Pembrolizumab in Patients With Leptomeningeal Disease

Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
Overall Status
Terminated
CT.gov ID
NCT03091478
Collaborator
Merck Sharp & Dohme LLC (Industry)
13
1
1
32.1
0.4

Study Details

Study Description

Brief Summary

This is an open-label phase II study of pembrolizumab in patients with advanced solid tumors with leptomeningeal carcinomatosis (LMD). Approximately 18 subjects in this study will receive pembrolizumab at a dose of 200mg intravenously (IV) every 3 weeks (Q3W) for 4 doses.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

This is an open-label phase II study of pembrolizumab in patients with advanced solid tumors with leptomeningeal carcinomatosis (LMD). Patients may have received any number of prior therapies for their respective solid tumors, but must not have received prior anti-PD-1 therapy and developed progressive disease. Approximately 18 subjects in this study will receive pembrolizumab at a dose of 200mg intravenously (IV) every 3 weeks (Q3W) for 4 doses. In patients who derive clinical benefit from therapy, pembrolizumab may be continued until documented disease progression, unacceptable adverse event(s), intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the subject, subject withdrawal of consent, noncompliance with trial treatment or procedure requirements, or for administrative reasons.

Study Design

Study Type:
Interventional
Actual Enrollment :
13 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Pembrolizumab in Patients With Leptomeningeal Disease
Actual Study Start Date :
Apr 12, 2017
Actual Primary Completion Date :
Dec 14, 2019
Actual Study Completion Date :
Dec 14, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Pembrolizumab 200 mg

Pembrolizumab 200 mg every 3 weeks

Drug: Pembrolizumab
200mg every 3 weeks
Other Names:
  • Keytruda
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With a Response [At 12 weeks]

      Eligible patients who receive at least one dose of pembrolizumab.

    Secondary Outcome Measures

    1. CNS Progression-free Survival in Patients With LMD From Solid Tumors Receiving Pembrolizumab [From the date of study entry until date of death from any cause, assessed up to 24 months]

      To determine whether pembrolizumab administered in patients with Leptomeningeal disease (LMD) from solid tumors improves central nervous system (CNS) progression-free survival (PFS).

    2. Overall Survival in Patients With LMD From Solid Tumors Receiving Pembrolizumab [From the date of study entry until date of death from any cause, assessed up to 24 months]

      To determine whether pembrolizumab administered in patients with LMD from solid tumors improves overall survival (OS).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 100 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Willing and able to provide written informed consent for the trial.

    2. 18 years of age on day of signing informed consent.

    3. Histologically or cytologically confirmed solid tumor malignancy.

    4. Cytologically confirmed LMD or radiologically detectable LMD defined as either/or:

    A measurable lesion on contrast-enhanced MRI of either the Brain or Total Spine greater than 3mm that has not been radiated within the last 3 months prior to commencement of study therapy.

    Positive cerebrospinal fluid (CSF) cytology

    1. Patients may be newly diagnosed or have received any number of lines of prior anti cancer therapy. However, patients are required to have received available therapies for their primary disease, as deemed appropriate by the treating investigator.

    2. Non escalating steroid requirement at the time of consent and study drug initiation for the treatment of central nervous system (CNS) symptoms.

    3. Local radiation therapy (RT) is allowed as needed to manage symptoms appropriately, as long as there remains a measurable lesion in the CNS.

    4. Whole brain RT may be used, without a pre-defined washout period, prior to commencement of study therapy if the lesion that has been radiated is not the sole measurable lesion, or the patient is eligible based on positive CSF cytology.

    5. Patients may continue therapy with a targeted agent if CNS disease developed while receiving the agent, and for defined regimens that have been deemed safe when combined with anti PD 1 therapy.

    6. Be willing to provide tissue from an archival tissue specimen in selected patients, where available.

    7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.

    8. Demonstrate adequate organ function as defined in Table 3, all screening labs should be performed within 10 days of treatment initiation.

    Table 3.

    1. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

    2. Female subjects of childbearing potential (Section 4.8.2) must be willing to use an adequate method of contraception as outlined in Section 4.8.2 Contraception, for the course of the study through 120 days after the last dose of study medication.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

    1. Male subjects of childbearing potential (Section 4.8.2) must agree to use an adequate method of contraception as outlined in Section 4.8.2 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.

    Exclusion Criteria:
    1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks or 5 half lives of the first dose of treatment, whichever is shorter.

    2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

    3. Has a known history of active Bacillus Tuberculosis (TB)

    4. Hypersensitivity to pembrolizumab or any of its excipients.

    5. Has had a prior anti cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

    6. Has had prior chemotherapy, targeted small molecule therapy other than pre specified allowed agents detailed in section 4.2.6, or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

    Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

    Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

    1. All major surgery including prior surgery to the brain within 3 weeks of commencement of study therapy.

    2. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.

