Clinical trial NCT03719131: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
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
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2018-10-25
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Number of Participants With Common Terminology Criteria (CTC) (Version [v]5.0) Grade 3 or Greater Immune-related Adverse Events
timeFrame: At 6 months after study start
Secondary outcomes:
measure: Rate of CTC (v5.0) Toxicity Related to Rituximab and Hyaluronidase Human
timeFrame: Up to 4 weeks after study start
measure: Objective Tumor Response
timeFrame: At 12 weeks and every 12 weeks thereafter up to 1 year
measure: Rate of Overall Survival
timeFrame: From start of treatment up to 1 year
measure: Rate of Progression-free Survival (PFS)
timeFrame: From start of treatment up to 1 year
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
Study officials:
affiliation: Emory University
name: Kavita Dhodapkar, MD
role: PRINCIPAL_INVESTIGATOR
References: