A Phase II/III Trial of Nivolumab, Ipilimumab, and GM-CSF in Patients With Advanced Melanoma
Purpose
This phase II/III trial studies the side effects of nivolumab and ipilimumab when given together with or without sargramostim and to see how well they work in treating patients with stage III-IV melanoma that cannot be removed by surgery (unresectable) and that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Colony-stimulating factors, such as sargramostim, may increase the production of white blood cells. It is not yet known whether nivolumab and ipilimumab are more effective with or without sargramostim in treating patients with melanoma.
Conditions
- Stage III Cutaneous Melanoma AJCC v7
- Stage IV Cutaneous Melanoma AJCC v6 and v7
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- All patients must be >= 18 years of age
- Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1
- Patients must have known BRAF mutational status of tumor; wild-type (WT) or mutated,
prior to randomization
- Patients must not be pregnant or breast-feeding due to use of cytotoxic
immunotherapy and risk of teratogenic side effects; all patients of childbearing
potential must have a blood test or urine study within 2 weeks prior to
randomization to rule out pregnancy; a patient of childbearing potential is anyone,
regardless of sexual orientation or whether they have undergone tubal ligation, who
meets the following criteria: 1) has not undergone a hysterectomy or bilateral
oophorectomy; or 2) has not been naturally postmenopausal for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months)
- Patients must not conceive or father children by using accepted and effective
method(s) of contraception or by abstaining from sexual intercourse from the time of
study registration and continuing (for patients of child bearing potential) for at
least 5 months after the last dose of protocol treatment; patients of childbearing
potential must also not donate eggs during this same time period
- Patients must have unresectable stage III or stage IV melanoma according to American
Joint Committee on Cancer (AJCC) version (v)7; patients must have histological or
cytological confirmation of melanoma that is metastatic or unresectable and clearly
progressive
- Patients must have measurable disease per RECIST 1.1 criteria; all sites of disease
must be evaluated within 4 weeks prior to randomization
- Patients may have had prior systemic therapy in the adjuvant setting (e.g.
interferon, BRAF, or MEK agents). Patients may have had prior anti-CTLA-4 in the
adjuvant setting, if at least one year from last dose of treatment has passed prior
to beginning treatment. Patients may have had any prior anti-PD-1 or anti-PD-L1
agent in the adjuvant setting, if at least one year from last dose of treatment has
passed prior to beginning treatment
- Patients may not have had any prior ipilimumab and/or anti-PD-1/PD-L1 agent in the
metastatic setting
- Patients must have discontinued chemotherapy, immunotherapy or other investigational
agents used in the adjuvant setting >= 4 weeks prior to randomization and recovered
from adverse events due to those agents; mitomycin and nitrosoureas must have been
discontinued at least 6 weeks prior to entering the study; patients must have
discontinued radiation therapy >= 2 weeks prior to entering the study and recovered
from any adverse events associated with treatment; prior surgery must be >= 4 weeks
from randomization and patients must be fully recovered from post-surgical
complications
- Patients must not receive any other investigational agents while on study or within
four weeks prior to randomization
- Patient must not have received any live vaccine within 30 days prior to
randomization, while participating in the study, and for 4 weeks (28 days) after the
last dose of protocol treatment; live vaccines include, but are not limited to, the
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, bacillus
Calmette-Guerin (BCG), and typhoid (oral) vaccine; patients are permitted to receive
inactivated vaccines and any non-live vaccines including those for the seasonal
influenza and coronavirus disease 19 (COVID-19) (Note: intranasal influenza
vaccines, such as Flu-Mist (registered trademark) are live attenuated vaccines and
are not allowed); if possible, it is recommended to separate study drug
administration from vaccine administration by about a week (primarily, in order to
minimize an overlap of adverse events)
- Patients are ineligible if they have any currently active central nervous system
(CNS) metastases; patients who have treated brain metastases (with either surgical
resection or stereotactic radiosurgery) that have been stable on head magnetic
resonance imaging (MRI) or contrast computed tomography (CT) scan for at least 4
weeks following treatment and within 4 weeks prior to randomization are eligible;
patients must not have taken any steroids =< 14 days prior to randomization for the
purpose of managing their brain metastases; patients with only whole brain
irradiation for treatment of CNS metastases will be ineligible
- Patients must not have other current malignancies, other than basal cell skin
cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular
carcinoma in situ of the breast; patients with other malignancies are eligible if
they have been continuously disease-free for > 3 years prior to the time of
randomization
- White blood count >= 3,000/uL (obtained within 4 weeks prior to randomization)
- Absolute neutrophil count (ANC) >= 1,500/uL (obtained within 4 weeks prior to
randomization)
- Platelet count >= 100,000/uL (obtained within 4 weeks prior to randomization)
- Hemoglobin >= 9 g/dL (obtained within 4 weeks prior to randomization)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance
(CrCl) >= 40 ml/min (obtained within 4 weeks prior to randomization)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5
x ULN for patients with documented liver metastases) (obtained within 4 weeks prior
to randomization)
- Alkaline phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver
involvement and =< 7 x ULN for patients with known bone involvement) (obtained
within 4 weeks prior to randomization)
- Total bilirubin =< 1.5 x ULN except patients with normal direct bilirubin; those
patients with known Gilbert's syndrome must have total bilirubin < 3 x ULN (obtained
within 4 weeks prior to randomization)
- Serum lactate dehydrogenase (LDH) =< 10 X ULN (obtained within 4 weeks prior to
randomization)
- Patients must not have any serious or unstable pre-existing medical conditions