    3. Subjects with previously treated brain metastases may participate provided they are not using escalating steroids for brain metastases at the time of trial consent and study drug initiation, and there remains a measurable lesion in the CNS, as per section 4.2.6.

    4. 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.

    5. Has history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.

    6. Has an active infection requiring systemic therapy.

    7. Prior disease progression on anti-PD-1 therapy

    8. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

    9. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

    10. 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.

    11. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

    12. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (HCV) (e.g., HCV RNA [qualitative] is detected).

    13. Has received a live vaccine within 30 days of planned start of study therapy.

    14. Contraindication to MRI.

    15. Patients with a condition related to their cancer or leptomeningeal disease requiring urgent intervention that has not been clinically managed or stabilized prior to the time of consent.

    16. Brain metastases with risk of mass effect that would contraindicate lumbar puncture, as detailed in section 6.1.2.8.3.

    17. Live vaccines within 30 days prior to the first dose of trial treatment. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore Maryland United States 21287

    Sponsors and Collaborators

    • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Merck Sharp & Dohme LLC

    Investigators

    • Principal Investigator: Jarushka Naidoo, MD, Johns Hopkins School of Medicine

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    ClinicalTrials.gov Identifier:
    NCT03091478
    Other Study ID Numbers:
    • J16156
    • IRB00116423
    First Posted:
    Mar 27, 2017
    Last Update Posted:
    Jan 26, 2021
    Last Verified:
    Jan 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Pembrolizumab 200 mg
    Arm/Group Description Pembrolizumab 200 mg every 3 weeks
    Period Title: Overall Study
    STARTED 13
    COMPLETED 13
    NOT COMPLETED 0

    Baseline Characteristics

    Arm/Group Title Pembrolizumab 200 mg
    Arm/Group Description Pembrolizumab 200 mg every 3 weeks
    Overall Participants 13
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    10
    76.9%
    >=65 years
    3
    23.1%
    Sex: Female, Male (Count of Participants)
    Female
    7
    53.8%
    Male
    6
    46.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    Not Hispanic or Latino
    11
    84.6%
    Unknown or Not Reported
    2
    15.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    2
    15.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    9
    69.2%
    More than one race
    0
    0%
    Unknown or Not Reported
    2
    15.4%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With a Response
    Description Eligible patients who receive at least one dose of pembrolizumab.
    Time Frame At 12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pembrolizumab 200 mg
    Arm/Group Description Pembrolizumab 200 mg every 3 weeks
    Measure Participants 13
    Complete Response
    2
    15.4%
    Partial Response
    1
    7.7%
    Stable Disease
    2
    15.4%
    Progressive Disease
    8
    61.5%
    2. Secondary Outcome
    Title CNS Progression-free Survival in Patients With LMD From Solid Tumors Receiving Pembrolizumab
    Description To determine whether pembrolizumab administered in patients with Leptomeningeal disease (LMD) from solid tumors improves central nervous system (CNS) progression-free survival (PFS).
    Time Frame From the date of study entry until date of death from any cause, assessed up to 24 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pembrolizumab 200 mg
    Arm/Group Description Pembrolizumab 200 mg every 3 weeks
    Measure Participants 13
    Median (95% Confidence Interval) [Months]
    2.9
    3. Secondary Outcome
    Title Overall Survival in Patients With LMD From Solid Tumors Receiving Pembrolizumab
    Description To determine whether pembrolizumab administered in patients with LMD from solid tumors improves overall survival (OS).
    Time Frame From the date of study entry until date of death from any cause, assessed up to 24 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pembrolizumab 200 mg
    Arm/Group Description Pembrolizumab 200 mg every 3 weeks
    Measure Participants 13
    Median (95% Confidence Interval) [Months]
    4.9

