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

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ClinicalTrials.gov Identifier: NCT03873818
Recruitment Status : Recruiting
First Posted : March 13, 2019
Last Update Posted : March 14, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Clinical Stage IV Cutaneous Melanoma Metastatic Malignant Neoplasm in the Brain Metastatic Melanoma Pathologic Stage IV Cutaneous Melanoma Biological: Ipilimumab Biological: Pembrolizumab Phase 2

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.

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 courses for ipilimumab and up to 35 courses 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Open Label Low Dose Ipilimumab in Combination With Pembrolizumab in Metastatic Melanoma Patients With Brain Metastases
Actual Study Start Date : February 21, 2019
Estimated Primary Completion Date : May 1, 2020
Estimated Study Completion Date : May 1, 2020


Arm Intervention/treatment
Experimental: Treatment (ipilimumab, pembrolizumab)
Patients receive ipilimumab IV over 90 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 courses for ipilimumab and up to 35 courses for pembrolizumab in the absence of disease progression or unacceptable toxicity.
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Clinical benefit rate (CBR) [ Time Frame: Up to 1 year ]
    CBR rate will be estimated along with a corresponding 95% credible interval by cohort.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: From the start of first treatment to death, assessed up to 1 year ]
    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.

  2. Progression-free survival (PFS) [ Time Frame: From start of first treatment to disease progression or death, assessed up to 1 year ]
    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.

  3. Cytokine levels [ Time Frame: Up to 1 year ]
    Cell-free CSF and serum samples from the same timepoints used for the characterization of immune cell populations will be analyzed for levels of immunomodulatory cytokines and chemoattractants. Multiplex assay will be used to measure the levels of soluble factors involved in 1) T-cell mediated antitumor activity (IFN, TNF), inflammation pathways (IL-1β, IL-6) or 3) immunosuppressive mechanisms (IL-10, TGFβ), markers and mediators of inflammation (IL-6 and IL-8). We will also measure the levels of well-characterized immunosuppressive soluble factors (i.e., IL-10 and IDO). Both absolute levels and changes from baseline will be determined.

  4. Changes in the T-cell population in the cerebrospinal fluid (CSF) and blood [ Time Frame: Baseline up to 1 year ]
    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.

  5. Change in relative apparent diffusion coefficient [ Time Frame: Baseline up to 1 year ]
    Will be evaluated by MRI response

  6. Incidence of adverse events [ Time Frame: Up to 1 year ]
    Safety will be assessed by adverse events as well as by vital signs and laboratory assessments for all patients. AEs, vital signs and laboratory assessments defined and graded according to NCI CTCAE v4.03.

  7. Incidence of serious adverse events [ Time Frame: Up to 1 year ]
    Safety will be assessed by serious adverse events. as well as by vital signs and laboratory assessments for all patients. AEs, vital signs and laboratory assessments defined and graded according to NCI CTCAE v4.03.

  8. Assess changes in circulating cell-free deoxyribonucleic acid (cfDNA) [ Time Frame: Baseline up to 1 year ]
    MRI response and/or markers of early progression



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • At least one measurable intracranial target lesion for which all of the following criteria are met: (1) Previously untreated or progressive after previous local therapy (2) Immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy (3) 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. Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable. For core-needle biopsy specimens, at least three cores should be submitted for evaluation (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 (minimum of three cores) 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 >= 30L/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.
  • (Cohort A) Prior PD-1 therapy. Note: Prior anti-PD1 therapy within the last 6 weeks of enrollment on this protocol is allowed for Cohort B.
  • 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.
  • Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than 1 month before the start of study medication).
  • 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.

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): NCT03873818


Contacts
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Contact: Isabella C Glitza 713-792-2921 icglitza@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Isabella C. Glitza    713-792-2921      
Principal Investigator: Isabella C. Glitza         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Isabella C Glitza M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03873818     History of Changes
Other Study ID Numbers: 2018-0875
NCI-2019-00406 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2018-0875 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: March 13, 2019    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Melanoma
Neoplasms
Skin Neoplasms
Neoplasms, Second Primary
Brain Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Skin Diseases
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Pembrolizumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents