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

Primary Purpose

Cutaneous Melanoma, Stage III, Cutaneous Melanoma, Stage IV, Stage III Melanoma

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Nivolumab
Rituximab and Hyaluronidase Human
Ipilimumab
Sponsored by
Emory University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cutaneous Melanoma, Stage III

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 prior history of, or serology suggestive of prior infection with Hepatitis B Virus (HBV) or Hepatitis C virus (HCV) are also 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).

Sites / Locations

  • Emory University Hospital/Winship Cancer InstituteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Arm A (standard of care)

Arm B (rituximab, hyaluronidase human)

Arm Description

This is standard of care arm: induction with 4 cycles (21 days each) of Ipilimumab and nivolumab followed by continuation with nivolumab alone every month X1 year (13 doses).

This includes induction with 4 cycles of ipilimumab and nivolumab X 4 cycles followed by continuation with nivolumab alone every month for 1 year as in standard of care arm. Each induction 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). First dose of Rituxan will be administered one week following the start of cycle 1 of ipilimumab and nivolumab. All treatments will have a +/-3 business day window for administration.

Outcomes

Primary Outcome Measures

Rate of Common Terminology Criteria (CTC) (version [v]5.0) grade 3 or greater immune-related adverse events
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

Rate of CTC (v5.0) toxicity related to rituximab and hyaluronidase human
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.
Objective tumor response
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.
Rate of overall survival
Overall survival is defined as the duration of time from start of treatment to time of death or last follow-up, whichever occurs first.
Rate of progression-free survival (PFS)
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.

Full Information

First Posted
October 23, 2018
Last Updated
June 27, 2022
Sponsor
Emory University
Collaborators
Genentech, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03719131
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Recruiting
Study Start Date
June 5, 2019 (Actual)
Primary Completion Date
October 31, 2023 (Anticipated)
Study Completion Date
October 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Emory University
Collaborators
Genentech, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial studies whether rituximab and hyaluronidase human (Rituxan Hycela) can prevent immune related adverse events in participants with stage III-IV melanoma that cannot be removed by surgery who are undergoing nivolumab and ipilimumab therapy.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
44 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm A (standard of care)
Arm Type
Active Comparator
Arm Description
This is standard of care arm: induction with 4 cycles (21 days each) of Ipilimumab and nivolumab followed by continuation with nivolumab alone every month X1 year (13 doses).
Arm Title
Arm B (rituximab, hyaluronidase human)
Arm Type
Experimental
Arm Description
This includes induction with 4 cycles of ipilimumab and nivolumab X 4 cycles followed by continuation with nivolumab alone every month for 1 year as in standard of care arm. Each induction 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). First dose of Rituxan will be administered one week following the start of cycle 1 of ipilimumab and nivolumab. All treatments will have a +/-3 business day window for administration.
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
Opdivo
Intervention Description
Receive standard of care nivolumab therapy
Intervention Type
Biological
Intervention Name(s)
Rituximab and Hyaluronidase Human
Other Intervention Name(s)
Rituxan Hycela
Intervention Description
Given IV or SC
Intervention Type
Drug
Intervention Name(s)
Ipilimumab
Other Intervention Name(s)
Yervoy
Intervention Description
Receive standard of care ipilimumab therapy
Primary Outcome Measure Information:
Title
Rate of Common Terminology Criteria (CTC) (version [v]5.0) grade 3 or greater immune-related adverse events
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.
Time Frame
At 6 months after study start
Secondary Outcome Measure Information:
Title
Rate of CTC (v5.0) toxicity related to rituximab and hyaluronidase human
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.
Time Frame
Up to 4 weeks after study start
Title
Objective tumor response
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.
Time Frame
At 12 weeks and every 12 weeks thereafter up to 1 year
Title
Rate of overall survival
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.
Time Frame
From start of treatment up to 1 year
Title
Rate of progression-free survival (PFS)
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.
Time Frame
From start of treatment up to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 prior history of, or serology suggestive of prior infection with Hepatitis B Virus (HBV) or Hepatitis C virus (HCV) are also 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).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kavita Dhodapkar, MD
Phone
404-778-3612
Email
kavita.dhodapkar@emory.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kavita Dhodapkar, MD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Emory University Hospital/Winship Cancer Institute
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Agnes Harutyunyan
Phone
404-778-3612
Email
agnieszka.anna.harutyunyan@emory.edu
First Name & Middle Initial & Last Name & Degree
Kavita Dhodapkar, MD

12. IPD Sharing Statement

Learn more about this trial

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

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