    Adverse Events

    Time Frame For the time period beginning at treatment allocation/registration through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.
    Adverse Event Reporting Description
    Arm/Group Title Pembrolizumab 200 mg
    Arm/Group Description Pembrolizumab 200 mg every 3 weeks Pembrolizumab: 200mg every 3 weeks
    All Cause Mortality
    Pembrolizumab 200 mg
    Affected / at Risk (%) # Events
    Total 9/13 (69.2%)
    Serious Adverse Events
    Pembrolizumab 200 mg
    Affected / at Risk (%) # Events
    Total 7/13 (53.8%)
    Gastrointestinal disorders
    Nausea 1/13 (7.7%) 1
    Musculoskeletal and connective tissue disorders
    Back pain 2/13 (15.4%) 3
    Bone Pain 1/13 (7.7%) 1
    Generalized Muscle Weakness 2/13 (15.4%) 2
    Muscle Weakness, Lower Limb 1/13 (7.7%) 1
    Nervous system disorders
    Paresthesia 1/13 (7.7%) 1
    Psychiatric disorders
    Confusion 2/13 (15.4%) 2
    Renal and urinary disorders
    Urinary Tract Obstruction 1/13 (7.7%) 1
    Reproductive system and breast disorders
    Pelvic Pain 1/13 (7.7%) 1
    Vascular disorders
    Thrombolic Event- PE 1/13 (7.7%) 1
    Other (Not Including Serious) Adverse Events
    Pembrolizumab 200 mg
    Affected / at Risk (%) # Events
    Total 13/13 (100%)
    Endocrine disorders
    Hypothyroidism 1/13 (7.7%) 1
    Eye disorders
    Anisocoria 1/13 (7.7%) 1
    Blurred Vision 1/13 (7.7%) 2
    Dry Eye 1/13 (7.7%) 1
    Twitching Eyelid 1/13 (7.7%) 1
    Gastrointestinal disorders
    Abdominal Pain 1/13 (7.7%) 1
    Constipation 3/13 (23.1%) 5
    Diarrhea 2/13 (15.4%) 2
    Dry Mouth 2/13 (15.4%) 2
    Dyspepsia 1/13 (7.7%) 1
    Dysphagia 1/13 (7.7%) 2
    Nausea 5/13 (38.5%) 7
    Vomitting 1/13 (7.7%) 2
    General disorders
    Face Edema 1/13 (7.7%) 1
    Edema Limbs 3/13 (23.1%) 3
    Fatigue 6/13 (46.2%) 10
    Fever 1/13 (7.7%) 1
    Infusion Related Reaction 1/13 (7.7%) 1
    Non-cardiac Chest Pain 1/13 (7.7%) 1
    Minimal Redness at site of LP 1/13 (7.7%) 1
    Investigations
    Creatinine Increased 1/13 (7.7%) 1
    Weight Loss 2/13 (15.4%) 2
    Metabolism and nutrition disorders
    Anorexia 3/13 (23.1%) 5
    Dehydration 1/13 (7.7%) 6
    Musculoskeletal and connective tissue disorders
    Arthralgia 3/13 (23.1%) 3
    Back Pain 3/13 (23.1%) 4
    Generalized Muscle Weakness 4/13 (30.8%) 7
    Joint range of motion decreased 2/13 (15.4%) 3
    Muscle Twitching 1/13 (7.7%) 1
    Myalgia 1/13 (7.7%) 1
    Neck Pain 2/13 (15.4%) 3
    Pain in Extremity 5/13 (38.5%) 16
    Edema Cerebral 1/13 (7.7%) 1
    Bone pain 1/13 (7.7%) 1
    Muscle cramping 1/13 (7.7%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Precancerious Cells from Scalp 1/13 (7.7%) 1
    Nervous system disorders
    Ataxia 2/13 (15.4%) 2
    Cerebrospinal fuild leakage 1/13 (7.7%) 1
    Cognitive Disturbance 1/13 (7.7%) 1
    Concentration Impairment 1/13 (7.7%) 3
    Depressed level of consciousness 1/13 (7.7%) 1
    Dizziness 1/13 (7.7%) 2
    Dysphagia 1/13 (7.7%) 1
    Headache 5/13 (38.5%) 8
    Lethargy 1/13 (7.7%) 1
    Memory Impairment 2/13 (15.4%) 2
    Paresthesia 2/13 (15.4%) 2
    Peripheral Motor Neuropathy 1/13 (7.7%) 1
    Peripheral Sensory Neuropathy 1/13 (7.7%) 1
    Seizure 1/13 (7.7%) 1
    Tremor 1/13 (7.7%) 1
    Confusion 2/13 (15.4%) 3
    Dysarthria 1/13 (7.7%) 1
    Psychiatric disorders
    Delusions 1/13 (7.7%) 1
    Insomnia 1/13 (7.7%) 1
    Renal and urinary disorders
    Urinary Tract Infection 2/13 (15.4%) 2
    Urinary Incontinence 2/13 (15.4%) 2
    Urinary Retention 1/13 (7.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 6/13 (46.2%) 6
    Epistaxis 1/13 (7.7%) 1
    Hoarseness 1/13 (7.7%) 1
    Nasal Congestion 1/13 (7.7%) 1
    Pneumonitis 1/13 (7.7%) 2
    Productive Cough 1/13 (7.7%) 1
    Skin and subcutaneous tissue disorders
    Dry Skin 3/13 (23.1%) 4
    Left cheek lesion 1/13 (7.7%) 1
    Pruritus 5/13 (38.5%) 8
    Rash maculo-papular 2/13 (15.4%) 6
    Surgical and medical procedures
    Left supine craniotomy 1/13 (7.7%) 1
    Vascular disorders
    Hypotension 1/13 (7.7%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Rachel Levy, MS, CCRP
    Organization Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
    Phone 410-502-8738
    Email rlevy16@jhmi.edu
    Responsible Party:
    Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    ClinicalTrials.gov Identifier:
    NCT03091478
    Other Study ID Numbers:
    • J16156
    • IRB00116423
    First Posted:
    Mar 27, 2017
    Last Update Posted:
    Jan 26, 2021
    Last Verified:
    Jan 1, 2021