(aside from malignancy exceptions specified above), including but not limited to,
ongoing or active infection requiring parenteral antibiotics on day 1, history of
bleeding diathesis or need for concurrent anticoagulation (international normalized
ratio [INR] =< 1.5 and partial thromboplastin time [PTT] within 1.1 x ULN), or
psychiatric illness/social situations that would limit compliance with study
requirements, interfere with patient's safety, or obtaining informed consent
- Patients with human immunodeficiency virus (HIV) infection are ineligible; due to
the mechanism of action of ipilimumab and GM-CSF, activity and side effects in an
immune compromised patient are unknown
- Patients with evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection are not eligible; patients with cleared HBV and HCV (0 viral load)
infection will be allowed
- Patients must not have autoimmune disorders or conditions of immunosuppression that
require current ongoing treatment with systemic corticosteroids (or other systemic
immunosuppressants), including oral steroids (e.g., prednisone, dexamethasone) or
continuous use of topical steroid creams or ointments or ophthalmologic steroids; a
history of occasional (but not continuous) use of steroid inhalers is allowed;
replacement doses of steroids for patients with adrenal insufficiency are allowed;
patients who discontinue use of these classes of medication for at least 2 weeks
prior to randomization are eligible if, in the judgment of the treating physician
investigator, the patient is not likely to require resumption of treatment with
these classes of drugs during the study
- Exclusion from this study also includes patients with a history of symptomatic
autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis
[scleroderma], systemic lupus erythematosus, Sjogren's syndrome, autoimmune
vasculitis [e.g., Wegener's granulomatosis]); motor neuropathy considered of
autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis); other CNS
autoimmune disease (e.g., multiple sclerosis)
- Patients with autoimmune hypothyroid disease or type I diabetes on replacement
treatment are eligible
- Patients must not have a history of inflammatory bowel disease or diverticulitis
(history of diverticulosis is allowed)
- Patients must not have other significant medical, surgical, or psychiatric
conditions or require any medication or treatment that in the opinion of the
investigator may interfere with compliance, make the administration of the study
drugs hazardous or obscure the interpretation of adverse events (AEs), such as a
condition associated with frequent diarrhea; patients must not have an active
infection requiring current treatment with parenteral antibiotics
Study Design
- Phase
- Phase 2/Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Arm A (nivolumab, ipilimumab, sargramostim) |
INDUCTION THERAPY: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle, ipilimumab IV over 30 minutes on day 1 of each cycle, and sargramostim SC on days 1-14 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive nivolumab and sargramostim as in Induction therapy. Patients with PR, SC, or CR at 24 weeks may continue maintenance therapy for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo MRI, CT scan, and blood sample collection throughout the study. Patients may also undergo a MUGA during screening, as well as an ECHO throughout the trial as clinically indicated. |
|
|
Experimental Arm B (nivolumab, ipilimumab) |
INDUCTION THERAPY: Patients receive nivolumab and ipilimumab as in Arm I. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive nivolumab as in Induction therapy. Patients with PR, SD, or CR at 24 weeks may continue maintenance therapy for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo MRI, CT scan, and blood sample collection throughout the study. Patients may also undergo a MUGA during screening, as well as an ECHO throughout the trial as clinically indicated. |
|
Recruiting Locations
Baltimore, Maryland 21237
Site Public Contact
443-777-7364
Washington, District of Columbia 20010
Site Public Contact
202-877-8839
Washington, District of Columbia 20007
Site Public Contact
202-444-2223
More Details
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
Study Contact
Detailed Description
PRIMARY OBJECTIVE: I. To compare the overall survival (OS) of nivolumab/ipilimumab/sargramostim (GM-CSF) versus nivolumab/ipilimumab. SECONDARY OBJECTIVES: I. To evaluate progression free survival (PFS) of patients treated with nivolumab/ipilimumab/GM-CSF versus nivolumab/ipilimumab. II. To assess for differences in tolerability, specifically the rate of grade III or higher adverse events, between nivolumab/ipilimumab/GM-CSF versus nivolumab/ipilimumab. III. To evaluate immune-related response rate (based on immune-related response criteria) and response rate (based on Response Evaluation Criteria in Solid Tumors [RECIST] criteria) and to compare them. EXPLORATORY TOBACCO USE OBJECTIVES: I. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity (adverse events [both clinical and hematologic] and dose modifications). II. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms. III. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization. IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: INDUCTION THERAPY: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle, ipilimumab IV over 30 minutes on day 1 of each age, and sargramostim subcutaneously (SC) on days 1-14 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive nivolumab and sargramostim as in induction therapy. Patients with partial response (PR), stable disease (SD), or complete response (CR) at 24 weeks may continue maintenance therapy for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI), computed tomography (CT) scan, and blood sample collection throughout the study. Patients may also undergo a multigated acquisition (MUGA) during screening, as well as an echocardiography (ECHO) throughout the trial as clinically indicated. ARM B: INDUCTION THERAPY: Patients receive nivolumab and ipilimumab as in Arm I. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive nivolumab as in induction therapy. Patients with PR, SD, or CR at 24 weeks may continue maintenance therapy for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo MRI, CT scan, and blood sample collection throughout the study. Patients may also undergo a MUGA during screening, as well as an ECHO throughout the trial as clinically indicated. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.