Clinical Trials /

Low Dose Ipilimumab With Pembrolizumab in Treating Patients With Melanoma That Has Spread to the Brain

NCT03873818

Description:

This phase II trial studies the side effects and how well low dose ipilimumab works in combination with pembrolizumab in treating patients with melanoma that has spread to the brain. Immunotherapy with monoclonal antibodies, such as ipilimumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Low Dose Ipilimumab With Pembrolizumab in Treating Patients With Melanoma That Has Spread to the Brain
  • Official Title: A Phase II Study of Open Label Low Dose Ipilimumab in Combination With Pembrolizumab in Metastatic Melanoma Patients With Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: 2018-0875
  • SECONDARY ID: NCI-2019-00406
  • SECONDARY ID: 2018-0875
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03873818

Conditions

  • Clinical Stage IV Cutaneous Melanoma AJCC v8
  • Metastatic Malignant Neoplasm in the Brain
  • Metastatic Melanoma
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (ipilimumab, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (ipilimumab, pembrolizumab)

Purpose

This phase II trial studies the side effects and how well low dose ipilimumab works in combination with pembrolizumab in treating patients with melanoma that has spread to the brain. Immunotherapy with monoclonal antibodies, such as ipilimumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess clinical benefit rate (CBR, defined as complete response [CR] + partial response
      [PR] + stable disease [SD]) > 6 months in the brain in subjects with melanoma metastatic to
      the brain per modified RECIST (Response evaluation criteria in solid tumors) 1.1 criteria and
      RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases), and who had experienced
      prior progression on anti-PD1 (programmed cell death protein).

      SECONDARY OBJECTIVES:

      I. Clinical benefit rate (CBR, defined as complete response [CR] + partial response [PR] +
      stable disease [SD]) > 6 months in the brain in subjects with melanoma metastatic to the
      brain per modified RECIST 1.1 and RANO-BM criteria, and who are treatment naive to anti- PD-1
      agents in the metastatic setting (prior adjuvant anti-PD1 allowed).

      II. To assess overall survival (OS) and progression free survival (PFS). III. To evaluate the
      brain-specific safety and tolerability of the combination regimen in patients with or without
      stereotactic radiotherapy (SRT) received prior to study entry, or on study.

      IV. To evaluate cytokine levels and changes in the T-cell population in the cerebrospinal
      fluid (CSF) and blood in patients treated with combination low dose ipilimumab and
      pembrolizumab.

      V. Changes in relative apparent diffusion coefficient as measured by MRI magnetic resonance
      imaging as an early predictor of response.

      VI. To assess changes in circulating cfDNA (cell-free deoxyribonucleic acid) as determinants
      of response and/or markers of early progression.

      VII. Evaluate molecular and immunological changes in extracranial lesions.

      OUTLINE:

      Patients receive ipilimumab intravenously (IV) over 90 minutes and pembrolizumab IV over 30
      minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles for ipilimumab and up to
      35 cycles for pembrolizumab in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 6 weeks for
      the first year, and then every 12 weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ipilimumab, pembrolizumab)ExperimentalPatients receive ipilimumab IV over 90 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 cycles for ipilimumab and up to 35 cycles for pembrolizumab in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Life expectancy > 12 weeks.

          -  Subjects must have signed and dated an IRB/IEC (Institutional Review Board/Independent
             Ethics Committee) approved written informed consent form in accordance with regulatory
             and institutional guidelines. This must be obtained before the performance of any
             protocol related procedures that are not part of normal subject care.

          -  Subjects must be willing and able to comply with scheduled visits, treatment schedule,
             laboratory testing, and other requirements of the study.

          -  Histologically confirmed malignant melanoma with measurable metastases in the brain
             (>= 0.5 cm).

          -  At least one measurable intracranial target lesion, which previously was not treated
             with local therapy (no prior stereotactic radiosurgery [SRS] to this lesion). Largest
             diameter of >= 0.5 cm, but =< 3 cm as determined by contrast-enhanced MRI.

