Clinical Trials /

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

NCT03620019

Description:

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.

Related Conditions:
  • Cutaneous Melanoma
  • Melanoma of Unknown Primary
  • Mucosal Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Denosumab + PD-1 in Subjects With Stage III/ IV Melanoma
  • Official Title: Phase 2 Study of Denosumab in Combination With a PD-1 Inhibitor in Subjects With Stage III/IV Melanoma

Clinical Trial IDs

  • ORG STUDY ID: LCCC1620
  • NCT ID: NCT03620019

Conditions

  • Melanoma Stage Iii
  • Melanoma Stage Iv
  • Melanoma
  • Melanoma (Skin)
  • Cutaneous Melanoma

Interventions

DrugSynonymsArms
DenosumabXGEVASingle Arm: Denosumab+ PD-1 Inhibitor
PembrolizumabKeytrudaSingle Arm: Denosumab+ PD-1 Inhibitor
NivolumabOpdivoSingle Arm: Denosumab+ PD-1 Inhibitor

Purpose

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.

Detailed Description

      STUDY OBJECTIVES

      Co-primary Objectives

        -  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 22) in patients with
           unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve
           cutaneous 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.

        -  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-naïve cutaneous melanoma (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.

      Secondary Objectives

        -  Assess the safety of the denosumab-anti-PD-1 agent combination in unresectable
           (resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve melanoma (AJCC
           stage III/IV) by NCI-CTCAE v.5.0.

        -  Determine antitumor response by RECIST v1.1 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-naïve melanoma (AJCC stage III/IV).

        -  Determine the 1-year OS 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-naïve melanoma (AJCC stage III/IV).

        -  Determine the 6-month 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).

      Endpoints Co-primary Endpoints

        -  The immune-mediated mechanism of action of denosumab alone will be evaluated in blood
           and tumor samples collected at baseline and after third loading dose of denosumab.
           Multiparameter flow cytometry and ELISA assays will be performed on peripheral
           blood/serum samples as outlined above in section 1.10.1 Tumor biopsy samples will be
           evaluated by IHC and IF studies as outlined above in section 1.10.2 (See referenced
           sections for assay details. The investigators will estimate differences after 3 weeks of
           denosumab treatment versus baseline).

        -  The immune-mediated mechanism of action of denosumab combined with anti-PD-1 agent will
           be evaluated in blood and tumor samples collected at weeks 16, 28 and 40 of the study.
           Multi-parameter flow cytometry and ELISA assays will be performed on peripheral
           blood/serum samples collected at weeks 16, 28 and 40 as outlined above in section
           1.10.1. Tumor biopsy samples obtained at week 16 will be evaluated by IHC and IF studies
           as outlined above in section 1.10.2 (See referenced sections for assay details. The
           investigators will describe differences in immunomodulatory/antitumor effects observed
           with denosumab therapy with later immunomodulatory/antitumor effects observed after the
           addition of an anti PD-1 agent to denosumab).

      Secondary Endpoints

        -  AEs experienced by patients receiving denosumab-anti- PD-1 agent will be assessed per
           NCI-CTCAE v.5.0.

        -  The overall RR (CR + PR) at 16 weeks will assessed based on RECIST v1.1 criteria.

        -  Overall Survival (OS) rate at 1-year is defined as the time from day 1 of study
           treatment until death as a result of any cause within one year of initiating study
           treatment.

        -  Progression Free Survival (PFS) rate at 6 months is defined as the time from day 1 of
           treatment until disease progression or death status measured 6 months after initiating
           study treatment. Progression events will be defined per RECIST v1.1 criteria.

      Procedures

      Subjects in this trial will be given denosumab, 120 mg s.c. q4 weeks, starting on day 1 of
      study treatment. Additional loading doses of Denosumab will be administered on day 8 and day
      22 ( after Amendment 1). Nivolumab, 480 mg will be administered intravenously (IV) every 4
      weeks and initiated 21 days after the first dose of Denosumab is given. In subjects enrolled
      prior to Amendment 1 Pembrolizumab, 200 mg will be administered intravenously (IV) every 3
      weeks and initiated 21 days after the first dose of denosumab is given. Combination therapy
      with both agents will continue as long as subjects benefit from therapy for up to 1 year.
      Study therapy will be discontinued for intolerable toxicity, disease progression or for other
      reasons at the discretion of the investigator. If subjects are not withdrawn prematurely then
      their last dose of study medications will be administered approximately 49 weeks after
      denosumab was initiated.
    

Trial Arms

NameTypeDescriptionInterventions
Single Arm: Denosumab+ PD-1 InhibitorExperimentalSubjects 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.
  • Denosumab
  • Pembrolizumab
  • Nivolumab

Eligibility 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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.
Measure:Overall response rate
Time Frame:16 weeks after start of treatment
Safety Issue:
Description: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.
Measure:Overall survival rate
Time Frame:1 year from start of study treatment
Safety Issue:
Description: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
Measure:Progression free survival rate
Time Frame:6 months from start of study treatment
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • Denosumab
  • Pembrolizumab
  • Melanoma
  • Unresectable
  • Cutaneous
  • Nivolumab

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