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Denosumab + PD-1 in Subjects With Stage III/ IV Melanoma

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ClinicalTrials.gov Identifier: NCT03620019
Recruitment Status : Recruiting
First Posted : August 8, 2018
Last Update Posted : September 9, 2020
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:
This is a multicenter open-label, single-arm, phase II study designed to investigate the pharmacodynamic and antitumor effects of denosumab alone and in combination with an anti-PD1 agent (pembrolizumab or nivolumab) in patients with unresectable PD-1/PD-L1 inhibitor-naïve regional and distant metastatic melanoma (AJCC stage III/IV). The pharmacodynamic and antitumor effects will be investigated by performing translational research on peripheral blood and tumor tissue collected before and during denosumab alone and in combination with anti-PD-1 treatment.

Condition or disease Intervention/treatment Phase
Melanoma Stage Iii Melanoma Stage Iv Melanoma Melanoma (Skin) Cutaneous Melanoma Drug: Denosumab Drug: Pembrolizumab Drug: Nivolumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study of Denosumab in Combination With a PD-1 Inhibitor in Subjects With Stage III/IV Melanoma
Actual Study Start Date : September 25, 2018
Estimated Primary Completion Date : November 15, 2021
Estimated Study Completion Date : August 2022

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Single Arm: Denosumab+ PD-1 Inhibitor
Subjects in this trial will be given denosumab every 4 weeks, starting on day 1 of study treatment. An additional loading dose of denosumab will be administered on day 8. Subjects who started Pembrolizumab (initiated 21 days after the first dose of denosumab is given) will continue to have it administered intravenously (IV) every 3 weeks. New subjects will receive Nivolumab administered intravenously (IV) every 4 weeks (initiated 21 days after the first dose of denosumab is given). Combination therapy will continue as long as subjects benefit from therapy for up to 1 year.
Drug: Denosumab
A dose of 120 mg will be administered as a subcutaneous (s.c.) injection every 4 weeks in the upper arm, upper thigh, or abdomen. Another loading dose of 120 mg s.c. denosumab will be administered on day 8. On days when denosumab is administered on the same day as pembrolizumab, the s.c. injection should be given after the infusion of pembrolizumab is completed.
Other Name: XGEVA

Drug: Pembrolizumab
Pembrolizumab will be administered as standard of care following the institutional guidelines.The recommended dose of pembrolizumab is 200 mg administered as an IV infusion over approximately 30 minutes (range: 25 - 40 minutes) every 3 weeks until disease progression or unacceptable toxicity.
Other Name: Keytruda

Drug: Nivolumab
Nivolumab will be given every four weeks at a dose of 480 mg to be administered as an IV infusion per institutional guidelines.
Other Name: Opdivo




Primary Outcome Measures :
  1. The antitumor effect of denosumab alone as represented by the change in recent thymic emigrant cells in peripheral blood [ Time Frame: 3 weeks after start of denosumab ]
    The antitumor effect of denosumab alone (i.e., after two loading doses of denosumab are given on day 1 and day 8) in patients with unresectable stage III or distant metastatic Programmed death-1 or Programmed death ligand 1 (PD-1/PD-L1) inhibitor-naïve cutaneous melanoma (stage III/IV) will be assessed by performing translational research on peripheral blood samples collected at baseline and on day 21 of the study. The hypothesis is that denosumab treatment will prevent destruction of autoreactive T cells within the thymus -and therefore will increase influx of those T cells into the blood, termed recent thymic emigrants (RTE). RTE will be measured by multiparameter flow cytometric analysis of cluster of differentiation (CD)8+ and CD 4+ RTE isolated from peripheral blood. Results will be expressed as the change in number of cells/microliter of peripheral blood between the baseline and the day 21 timepoints.