          -  Representative formalin-fixed paraffin-embedded tumor specimens in paraffin blocks OR
             at least 4 unstained slides with an associated pathology report for testing of tumor
             PD-L1 expression (a) tumor tissue should be of good quality based on total and viable
             tumor content. (b) patients who do not have tissue specimens may undergo a biopsy
             during the screening period. Acceptable samples include core-needle biopsies for deep
             tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous,
             subcutaneous, or mucosal lesions (i) tumor tissue from bone metastases is not
             evaluable for PD-L1 expression and is therefore not acceptable (c) however, if repeat
             biopsy is not feasible, and no archival tissue available patient still may be
             enrolled.

          -  Prior stereotactic radiotherapy (SRT) and prior excision of up to 5 melanoma brain
             metastasis (MBM) is permitted if there has been complete recovery, with no neurologic
             sequelae, and measurable lesions remain. Growth or change in a lesion previously
             irradiated will not be considered measurable. Regrowth in cavity of previously excised
             lesion will not be considered measurable. Note: Any prior SRT to brain lesions or
             prior excision must have occurred >= 2 weeks before the start of dosing for this
             study.

          -  Subjects must be free of neurologic signs and symptoms related to metastatic brain
             lesions and must not have required or received systemic corticosteroid therapy in the
             10 days prior to beginning protocol therapy.

          -  ECOG (Eastern Cooperative Oncology Group) performance status =< 1.

          -  Absolute neutrophil count >= 1500/uL.

          -  Platelets >= 100,000/uL.

          -  Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L.

          -  Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
             clearance >= 30 L/min with creatinine levels > 1.5 x institutional ULN. GFR
             (glomerular filtration rate) can also be used in place of creatinine or CrCl
             (creatinine clearance).

          -  Total bilirubin =< 1.5 ULN OR direct bilirubin =< ULN for participants with total
             bilirubin levels > 1.5 x ULN.

          -  AST (aspartate aminotransferase) and ALT (alanine aminotransferase) =< 2.5 x ULN (=< 5
             x ULN for participants with liver metastasis).

          -  International normalized ratio (INR) OR prothrombin time (PT) and activated partial
             thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant
             therapy as long as PT or PTT is within therapeutic range of intended use of
             anticoagulants.

          -  Women of child-bearing potential (WOCBP) must not be breastfeeding and must have a
             negative pregnancy test within 3 days prior to initiation of dosing. She must agree to
             use an acceptable method of birth control from the time of the negative pregnancy test
             up to 120 days after the last dose of study drug. WOCBP must agree to adhere to the
             contraceptive guidance in the protocol. Note: A female participant is eligible to
             participate if she is not a woman of childbearing potential as defined by the
             protocol.

          -  Fertile men must agree to use an acceptable method of birth control as described in
             the protocol while on study drug and up to 120 days after the last dose of study drug
             and also refrain from donating sperm during this period.

          -  All associated toxicity from previous or concurrent cancer therapy must be resolved
             (to =< grade 1 or baseline) prior to study treatment administration.

          -  Steroids for physiological replacement are allowed.

        Exclusion Criteria:

          -  History of known leptomeningeal involvement (lumbar puncture not required).

          -  Previous stereotactic or highly conformal radiotherapy within 2 weeks before the start
             of dosing for this study. Note the stereotactic radiotherapy field must not have
             included the brain index lesion(s).

          -  Subjects previously treated with SRT > 5 lesions in the brain

          -  Brain lesion size > 3 cm.

          -  Prior checkpoint inhibitor therapy. Allowable prior therapy: Approved adjuvant
             therapies, which may include molecularly-targeted agents, IFN-a·, and ipilimumab.

               -  Patients who received ipilimumab as adjuvant or neoadjuvant therapy must have a 6
                  month washout before receiving any dosing on this study.

               -  Cohort A: Prior anti-PD in the adjuvant setting is allowed, but washout period is
                  6 months.

               -  For Cohort B: Patients with unresectable metastatic melanoma who received either
                  anti-PD-1 or PDL-1 in the past are eligible. Washout period a minimum 3 weeks.

          -  Subjects with an active, known or suspected autoimmune disease. Subjects with type I
             diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
             (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or
             conditions not expected to recur in the absence of an external trigger are permitted
             to enroll.

          -  Subjects with major medical, neurologic or psychiatric condition who are judged as
             unable to fully comply with study therapy or assessments should not be enrolled.

