Cutaneous Melanoma, Stage III, Cutaneous Melanoma, Stage IV, Stage IIIA Skin Melanoma, Stage IIIB Skin Melanoma, Stage IIIC Skin Melanoma, Stage III Melanoma, Stage IV Skin Melanoma, Unresectable Melanoma
Conditions
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.
Interventions
DRUGNivolumab
Receive standard of care nivolumab therapy
BIOLOGICALRituximab and Hyaluronidase Human
Given IV or SC
DRUGIpilimumab
Receive standard of care ipilimumab therapy
Sponsors
Genentech, Inc.
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Common Terminology Criteria (CTC) (Version [v]5.0) Grade 3 or Greater Immune-related Adverse Events | 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
| Measure | Time frame | Description |
|---|---|---|
| Rate of CTC (v5.0) Toxicity Related to Rituximab and Hyaluronidase Human | 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. |
| Objective Tumor Response | 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. |
| Rate of Overall Survival | 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. |
| Rate of Progression-free Survival (PFS) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Standard of Care) 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).
Nivolumab: Receive standard of care nivolumab therapy
Ipilimumab: Receive standard of care ipilimumab therapy | 7 |
| Arm B (Rituximab, Hyaluronidase Human) 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: Receive standard of care nivolumab therapy
Rituximab and Hyaluronidase Human: Given IV or SC
Ipilimumab: Receive standard of care ipilimumab therapy | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 2 |
Baseline characteristics
| Characteristic | Arm A (Standard of Care) | Arm B (Rituximab, Hyaluronidase Human) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 4 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 7 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 4 Participants | 10 Participants |
| Region of Enrollment United States | 7 participants | 7 participants | 14 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 7 | 2 / 7 |
| other Total, other adverse events | 7 / 7 | 7 / 7 |
| serious Total, serious adverse events | 4 / 7 | 4 / 7 |
Outcome results
Primary
Number of Participants With 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.
Time frame: At 6 months after study start
Population: All patients were evaluated for toxicity from the time of their first treatment with ipilimumab/nivolumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Standard of Care) | Number of Participants With Common Terminology Criteria (CTC) (Version [v]5.0) Grade 3 or Greater Immune-related Adverse Events | 4 Participants |
| Arm B (Rituximab, Hyaluronidase Human) | Number of Participants With Common Terminology Criteria (CTC) (Version [v]5.0) Grade 3 or Greater Immune-related Adverse Events | 1 Participants |
Secondary
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.
Time frame: At 12 weeks and every 12 weeks thereafter up to 1 year
Secondary
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.
Time frame: Up to 4 weeks after study start
Secondary
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.
Time frame: From start of treatment up to 1 year
Secondary
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.
Time frame: From start of treatment up to 1 year