  2. The antitumor effect of denosumab alone as represented by the change in density of tumor-infiltrating cluster of differentiation (CD8+) cells (TILs) in tumor tissue. [ Time Frame: 3 weeks after start of denosumab ]
    The antitumor effect of denosumab alone (i.e., after two loading doses of denosumab are given on day 1 and day 8) in patients with unresectable stage III or distant metastatic Programmed death-1 or Programmed death ligand 1 (PD-1/PD-L1) inhibitor-naïve cutaneous melanoma (stage III/IV) will be assessed by performing translational research on tumor biopsy samples collected at baseline and on day 21 of the study. The hypothesis is that denosumab alone will increase influx of tumor-infiltrating CD8+ cells (TIL). The density of TILs (number of cells by tumor surface area in mm2) in tumor tissues will be evaluated by Immunohistochemistry (IHC) and Immunofluorescence (IF) studies.

  3. The antitumor effect of denosumab combined with anti-PD-1 inhibitor as represented by the change in recent thymic emigrant cells in peripheral blood [ Time Frame: 16, 28 and 40 weeks after start of denosumab ]
    The antitumor effect of denosumab combined with anti-PD-1 inhibitor (Pembrolizumab or Nivolumab) in patients with unresectable stage III or distant metastatic Programmed death-1 or Programmed death ligand 1 (PD-1/PD-L1) inhibitor-naïve cutaneous melanoma (stage III/IV) will be assessed by performing translational research on peripheral blood samples collected at weeks 16, 28 and 40 of the study. The hypothesis is that denosumab treatment will prevent destruction of autoreactive T cells within the thymus -and therefore will increase influx of those T cells into the blood, termed recent thymic emigrants (RTE). RTE will be measured by multiparameter flow cytometric analysis of cluster of differentiation (CD)8+ and CD 4+ RTE isolated from peripheral blood. Results will be expressed as the change in number of cells/microliter of peripheral blood between the week 16, 28 and 40 timepoints.

  4. The antitumor effect of denosumab combined with anti-PD-1 inhibitor as represented by the change in density of tumor-infiltrating cluster of differentiation (CD8+) cells (TILs) in tumor tissue. [ Time Frame: Baseline, 21 days and 16 weeks after start of denosumab ]
    The antitumor effect of denosumab combined with anti-PD-1 inhibitor (Pembrolizumab or Nivolumab) in patients with unresectable stage III or distant metastatic Programmed death-1 or Programmed death ligand 1 (PD-1/PD-L1) inhibitor-naïve cutaneous melanoma (stage III/IV) will be assessed by performing translational research on tumor biopsy samples collected at baseline, on day 21, and week 16 of the study. The density of TILs (number of cells by tumor surface area in mm2) in tumor tissues will be evaluated by Immunohistochemistry (IHC) and Immunofluorescence (IF) studies.


Secondary Outcome Measures :
  1. Safety of the denosumab- anti-PD-1 inhibitor combination in unresectable stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve cutaneous melanoma [ Time Frame: 30 days after treatment is discontinued ]
    The safety of the denosumab- anti-PD-1 inhibitor (Pembrolizumab or Nivolumab) combination will be assessed by continuous toxicity monitoring focusing on the incidence of serious adverse events (SAEs) with toxicity boundary rules. The NCI Common Terminology Criteria for Adverse Events V5 is a descriptive terminology which will be used for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

  2. Overall response rate [ Time Frame: 16 weeks after start of treatment ]
    Antitumor response to the denosumab- anti-PD-1 inhibitor (Pembrolizumab or Nivolumab) combination at 16 weeks in patients with unresectable stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve cutaneous melanoma (AJCC stage III/IV) will be assessed per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) which defines Complete Response (CR) as Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and Overall Response Rate (ORR) = CR + PR/total number of subjects.

  3. Overall survival rate [ Time Frame: 1 year from start of study treatment ]
    The Overall Survival rate at 1-year is defined as the proportion of subjects still alive from day 1 of study treatment until one year after initiating study treatment

  4. Progression free survival rate [ Time Frame: 6 months from start of study treatment ]
    Progression Free survival rate at 6 months is defined as the proportion of subjects without a progression or death event measured from day 1 of treatment until 6 months after initiating study treatment. Progression events will be defined per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions



