Clinical Trials /

Pembrolizumab Plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-small Cell Lung Cancer

NCT02681549

Description:

The purpose of this phase 2 trial is to study the activity of pembrolizumab in combination with bevacizumab in patients with untreated brain metastases from melanoma or NSCLC to determine activity and safety of the drug combination. Furthermore, in patients who undergo resection of biopsy of a brain metastasis, we will evaluate biomarkers predictive of treatment benefit, and will also conduct correlative biomarker studies on extra-cerebral specimens in all patients in whom a systemic biopsy is feasible or in archival tumor tissue when available. A total of 53 eligible patients will be enrolled on this trial (20 with melanoma and 33 with NSCLC). Individual cohorts of the study can be stopped if insufficient activity is observed in the first stage of that cohort. The study will accrue for approximately 48 months, and will be open for approximately 12 additional months as patients on study are being followed.

Related Conditions:
  • Melanoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Pembrolizumab</span> Plus <span class="go-doc-concept go-doc-intervention">Bevacizumab</span> for Treatment of Brain Metastases in Metastatic <span class="go-doc-concept go-doc-disease">Melanoma</span> or Non-small Cell Lung Cancer

Title

  • Brief Title: Pembrolizumab Plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-small Cell Lung Cancer
  • Official Title: A Phase 2 Trial of Pembrolizumab Plus Bevacizumab in Patients With Metastatic Melanoma or Non-small Cell Lung Cancer With Untreated Brain Metastases
  • Clinical Trial IDs

    NCT ID: NCT02681549

    ORG ID: 1512016953

    Trial Conditions

    Melanoma

    Non-small Cell Lung Cancer

    Brain Metastasis

    Trial Interventions

    Drug Synonyms Arms
    Pembrolizumab plus Bevacizumab pembrolizumab plus bevacizumab

    Trial Purpose

    The purpose of this phase 2 trial is to study the activity of pembrolizumab in combination
    with bevacizumab in patients with untreated brain metastases from melanoma or NSCLC to
    determine activity and safety of the drug combination. Furthermore, in patients who undergo
    resection of biopsy of a brain metastasis, we will evaluate biomarkers predictive of
    treatment benefit, and will also conduct correlative biomarker studies on extra-cerebral
    specimens in all patients in whom a systemic biopsy is feasible or in archival tumor tissue
    when available.

    A total of 53 eligible patients will be enrolled on this trial (20 with melanoma and 33 with
    NSCLC). Individual cohorts of the study can be stopped if insufficient activity is observed
    in the first stage of that cohort. The study will accrue for approximately 24 months, and
    will be open for approximately 12 additional months as patients on study are being followed.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    pembrolizumab plus bevacizumab Experimental Pembrolizumab plus Bevacizumab

    Eligibility Criteria

    Inclusion Criteria:

    1. Biopsy proven metastatic melanoma or non-squamous NSCLC with at least one untreated
    cerebral metastasis that is at least 5 mm AND twice the MRI slice thickness, but less
    than Page 22 of 71 20 mm, that is asymptomatic and does not require local therapy at
    the time of enrollment ("clinically evaluable lesion(s)").

    2. Age 18

    3. ECOG performance status < 2

    4. Any number of previous treatments with the exception of previous inhibitors of PD-1,
    PD-L1, or PD-L2. Other prior systemic therapies must have been administered at least
    2 weeks before administration of pembrolizumab; the exception to this is ipilimumab
    which must have been administered at least 4 weeks prior to the start of
    pembrolizumab. Patients are not required to have had prior systemic therapy.

    5. Life expectancy of at least 3 months

    6. A history of previously treated brain metastases is allowed, provided that at least
    14 days have lapsed between radiation and initiation of pembrolizumab. Any lesion
    present at the time of WBRT or included in the stereotactic radiotherapy field (or
    within 2mm of the treated lesion) will NOT be considered evaluable unless it is new
    or documented to have progressed since treatment.

    7. PD-L1 expression in tumor tissue from any site is required for patients with NSCLC.
    Tumor tissue can be archival, however if no archival tissue is available then a
    biopsy mube obtained for PD-L1 testing. PD-L1 expression will be analyzed by a Merck
    assay. PD-L1 expression is not required for patients with melanoma, but melanoma
    patients are required to submit an extra-cerebral specimen for analysis, unless it is
    not feasible to obtain one.

    8. Patients must have normal organ and marrow function Exclusion Criteria:

    9. 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.

