Description:Overall survival is defined as the duration of time from start of treatment to time of death or last follow-up, whichever occurs first.
Measure:Rate of progression-free survival (PFS)
Time Frame:From start of treatment up to 1 year
Safety Issue:
Description:PFS is defined as the duration of time from start of treatment to time of progression or death or last follow-up, whichever occurs first.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Emory University

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