Denosumab and Pembrolizumab or Nivolumab in Treating Patients with Stage III-IV Cutaneous or Mucosal Melanoma
This phase II trial studies the side effects of denosumab and pembrolizumab or nivolumab and to see how well they work in treating patients with stage III-IV cutaneous or mucosal melanoma. Immunotherapy with monoclonal antibodies, such as denosumab, pembrolizumab, 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.
- Signed written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 – 2
- Histologically confirmed melanoma of cutaneous or mucosal primary (e.g. sinus, vagina, anus, gastrointestinal tract); metastatic melanomas from unknown primary are allowed because melanoma of unknown primary is biologically similar to cutaneous melanomas
- AJCC stage III/IV unresectable (or resectable) disease. Both should be measurable by RECIST v. 1.1 criteria. Subjects with resectable bulky stage IIIB, stage IIIC or stage IIID melanoma (>= 2-cm in shortest diameter for lymph nodes infiltrated by tumor and >= 2-cm in longest diameter for non-lymph nodes infiltrated by tumor) can also be entered into the study at the discretion of the principal investigator
- Must have available and consent to collect archived tumor blocks from previous surgeries confirming or treating metastatic disease (e.g. radical lymph node dissection); if not available or of insufficient quantity (e.g. < 2-mm^2 size tumor) or quality (> 50% necrosis, < 30% tumor cells) they can be enrolled into the trial, if they consent to have a tumor biopsy before treatment initiation
- Must agree to undergo one on-treatment biopsy on week 4 of the study; the biopsy at week 16 is optional
- Must agree to have 100 mL blood drawn for study purposes on week 1, week 4, week 16, week 28, week 40 and end of treatment
- Hemoglobin (Hgb) >= 10 g/dL without transfusion or erythropoietin dependency (within 7 days of assessment) (within 21 days prior to registration)
- Absolute neutrophil count (ANC) >= 1,500/mm^3 (within 21 days prior to registration)
- Absolute lymphocyte count (ALC) >= 1,000/mm^3 (within 21 days prior to registration)
- Platelets >= 100,000/mm^3 (within 21 days prior to registration)
- Serum creatinine =< 1.5 x upper limits of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min using the Cockcroft-Gault formula for subject with creatinine levels > 1.5 x ULN (within 21 days prior to registration)
- Serum total bilirubin =< 1.5 x ULN or =< 2 x ULN for subjects with Gilbert’s syndrome (within 21 days prior to registration)
- Aspartate aminotransferase (AST) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases (within 21 days prior to registration)
- Alanine aminotransferase (ALT) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases (within 21 days prior to registration)
- Albumin >= 2.5 mg/dL (within 21 days prior to registration)
- Serum calcium >= 2.0 mmol/L (8.0 mg/dL) (within 21 days prior to registration)
- Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to study treatment * NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
- Females of childbearing potential must be willing to use adequate method of contraception. Oral contraception is required 14 days prior to initiation of study medications until 150 days after treatment discontinuation * NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Male patients with female partners must have had a prior vasectomy or agree to use an adequate method of contraception. Contraception, starting with the first dose of study therapy through 150 days after the last dose of study therapy * NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- As determined by the enrolling physician or protocol designee, willingness and ability of the subject to understand and comply with study procedures
- Previous radiation therapy is allowed, provided it is completed >= 14 days prior to starting therapy and subject has recovered adequately from any related toxicities (grade =< 1, or grade =< 2 that is stable for >= 3 months)
- If patient has received adjuvant treatments, in particular ipilimumab and high dose interferon, any toxicities must have resolved to grade 1 or less. Grade 2 toxicities attributed to ipilimumab from autoimmune endocrinopathies that require permanent hormone replacement therapy are allowed as long as they are adequately treated. This implies that patients should be off systemic steroids for treatment of any of these or other autoimmune toxicities (e.g. colitis, rash)
