Clinical Trials /

MK-3475 in Melanoma and NSCLC Patients With Brain Metastases



The purpose of this trial is to study the activity of MK-3475 in untreated brain metastases from melanoma or non-small cell lung cancer.

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



Phase 2

Trial Eligibility



  • Brief Title: MK-3475 in Melanoma and NSCLC Patients With Brain Metastases
  • Official Title: A Phase 2 Study of MK-3475 in Patients With Metastatic Melanoma and Non-Small Cell Lung Cancer With Untreated Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: 1401013290
  • SECONDARY ID: IND 121564
  • NCT ID: NCT02085070


  • Melanoma
  • Non-Small Cell Lung Cancer
  • Brain Metastases


MK-3475Melanoma patients


The purpose of this trial is to study the activity of MK-3475 in untreated brain metastases from melanoma or non-small cell lung cancer.

Detailed Description

      While recent advances in the treatment of metastatic melanoma and NSCLC (non-small cell lung
      cancer) with agents targeting PD-1 are striking, there remains a significant need to develop
      therapies for patients with untreated brain metastases who were excluded from prior trials
      with MK-3475 and the majority of other studies in these diseases. The brain is a common site
      of disease spread in many solid tumors, most notably metastatic melanoma and NSCLC. 10-40% of
      patients with metastatic melanoma develop brain metastases during their lifetime and >75%
      have brain metastases at autopsy. Overall, historical melanoma patient cohorts have reported
      a median survival of patients with brain metastases in the order of 2.5 - 4 months despite
      use of whole brain radiation therapy (WBRT) and surgery. One older patient series showed a
      median survival of < 4 months in melanoma patients with brain metastases and a neurological
      death rate of >30% despite the treatment of intracranial metastases with whole brain
      radiation therapy (WBRT). Among those with NSCLC, 10% have brain metastases at presentation
      and another 30% develop them over the course of their disease. Survival after the development
      of brain metastases is as dismal in those with NSCLC as it is for melanoma. Multifocal
      disease is common in both of these diseases, with about half of patients with CNS disease
      presenting with more than one brain lesion.

      Patients with untreated brain metastases have been excluded from most clinical trials of
      systemic therapy for two reasons: (1) historically their prognosis has been poor (overall
      survival ≤ 4 months) and (2) experimental drugs are presumed to not penetrate the blood brain
      barrier (BBB) or BBB penetration is not well studied. In melanoma, for example, one phase III
      study evaluating ipilimumab excluded patients with untreated brain metastases and another
      study evaluating ipilimumab and dacarbazine excluded all patients with a history of brain
      metastases, regardless of prior treatment. A subsequent trial with ipilimumab for patients
      with untreated brain metastases indeed showed that the drug had some activity in treating CNS
      disease. In the initial vemurafenib studies, patients with progressing or unstable CNS
      metastases were excluded. The pivotal BRIM-3 trial excluded patients with brain metastases
      unless metastases had been definitively treated more than three months prior to trial
      enrollment. Both temodar and sorafenib cross the BBB. Initial studies with sorafenib alone
      and in combination with chemotherapy excluded patients with active brain metastases. A
      combination study of temodar and sorafenib in patients with or without brain metastases
      showed modest activity in patients without a history of prior temodar, and was thought to be
      favorable in part due to local therapies. Although a number of studies have been conducted
      for melanoma patients with untreated brain metastases using established therapies, most
      initial clinical trials with novel agents exclude these patients. A recent trial with
      dabrafenib, an inhibitor of mutated B-raf, is an exception to the long-standing paradigm. A
      phase I/II study of this agent included a subset of patients with untreated brain metastases.
      At the 2010 meeting of the European Society for Medical Oncology, Long et al reported that
      nine of the ten patients with untreated cerebral metastases enrolled in this trial had
      shrinkage of their brain lesions. This was the basis for a recent phase II trial of
      dabrafenib specific for patients with untreated brain metastases61. In NSCLC, a small number
      of trials have shown that combination chemotherapy regimens can induce a response in the CNS
      with untreated brain metastases with a median PFS up to 4 months. These studies demonstrate
      that asymptomatic brain metastases, similar to asymptomatic metastases in other sites, can be
      treated systemically on clinical trials, and that drug activity in the CNS is not necessarily
      different than in other metastatic locations.

      Current standard of care for brain metastases that require immediate local intervention
      (based on symptoms, location, size, or other concerning features) is craniotomy with
      resection or radiation therapy. As an adjunct to standard craniotomy, LITT is emerging as a
      new, minimally invasive local therapy to treat previously surgically inaccessible brain
      metastases. Not only is cell death instantaneous, thus decreasing the risk of delayed
      intra-tumoral hemorrhage, but another theoretical advantage of using LITT as part of
      management of brain metastases is that the hyperthermia breaks down the blood brain barrier
      at the edge of the coagulation region thereby possibly increasing access of chemotherapeutic
      agents into the lesion. In patients in whom either craniotomy or LITT are performed, biopsies
      of tumor and surrounding normal brain can also be obtained at the time of local therapy.

