Clinical Trials /

Pembrolizumab In Central Nervous System Metastases

NCT02886585

Description:

This research study is studying Pembrolizumab as a possible treatment for this diagnosis for metastases in the central nervous system (brain and spinal cord).

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab In Central Nervous System Metastases
  • Official Title: Phase II Trial of Pembrolizumab in Central Nervous System Metastases From Multiple Histologies

Clinical Trial IDs

  • ORG STUDY ID: 16-153
  • NCT ID: NCT02886585

Conditions

  • Brain Metastases

Interventions

DrugSynonymsArms
PembrolizumabPreviously Untreated Brain Metastases-Cohort A

Purpose

This research study is studying Pembrolizumab as a possible treatment for this diagnosis for metastases in the central nervous system (brain and spinal cord).

Detailed Description

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational intervention to learn whether the intervention works
      in treating a specific disease. "Investigational" means that the intervention is being
      studied.

      Pembrolizumab may help the immune system fight cancer.

      The FDA (the U.S. Food and Drug Administration) has approved pembrolizumab FDA for some
      diseases that are being treated on this study, but not for central nervous system
      metastases. Researchers hope to study the effects of pembrolizumab. Many cancers use
      specific pathways (such as PD-1/PD-L1 and CTLA-4) to evade the body's immune system.
      Pembrolizumab works by blocking the PD-1/PD-L1 pathways and thus releasing the brakes on the
      immune system so it can stop or slow cancer.

      Researchers hope to study the effects of pembrolizumab in cancer that has metastasized to
      the brain. These drugs work by stimulating the immune system to fight cancer.
    

Trial Arms

NameTypeDescriptionInterventions
Previously Untreated Brain Metastases-Cohort AExperimental- Previously Untreated Brain Metastases Baseline Brain MRI and PET CT For all cohorts, pembrolizumab will be administered every 3 weeks, with 21 consecutive days defined as a treatment cycle. Treatment will be administered on an outpatient basis. Brain MRI and PET/CT
  • Pembrolizumab
Progressive Brain Metastases-Cohort BExperimental- Progressive Brain Metastases Baseline Brain MRI and PET CT For all cohorts, pembrolizumab will be administered every 3 weeks, with 21 consecutive days defined as a treatment cycle. Treatment will be administered on an outpatient basis. Brain MRI and PET/CT
  • Pembrolizumab
Neoplastic Meningitis-Cohort CExperimentalNeoplastic Meningitis Histologically confirmed solid malignancy Positive Cytology Baseline Brain MRI For all cohorts, pembrolizumab will be administered every 3 weeks, with 21 consecutive days defined as a treatment cycle. Treatment will be administered on an outpatient basis. Brain MRI and PET/CT
  • Pembrolizumab
1-4 Brain Metastases from Melanoma Cohort DExperimental1-4 Brain Metastases from Melanoma Clinical indication for stereostatic radiosurgery Evaluable extracranial focus For all cohorts, pembrolizumab will be administered every 3 weeks, with 21 consecutive days defined as a treatment cycle. In Cohort D, cycle 1 and 2 of pembrolizumab will be administered 3 weeks apart and stereotactic radiosurgery will be administered between cycles. Treatment will be administered on an outpatient basis. Brain MRI and PET CT
  • Pembrolizumab

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 ≥10 mm .

          -  Age ≥18 years.

          -  ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A)

          -  Life expectancy of greater than 6 weeks

          -  Participants must have normal organ and marrow function as defined in Table 1, all
             screening labs should be performed within 10 days of treatment initiation.