    10. Female subjects of childbearing potential should be willing to use 2 methods of birth
    control or be surgically sterile, or abstain from heterosexual activity for the
    course of the study through 120 days after the last dose of study medication
    (Reference Section 5.7.2). Subjects of childbearing potential are those who have not
    been surgically sterilized or have not been free from menses for > 1 year.

    11. Male subjects should agree to use an adequate method of contraception starting with
    the first dose of study therapy through 120 days after the last dose of study
    therapy. -

    Exclusion criteria:

    1. Symptomatic brain metastases. Any neurologic symptoms present must have resolved
    withlocal therapy by the time of administration of study drug.

    2. Patients with brain metastases for whom complete surgical resection is clinically
    appropriate.

    3. Patients with lung cancer with squamous histology.

    4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy to
    the lung or brain within 2 weeks prior to study Day 1 or who has not recovered (i.e.,
    Grade 1 or at baseline) from adverse events due to a previously administered agent.
    Previous radiation to other sites may be completed at any time prior to initiation of
    pembrolizumab. Note: If subject received major surgery, they must have recovered
    adequately from the toxicity and/or complications from the intervention prior to
    starting therapy.

    Note: Toxicity that has not recovered to Grade 1 is allowed if it meets the
    inclusion requirements for laboratory parameters.

    5. Has had prior treatment with any other anti-PD-1 or PD-L1 or PD-L2 agent.

    6. The use of corticosteroids to control cerebral edema or treat neurologic symptoms
    will not be allowed, and patients who previously required corticosteroids for symptom
    control must be off steroids for at least 2 weeks. Low-dose steroid use (10 mg of
    prednisone or equivalent) as corticosteroid replacement therapy is allowed

    7. Has not recovered (i.e., Grade 1 or at baseline) from adverse events due to agents
    administered more than 4 weeks earlier.

    8. Presence of leptomeningeal disease

    9. 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 (eg., thyroxine, insulin, or physiologic corticosteroid
    replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
    form of systemic treatment.

    10. Pregnancy or breast feeding. Should a woman become pregnant or suspect she is
    pregnant while participating in this study, she should inform her treating physician
    immediately. Because there is an unknown but potential risk for adverse events in
    nursing infants secondary to treatment of the mother with pembrolizumab,
    breastfeeding must be discontinued if the mother is treated with pembrolizumab.

    11. Patients may not be receiving any other investigational agents and may not have
    participated in a study of an investigational agent or using an investigational
    device within 4 weeks of the first dose of treatment.

    12. Either a concurrent condition (including medical illness, such as active infection
    requiring treatment with intravenous antibiotics or the presence of laboratory
    abnormalities) or history of a prior condition that places the patient at
    unacceptable risk if he/she were treated with the study drug or a medical condition
    that confounds the ability to interpret data from the study.

    13. Concurrent, active malignancies in addition to those being studied (other than
    cutaneous squamous cell carcinoma or basal cell carcinoma)

    14. Patients with active hemoptysis.

    15. Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted
    medical devices). An MRI safety questionnaire is required prior to MR imaging.

    16. Has active non-infectious pneumonitis

    17. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C
    (HCV) infection.

    18. Has received a live vaccine within 30 days prior to the first dose of trial
    treatment.

    19. Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
    and/or diastolic blood pressure > 100 mmHg). Anti-hypertensive therapy to achieve
    these parameters is allowable.

    20. History of myocardial infarction or unstable angina within 3 months prior to Cycle 1,
    Day 1

    21. History of stroke or transient ischemic attack within 3 months prior to Cycle 1, Day
    1

    22. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
    recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1

    23. Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence
    of therapeutic anticoagulation). Any history of significant bleeding or thrombosis
    should be discussed the study PIs.

    24. Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of
    dipyramidole, ticlopidine, clopidogrel, or cilostazol

    25. Warfarin is not permitted. Prophylactic or therapeutic use of low molecular-weight
    heparin (e.g., enoxaparin) or direct thrombin inhibitors are permitted.

    26. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation
    within 6 months prior to Cycle 1, Day 1

    27. Serious, non-healing or dehiscing wound

    28. Proteinuria > 2.0 g of protein in a 24-hour urine collection. All patients with 2
    protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection
    for protein.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    brain metastasis response rate (BMRR) using modified RECIST (mRECIST) criteria

    Secondary Outcome Measures

    Proportion of patients using steroids to control of cerebral edema for greater than 96 hours

    best overall response rate (ORR) by mRECIST criteria in the brain or RECIST criteria in the body

    progression-free survival by mRECIST criteria in the brain or RECIST criteria in the body

    Safety and toxicity of combination pembrolizumab and bevacizumab assessed using common terminology criteria for adverse events v. 4.

    Trial Keywords