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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed written informed consent and HIPAA authorization for release of personal health information.
  2. Age ≥ 18 years at the time of consent.
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
  4. 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.
  5. AJCC stage III/IV unresectable (or resectable) disease. Both should be measurable by RECIST v1.1 criteria. Patients with resectable bulky stage IIIB, state 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.
  6. 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-mm2 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.
  7. Must agree to undergo one on-treatment biopsy on week 4of the study; the biopsy at week 16 is optional.
  8. Must agree to have 100 mL blood drawn for study purposes on week 1 , day 20+or-2 (week 4), week 16, week 28, week 40 and end of treatment.
  9. Demonstrate adequate organ function, as defined in the table; all screening labs to be obtained within 21 days prior to registration.
  10. 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.
  11. Females of childbearing potential must be willing to use adequate method of contraception, as outlined in Section 4.5.2 - Oral contraception is required 14 days prior to initiation of study medications until 120 days after treatment discontinuation. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  12. Male patients with female partners must have had a prior vasectomy or agree to use an adequate method of contraception as outlined in Section 4.5.2 - Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  13. As determined by the enrolling physician or protocol designee, willingness and ability of the subject to understand and comply with study procedures.
  14. Previous radiation therapy is allowed, provided it is completed ≥14 days prior to starting denosumab and patient has recovered adequately from any related toxicities (grade≤1, or grade ≤2 that is stable for ≥3 months).
  15. 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:

  1. 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,
  2. 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 PD-1 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.
  3. 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).

Exclusion Criteria:

  1. 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 or hairy-cell leukemia, provided patient is not on an active systemic treatment and is in complete remission, as evidenced by Positron Emission Tomography (PET)/CT scans and bone marrow biopsies for at least 3 months,
    • History of other malignancy, provided patient has completed therapy, or does not require therapy, and is free of disease for ≥ 2 years. If patient 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.
  2. 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 MRI or by cytology (e.g. lumbar puncture) or also excluded.
  3. 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. Mitogen-Activated Protein Kinases (MAPK) inhibitors) is allowed as long as at least 15 days have elapsed since last dose of drug.
  4. Patients discontinuing prior therapy with tyrosine kinase inhibitors for melanoma should be off these medications for at least 15 days before starting study treatment.
  5. Prior PD-1/PD-L1 therapies in the adjuvant setting; targeted therapies or prior ipilimumab in the adjuvant setting are allowed.
  6. 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.
  7. 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.
  8. Has a known history of active tuberculosis (Mycobacterium Bacillus Tuberculosis).
  9. 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.
  10. Hypersensitivity to nivolumab, pembrolizumab or denosumab or any of their excipients.
  11. 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.
  12. Has a history of non-infectious pneumonitis that required systemic corticosteroids or evidence of interstitial lung disease or current active, non-infectious 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.
  13. 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.
  14. Has an active infection requiring systemic therapy within 7 days prior to treatment initiation.
  15. Has a known history of Human Immunodeficiency Virus (HIV 1/2 antibodies).
  16. Known serologic status reflecting active hepatitis B or C infection. Patients 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 patients will be excluded].
  17. 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.
  18. 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 upper limit of normal (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.
  19. Prior treatment with denosumab. Use of bisphosphonates for treatment of metastatic bone disease, but not for hypercalcemia of malignancy, is allowed.
  20. 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: Patient 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03620019


Contacts
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Contact: Diana Wallack 984 974-8652 diana_wallack@med.unc.edu
Contact: Deeanna Bouchard 984 974-8250 deeanna_bouchard@med.unc.edu

Locations
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United States, North Carolina
UNC Lineberger Comprehensive Cancer Center Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Diana Wallack    984-974-8652    diana_wallack@med.unc.edu   
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Amgen
Investigators
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Principal Investigator: Stergios Moschos, MD UNC Lineberger Comprehensive Cancer Center
Additional Information:
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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03620019    
Other Study ID Numbers: LCCC1620
First Posted: August 8, 2018    Key Record Dates
Last Update Posted: September 9, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by UNC Lineberger Comprehensive Cancer Center:
Denosumab
Pembrolizumab
Melanoma
Unresectable
Cutaneous
Nivolumab
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Denosumab
Pembrolizumab
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Bone Density Conservation Agents
Physiological Effects of Drugs