Pembrolizumab with or without Stereotactic Radiosurgery in Treating Patients with Central Nervous System Metastases

Status: Active

Description

This phase II trial studies how well pembrolizumab with or without stereotactic radiosurgery works in treating patients with cancer that has spread to the central nervous system. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving pembrolizumab and stereotactic radiosurgery may work better in treating patients with cancer that has spread to the central nervous system.

Eligibility Criteria

Inclusion Criteria

  • Participants must have histologically or cytologically confirmed disease from any solid tumor
  • Participants must have measurable disease in the CNS, defined as at least one lesion that can be accurately measured in at least one dimension as >= 5 mm (for cohorts A, B, D only)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 6 weeks
  • Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 14 days of treatment initiation)
  • Platelets >= 100,000/mcL (performed within 14 days of treatment initiation)
  • Hemoglobin >= 9 g/dL (performed within 14 days of treatment initiation) or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
  • Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (performed within 14 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
  • Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 14 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases (performed within 14 days of treatment initiation)
  • Albumin >= 2.5 g/dL (performed within 14 days of treatment initiation)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 14 days of treatment initiation)
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 14 days of treatment initiation)
  • 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
  • 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; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
  • 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
  • Ability to understand and the willingness to sign a written informed consent document
  • Stable dose of dexamethasone 2 mg or less for 7 days prior to initiation of treatment
  • COHORT A: Measurable CNS disease (one intracranial lesion >= 5 mm)
  • COHORT A: Previously untreated asymptomatic brain metastases
  • COHORT A: Patients with newly diagnosed, previously untreated primary tumors that present with brain metastases should not forego available therapy that has demonstrated a definitive overall survival benefit as first line therapy for metastatic disease; therefore, in cases of previously untreated systemic solid tumors only those patients for whom there is no available therapy with definitive overall survival benefit, those that have failed at least one line of prior therapy for their primary tumor, or those refusing standard therapy will be eligible for this study; specifically, for patients with previously untreated primary tumors, the following diagnoses will be excluded: HER2-positive breast cancer; small cell lung cancer; non-small cell lung carcinoma (NSCLC) with targetable genomic tumor aberrations (e.g. EGFR, ALK)
  • COHORT B: Measurable CNS disease (one intracranial lesion >= 5 mm)
  • COHORT B: Progressive brain metastases after prior local CNS-directed therapy such as radiation or surgery as defined by: * Untreated measurable lesions in patients that have received surgery and/or SRS to one or more other lesions * Residual or progressive lesions after surgery if asymptomatic * Patients who have had prior whole-brain radiotherapy (WBRT) and/or SRS and then whose lesions have progressed are eligible; lesions treated with SRS may be eligible if there is unequivocal evidence of progression
  • COHORT C: Carcinomatous meningitis, as defined by positive cytology
  • COHORT D: Measurable CNS disease (one intracranial lesion >= 5 mm) from any solid tumor
  • COHORT D: No limit on number of brain metastases
  • COHORT D: Radiation therapy over 7 Gy is indicated to any intracranial disease
  • COHORT D: Prior stereotactic radiosurgery or whole brain radiation is allowed
  • Patients may have progressive systemic disease
  • Patients with untreated spinal cord metastases are eligible if lesions are asymptomatic
  • Patients with untreated brainstem metastases are eligible if lesions are small and asymptomatic

Exclusion Criteria

  • Participants who have had chemotherapy, targeted small molecule therapy or study therapy within 14 days of protocol treatment, or those who have not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 2 weeks earlier; subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study; if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • Participants who are receiving any other investigational agents
  • Has a diagnosis of immunodeficiency
  • Requires treatment with high dose systemic corticosteroids defined as dexamethasone > 2 mg/day or bioequivalent within 7 days of initiating therapy
  • Has received systemic immunosuppressive treatments, aside from systemic corticosteroids, within three months of start of study drug
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Has a known history of active (TB) (Bacillus tuberculosis)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • 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
  • Human immunodeficiency virus (HIV)-positive participants on combination antiretroviral therapy are ineligible
  • 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
  • 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
  • Has known history of, or any evidence of active, non-infectious pneumonitis
  • Has an active infection requiring systemic therapy
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • 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
  • Unable to undergo brain MRI
  • Participants who are receiving or will receive other concurrent chemotherapies or immunotherapies for their cancer (except for patients who will receive letrozole, anastrozole, exemestane, tamoxifen, fulvestrant, trastuzumab, bisphosphonates, denosumab or ovarian suppression therapy)
  • Will need immediate local surgery or radiation for their brain metastases
  • Acute symptomatic CNS hemorrhage

Locations & Contacts

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Eudocia Quant Lee
Phone: 617-632-2166
Email: EQLee@partners.org
Dana-Farber Cancer Institute
Status: Active
Contact: Eudocia Quant Lee
Phone: 617-632-2166
Email: EQLee@partners.org
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Priscilla Kaliopi Brastianos
Phone: 617-724-1074
Email: pbrastianos@partners.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To estimate the clinical benefit rate (as defined by complete response, partial response or stable disease) of pembrolizumab in newly diagnosed or recurrent brain metastases. (Cohorts A and B)

II. To estimate the overall survival of pembrolizumab in leptomeningeal metastases. (Cohort C)

III. To estimate the systemic overall response rate to the combination of pembrolizumab and intracranial radiation in oligometastatic brain metastases from melanoma. (Cohort D)

SECONDARY OBJECTIVES:

I. To describe the toxicity of pembrolizumab in brain and leptomeningeal metastases. (Cohorts A, B, C, D)

II. To estimate the overall survival in patients with brain metastases receiving pembrolizumab. (Cohorts A, B, D)

III. To estimate the central nervous system response rate of pembrolizumab in patients with leptomeningeal metastases. (Cohort C)

IV. To estimate the systemic response rate of pembrolizumab in patients with brain metastases. (Cohorts A, B, C)

V. To estimate the systemic progression free-survival of patients receiving pembrolizumab. (Cohorts A, B, C, D)

VI. To estimate the intracranial progression free-survival of patients receiving pembrolizumab. (Cohorts A, B, C, D)

TERTIARY OBJECTIVES:

I. To determine molecular biomarkers of response using next generation sequencing techniques.

II. To determine if changes in brain magnetic resonance imaging (MRI) parameters correlate with tumor response.

OUTLINE: Patients are assigned to 1 of 4 cohorts.

COHORT A: Patients with measurable central nervous system (CNS) disease or previously untreated brain metastases receive pembrolizumab intravenously (IV) over 30 minutes on day 1.

COHORT B: Patients with measurable CNS disease or progressive brain metastases receive pembrolizumab IV over 30 minutes on day 1.

COHORT C: Patients with carcinomatous meningitis receive pembrolizumab IV over 30 minutes on day 1.

COHORT D: Patients with measurable CNS disease or brain metastases receive pembrolizumab IV over 30 minutes on day 1. Patients also undergo stereotactic radiosurgery (SRS) between courses 1 and 2.

For all cohorts, courses repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, every 6 weeks for up to 6 months, and every 3 months thereafter.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Priscilla Kaliopi Brastianos

Trial IDs

Primary ID 16-153
Secondary IDs NCI-2016-01565
Clinicaltrials.gov ID NCT02886585