- Subjects who have previously received PD-1 inhibitors in stage III (adjuvant) or stage IV are allowed as long as: * The interval between the last dose of the adjuvant PD-1 inhibitor and the date of relapse (clinical or radiographic) is at least 1 year * If subjects who received treatment for stage IV had antitumor response (partial response or complete response) by RECIST criteria version 1.1 but they stopped due to subject/investigator preference for at least a year between the last dose of the PD-1 inhibitor and the date of relapse (clinical or radiographic). Allowing for these subjects who have previously received PD-1 inhibitors in the adjuvant setting (i.e. no knowledge about clinical benefit) or following definite antitumor response in the metastatic setting is based on a recent case series of subjects who responded to PD-1 inhibitor rechallenge, if they had previously responded to PD1 inhibitors. This implies that waning antitumor immunity in the absence (i.e. > 1 year) of costimulation with PD-1 inhibitors may be the reason for cancer recurrence and NOT primary resistance of PD-1 inhibitors * Any side effects that may have occurred during the previous exposure to PD-1 inhibitors are not serious (i.e. grade 1 or 2 by CTCAE version 5.0 criteria)
- History of prior malignancy, with the exception of the following: * Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of the cervix * Prior history of prostate, provided that patient is not under active systemic treatment other than hormonal therapy and with documented undetectable prostate specific antigen (PSA < 0.2 ng/mL) * Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) provided patient has isolated lymphocytosis (Rai stage O), and does not require systemic treatment (for “B” symptoms, Richter’s transformation, lymphocyte doubling time [< 6 months], lymphadenopathy or hepatosplenomegaly) * Lymphoma or any type of hairy-cell leukemia, provided patient is not on an active systemic treatment and is in complete remission, as evidenced by positron emission tomography (PET)/computed tomography (CT) scans and bone marrow biopsies for at least 3 months * History of other malignancy, provided subject has completed therapy, or does not require therapy, and is free of disease for >= 2 years. If subject has had other malignancy within the last 2 years from which he/she may have been completely cured by surgery alone, or does not require any treatment other than observation at the specialist's discretion, he/she may considered to be enrolled on condition that the risk of development of recurrent or distant metastatic disease based on the American Joint Committee in Cancer (AJCC) staging system is less than 30% in 3 years from the original diagnosis of other malignancy
- Has known active central nervous system (CNS) metastases that are symptomatic and require antiepileptic drugs or corticosteroids. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging) for at least 2 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Patients with leptomeningeal disease, detected either by brain magnetic resonance imaging (MRI) or by cytology (e.g. lumbar puncture) are also excluded
- Treatment with any investigational drug, immunotherapy or chemotherapy within 28 days prior to study treatment (i.e., initiation of denosumab). Treatment with any targeted therapy (e.g. MAPK inhibitors) is allowed as long as at least 15 days have elapsed since last dose of drug
- Subjects discontinuing prior therapy with tyrosine kinase inhibitors for melanoma should be off these medications for at least 15 days before starting study treatment
- Prior PD-1/PD-L1 therapies in the adjuvant setting; targeted therapies or prior ipilimumab in the adjuvant setting are allowed
- Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk, if he/she were to participate in the study. This includes, but is not limited, to serious medical conditions or psychiatric illness likely to interfere with participation in this clinical study
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy equivalent to daily doses of prednisone of 10 mg or greater (or an equivalent dose of other corticosteroids) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Has a known history of active tuberculosis (Mycobacterium tuberculosis)
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
- Hypersensitivity to nivolumab, pembrolizumab or denosumab or any of their excipients
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease-modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Has a history of non-infectious pneumonitis that required systemic corticosteroids or evidence of interstitial lung disease or current active, noninfectious pneumonitis. Episodic, brief (< 7 day) exposure to systemic corticosteroids (e.g. steroid taper for poison ivy or chronic obstructive pulmonary disease [COPD] exacerbation) is allowed