          -  Active secondary malignancy unless the malignancy is not expected to interfere with
             the evaluation of safety and is approved by the medical monitor. Examples of the
             latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the
             cervix, and isolated elevation of prostate-specific antigen. Subjects with a
             completely treated prior malignancy and no evidence of disease for >= 2 years are
             eligible.

          -  Has a known history of or is positive for hepatitis B (hepatitis B surface antigen
             [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] ribonucleic acid (RNA)
             [qualitative] is detected). Note: Without known history, testing needs to be performed
             to determine eligibility. Hepatitis C antibody (Ab) testing is allowed for screening
             purposes in countries where HCV RNA is not part of standard of care.

          -  Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is
             required unless mandated by local health authority.

          -  The use of corticosteroids is not allowed for 10 days prior to initiation of therapy
             (based upon 5 times the expected half-life of dexamethasone) except patients who are
             taking steroids for physiological replacement. If alternative corticosteroid therapy
             has been used, consultation with the sponsor medical monitor is required to determine
             the washout period prior to initiating study treatment.

          -  Subjects with a condition requiring systemic treatment with either corticosteroids (>
             10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
             days of study initiation. Inhaled or topical steroids, and adrenal replacement steroid
             doses > 10 mg daily prednisone equivalent, are permitted in the absence of active
             autoimmune disease.

          -  Subjects with history of life-threatening toxicity related to prior ipilimumab
             adjuvant therapy except those that are unlikely to re-occur with standard
             countermeasures (e.g. hormone replacement after adrenal crisis).

          -  Major surgical procedure, open biopsy (excluding skin cancer resection), or
             significant traumatic injury within 14 days of initiating study drug (unless the wound
             has healed) or anticipation of the need for major surgery during the study.

          -  Non-healing wound, ulcer, or bone fracture.

          -  Women who are breast-feeding or pregnant.

          -  Uncontrolled intercurrent illness (i.e., active infection >= grade 2) or concurrent
             condition that, in the opinion of the Investigator, would interfere with the study
             endpoints or the subject's ability to participate.

          -  History of clinically significant cardiac disease or congestive heart failure > New
             York Heart Association (NYHA) class 2. Subjects must not have unstable angina (anginal
             symptoms at rest) or new-onset angina within the last 3 months or myocardial
             infarction within the past 6 months.

          -  Investigational drug use within 14 days (or 5 half-lives, whichever is longer) of the
             first dose of ipilimumab and pembrolizumab.

          -  Has a history of non-infectious pneumonitis that required steroids or current
             pneumonitis.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical benefit rate (CBR)
Time Frame:Up to 1 year
Safety Issue:
Description:CBR rate will be estimated along with a corresponding 95% credible interval by cohort.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From the start of first treatment to death, assessed up to 1 year
Safety Issue:
Description:OS will be assessed using the Kaplan-Meier method. Associations between OS and PFS and demographic and clinical covariates of interest will be assessed by Cox proportional hazards regression models.
Measure:Progression-free survival (PFS)
Time Frame:From start of first treatment to disease progression or death, assessed up to 1 year
Safety Issue:
Description:PFS will be assessed using the Kaplan-Meier method. Associations between OS and PFS and demographic and clinical covariates of interest will be assessed by Cox proportional hazards regression models.
Measure:Cytokine levels
Time Frame:Up to 1 year
Safety Issue:
Description:Will be summarized using means, standard deviations, medians, minimums, and maximums. Within group changes will be evaluated using either paired t-test or Wilcoxon signed rank test, depending on the data distribution.
Measure:Changes in the T-cell population in the cerebrospinal fluid (CSF) and blood
Time Frame:Baseline up to 1 year
Safety Issue:
Description:Will be summarized using means, standard deviations, medians, minimums, and maximums. Within group changes will be evaluated using either paired t-test or Wilcoxon signed rank test, depending on the data distribution.
Measure:Change in relative apparent diffusion coefficient and circulating cell-free deoxyribonucleic acid (cfDNA) by CBR (yes versus no)
Time Frame:Baseline up to 1 year
Safety Issue:
Description:Will be evaluated by either two sample t-test or Wilcoxon rank-sum test, depending on the data distribution.
Measure:Incidence of adverse events and serious adverse events
Time Frame:Up to 1 year
Safety Issue:
Description:Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Safety will be assessed by adverse events and serious adverse events as well as by vital signs and laboratory assessments for all patients.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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