               -  Adequate Organ Function Laboratory Values

                    -  Hematological

                       ---- Absolute neutrophil count (ANC) ≥1,500 /mcL

                       ---- Platelets ≥100,000 / mcL

                       ---- Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO
                       dependency (within 7 days of assessment)

                    -  Renal

                       ---- Serum creatinine ≤1.5 X upper limit of normal (ULN)

                       ----- OR

                       ---- Measured or calculated a creatinine clearance ≥60 mL/min for subject
                       with creatinine levels > 1.5 X institutional ULN (GFR can also be used in
                       place of creatinine or CrCl)

                    -  Hepatic

                       ---- Serum total bilirubin ≤ 1.5 X ULN

                       ----- OR

                       ---- Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5
                       ULN

                       ---- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN

                       ----- OR

                       ---- ≤ 5 X ULN for subjects with liver metastases

                    -  Albumin >2.5 mg/dL

                    -  Coagulation ---- International Normalized Ratio (INR) or Prothrombin Time
                       (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long
                       as PT or PTT is within therapeutic range of intended use of anticoagulants

                         -  Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject
                            is receiving anticoagulant therapy as long as PT or PTT is within
                            therapeutic range of intended use of anticoagulants

                         -  aCreatinine clearance should be calculated per institutional standard.

          -  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
             (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.

          -  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 2mg or less for 7 days prior to initiation of treatment

          -  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

          -  Cohort Specific Eligibility Criteria

               -  Cohort A:

                    -  Measurable CNS disease (one parenchymal lesion ≥1 cm)

                    -  Previously untreated asymptomatic brain metastases

                    -  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 firstline 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;
                       NSCLC with targetable genomic tumor aberrations (e.g. EGFR, ALK).

               -  Cohort B:

                    -  Measurable CNS disease (one intracranial lesion ≥ 1 cm)

                    -  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 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 parenchymal lesion ≥ 1 cm)

                    -  1-4 brain metastases (where stereotactic radiosurgery would be indicated)

                    -  Histologically confirmed diagnosis of melanoma

        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
             >2mg/day or bioequivalent within 7 days of initiating therapy.

          -  Has received systemic immunosuppressive treatments, aside from systemic
             corticosteroids as described in Section 3.2.4, 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.

          -  HIV-positive participants on combination antiretroviral therapy are ineligible
             because of the potential for pharmacokinetic interactions with pembrolizumab. In
             addition, these participants are at increased risk of lethal infections when treated
             with marrow-suppressive therapy. Appropriate studies will be undertaken in
             participants receiving combination antiretroviral therapy when indicated.

          -  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 (eg., 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., HBsAg reactive) or Hepatitis C (e.g., HCV 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 other concurrent chemotherapies or immunotherapies for
             their cancer (except for patients who will receive trastuzumab, bisphosphonates,
             denosumab or ovarian suppression therapy Radiation therapy to a symptomatic single
             metastatic site or to the brain may be allowed at the investigator's discretion).

          -  Will need immediate local surgery or radiation for their brain metastases

          -  Acute symptomatic CNS hemorrhage
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate
Time Frame:6 Weeks
Safety Issue:
Description:Contrast-enhanced cranial MRI will be performed every 6 weeks. The proportion of patients in each cohort with a best response of CR or PR will be presented with a 90% confidence interval estimated using the method of Atkinson and Brown, which allows for the two-stage design.

Secondary Outcome Measures

Measure:Number of Participants with grade-3 or higher hematologic toxicities or grade-3 or higher neurologic toxicities
Time Frame:Baseline to 21 Days
Safety Issue:
Description:
Measure:Overall Survival Rate
Time Frame:3 Months and 6 Months
Safety Issue:
Description:Kaplan-Meier
Measure:Intracranial Response Rate
Time Frame:6 Months
Safety Issue:
Description:intracranial response (CR or PR by RANO) will be presented with a two-sided, 90% exact binomial confidence interval
Measure:Extracranial Response Rate
Time Frame:6 Months
Safety Issue:
Description:Extracranial response rates (CR or PR) according to RECIST and irRC will be summarized for Cohorts A, B, C, and D
Measure:Extracranial PFS
Time Frame:3 Months and 6 Months
Safety Issue:
Description:
Measure:Intracranial PFS
Time Frame:3 Months and 6 Months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Brain Metastases

Last Updated

March 3, 2017