- Has a history of an acute coronary event (e.g. myocardial infarction) within 3 months since study entry, uncontrolled and symptomatic coronary artery disease, or congestive heart failure New York Heart Association class III/IV
- Has an active infection requiring systemic therapy within 7 days prior to treatment initiation
- Has a known history of human immunodeficiency virus (HIV 1/2 antibodies)
- Known serologic status reflecting active hepatitis B or C infection. Subjects that are hepatitis B core antibody positive, but antigen negative, will need a negative polymerase chain reaction (PCR) prior to enrollment * NOTE: Hepatitis B antigen or PCR positive subjects will be excluded
- Has received a live vaccine within 30 days of planned start of study therapy * NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
- Known active metabolic bone disease such as Paget’s disease, Cushing’s disease, hyperprolactinemia, over the last year 12 months, known history of osteoporosis that is symptomatic (e.g. history of fractures, bone pain), or hypercalcemia/hypocalcemia of any type (serum free calcium being more than 1.1 x ULN and less than 0.9 x, lower limits normal [LLN]) over the last 2 weeks since study initiation that requires treatment beyond calcium and vitamin D supplementation
- Prior treatment with denosumab. Use of bisphosphonates for treatment of metastatic bone disease, but not for hypercalcemia of malignancy, is allowed
- History of current evidence of osteonecrosis or osteomyelitis of the jaw, active dental or jaw problems necessitating known invasive dental procedure during the study, or non-healed dental or oral surgery * Note: Subject should be referred to dentist before study treatment initiation for poor dentition or other dental issues that, in the opinion of the treating physician, may increase the risk of osteonecrosis of the jaw
Locations & Contacts
Contact: Stergios J. Moschos
Trial Objectives and Outline
I. Assess the mechanistic (immune-mediated and/or direct antitumor effect) and pharmacodynamics effect (tissue saturation studies) of denosumab alone (i.e., after three loading doses of denosumab are given on day 1, 8 and day 22) in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naive melanoma (stage III/IV) by performing translational research on peripheral blood and tumor biopsy samples collected at baseline and after third loading dose of denosumab.
II. Assess the immune-mediated and direct antitumor effect of denosumab in combination with anti-PD-1-agent in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naive melanoma (American Joint Committee on Cancer [AJCC] stage III/IV) by performing translational research on peripheral blood and tumor biopsy samples collected at weeks 16, 28 and 40 of the study and comparing the results with those from baseline and after third loading dose of denosumab.
I. Assess the safety of the denosumab-anti-PD-1-agent combination in unresectable (unresectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naive melanoma (AJCC stage III/IV) by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
II. Determine antitumor response by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 criteria of the denosumab-anti-PD-1-agent combination at 16 weeks in patients with unresectable (resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naive melanoma (AJCC stage III/IV).
III. Determine the 1-year overall survival (OS) rate of the pembrolizumab-anti-PD-1-agent combination in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor naive melanoma (AJCC stage III/IV).
IV. Determine the 6-month progression-free survival (PFS) rate of the denosumab-anti-PD-1-agent combination in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor naive melanoma (AJCC stage III/IV).
Patients receive denosumab subcutaneously (SC) on days 1, 8, and 22 of weeks 1-2 and then once every 4 weeks beginning day 1 of week 5. Beginning 21 days after the first dose of denosumab, patients also receive nivolumab intravenously (IV) over 30 minutes once every 4 weeks. Patients enrolled prior to 12/17/2018 receive pembrolizumab IV over 30 minutes beginning 21 days after the first dose of denosumab. Cycles with denosumab and nivolumab repeat every 4 weeks and cycles with pembrolizumab repeat every 3 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for up to 2 or 3 years.
Trial Phase & Type
UNC Lineberger Comprehensive Cancer Center
Stergios J. Moschos
Secondary IDs NCI-2018-01673
Clinicaltrials.gov ID NCT03620019