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

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ClinicalTrials.gov Identifier: NCT03719131
Recruitment Status : Not yet recruiting
First Posted : October 25, 2018
Last Update Posted : October 25, 2018
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Kavita Dhodapkar, Emory University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Nivolumab Biological: Rituximab and Hyaluronidase Human Drug: Ipilimumab Phase 2

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. 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase 2 Study of Rituxan Hycela in Patients With Advanced Melanoma Undergoing Combination Immune Checkpoint Blockade With Nivolumab and Ipilimumab
Estimated Study Start Date : October 1, 2019
Estimated Primary Completion Date : October 31, 2021
Estimated Study Completion Date : October 31, 2022


Arm Intervention/treatment
Active Comparator: Arm A (standard of care)
Participants receive standard of care ipilimumab and nivolumab therapy.
Drug: Nivolumab
Receive standard of care nivolumab therapy
Other Name: Opdivo

Drug: Ipilimumab
Receive standard of care ipilimumab therapy
Other Name: Yervoy

Experimental: Arm B (rituximab, hyaluronidase human)
Participants receive standard of care ipilimumab and nivolumab therapy. Participants also receive rituximab and hyaluronidase human IV or SC weekly starting week 1 for 4 doses in the absence of disease progression or unacceptable toxicity.
Drug: Nivolumab
Receive standard of care nivolumab therapy
Other Name: Opdivo

Biological: Rituximab and Hyaluronidase Human
Given IV or SC
Other Name: Rituxan Hycela

Drug: Ipilimumab
Receive standard of care ipilimumab therapy
Other Name: Yervoy




Primary Outcome Measures :
  1. 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 ]
    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 :
  1. Rate of CTC (v5.0) toxicity related to rituximab and hyaluronidase human [ Time Frame: Up to 4 weeks after study start ]
    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.

  2. Objective tumor response [ Time Frame: At 12 weeks and every 12 weeks thereafter up to 1 year ]
    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.

  3. Rate of overall survival [ Time Frame: From start of treatment up to 1 year ]
    Overall survival is defined as the duration of time from start of treatment to time of death or last follow-up, whichever occurs first.

  4. Rate of progression-free survival (PFS) [ Time Frame: From start of treatment up to 1 year ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. 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 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03719131


Contacts
Contact: Kavita Dhodapkar, MD 404-778-3612 kavita.dhodapkar@emory.edu

Locations
United States, Georgia
Emory University Hospital/Winship Cancer Institute Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Cabell Pietras    404-778-3612    cabell.pietras@emory.edu   
Sponsors and Collaborators
Emory University
Genentech, Inc.
Investigators
Principal Investigator: Kavita Dhodapkar, MD Emory University

Responsible Party: Kavita Dhodapkar, Principal Investigator, Emory University
ClinicalTrials.gov Identifier: NCT03719131     History of Changes
Other Study ID Numbers: IRB00105605
NCI-2018-01804 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Winship4457-18 ( Other Identifier: Emory University Hospital/Winship Cancer Institute )
First Posted: October 25, 2018    Key Record Dates
Last Update Posted: October 25, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Nivolumab
Rituximab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents