Description:
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.
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
Drug | Synonyms | Arms |
---|
Nivolumab | Opdivo | Arm A (standard of care) |
Rituximab and Hyaluronidase Human | Rituxan Hycela | Arm B (rituximab, hyaluronidase human) |
Ipilimumab | Yervoy | Arm A (standard of care) |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Arm A (standard of care) | Active Comparator | 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 B (rituximab, hyaluronidase human) | Experimental | 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. | - 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 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).
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 |
Last Updated
June 22, 2021