      The purpose of this trial is to study the activity of MK-3475 in untreated brain metastases
      from melanoma or NSCLC. Given the promising initial results of MK-3475 in these diseases but
      the lack of data in patients with untreated brain metastases thus far, this trial will study
      treatment in this patient population. Additionally, for patients with melanoma this trial
      requires local therapy with craniotomy or LITT to at least 1 brain lesion prior to systemic
      therapy, thereby allowing the acquisition of brain tumor tissue for correlative studies on
      biomarkers that may be predictive of clinical response in the CNS and systemically. There
      will also be a biopsy of an extra-cerebral metastasis when feasible, particularly when tissue
      from the brain lesion is not obtained in patients with NSCLC.

      Upon results entry, the primary outcome measure was aligned as originally presented in the
      study protocol (attached with results).

Trial Arms

Melanoma patientsExperimentalAfter establishing eligibility criteria, for patients with melanoma the investigator will determine at least one lesion that requires local therapy (surgical resection or LITT) based on size, location, and/or risk of hemorrhage; this will be considered the "surgical lesion". All other eligible brain lesions will be considered "clinically evaluable lesions" and will be followed by modified RECIST (mRECIST) criteria to determine best response.
  • MK-3475
Non-small cell lung cancer patientsOtherNSCLC patients are not required to have a "surgical lesion" but must have at least one "clinically evaluable lesion" in the central nervous system. Patients on NSCLC are required to have formalin-fixed, paraffin-embedded tumor tissue available for biomarker analysis.
  • MK-3475

Eligibility Criteria

        Inclusion Criteria:

          1. Biopsy proven metastatic melanoma or NSCLC as follows:

               1. Patients with metastatic melanoma must have untreated brain metastases including:

                    -  At least one cerebral metastasis that requires local intervention and is
                       amenable to craniotomy or LITT therapy either due to symptoms, lesion size,
                       location, edema or hemorrhage ("surgical lesion"). Alternatively, a patient
                       may be eligible if a cerebral metastasis was resected or biopsied any time
                       prior to enrollment and there is tumor tissue available for analysis.

                    -  At least one cerebral metastasis that is at least 5 mm AND twice the MRI
                       slice thickness, but less than 20 mm, that is asymptomatic and does not
                       require local therapy at the time of enrollment ("clinically evaluable
                       lesion(s)"). OR

               2. Patients with stage IV NSCLC with at least one cerebral metastasis that is at
                  least 5 mm AND twice the MRI slice thickness, but less than 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 MK-3475 with the exception of bevacizumab which must
             have been administered at least 4 weeks prior to MK-3475. Patients are not required to
             have had prior systemic therapy. The exception to this is patients with NSCLC who test
             negative for PD-L1 expression or are unevaluable for PD-L1 expression must have
             received prior platinum-based chemotherapy for entry into Cohort 2. Note: Ipilimumab
             treatment should have been administered at least 4 weeks prior to the start of

          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 MK-3475. 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 for
             entry into Cohort 1. Tumor tissue must be obtained after the last systemic therapy.
             PD-L1 expression will be analyzed by a Merck assay. For NSCLC Cohort 2, patients may
             test PD-L1 negative or may be unevaluable for PD-L1 expression (i.e. insufficient
             tumor tissue). 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 as defined per protocol.

          9. For women of childbearing potential, agreement to the use of two acceptable methods of
             contraception, including one barrier method, during the study and for 6 months after
             discontinuation of MK-3475.

         10. For men with female partners of childbearing potential, agreement to use a latex
             condom, and to advise their female partner to use an additional method of
             contraception during the study and for 6 months after discontinuation of MK-3475.

         11. Negative serum or urine pregnancy test within 72 hours of commencement of treatment in
             premenopausal women.

         12. Patients must have the ability to understand and the willingness to sign a written
             informed consent document.

        Exclusion Criteria:

          1. Symptomatic brain metastases. Symptoms may be present from the surgical lesion prior
             to resection or LITT but must have resolved by the time of administration of study

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

          3. 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

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

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

          4. Has had prior treatment with any other anti-PD-1 or PD-L1 or PD-L2 agent or an
             antibody targeting other immune-regulatory receptors or mechanisms. Examples of such
             antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R,
             GITR. Prior ipilimumab, IL2, bevacizumab and adoptive cell therapy is allowed.

          5. 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

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

          7. Presence of leptomeningeal disease

          8. Has an active automimmune disease requiring systemic treatment within the past 3
             months or a documented history of clinically severe autoimmune disease, or a syndrome
             that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or
             resolved childhood asthma/atopy would be an exception to this rule. Subjects that
             require intermittent use of inhaled steroids or local steroid injections would not be
             excluded from the study. Subjects with hypothyroidism stable on hormone replacement or
             Sjorgen's syndrome will not be excluded from the study.

          9. 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

             Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with MK-3475, breastfeeding must be discontinued
             if the mother is treated with MK-3475.

         10. 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.

         11. 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.

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

         13. 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.

         14. Has a history of (non-infectious) pneumonitis that required steroids or current

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

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

         17. Evidence of interstitial lung disease
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response in the Brain by mRECIST
Time Frame:8 weeks
Safety Issue:
Description:RECIST criteria v1.1 was modified to account for differences in measuring the response of clinically evaluable brain lesions as opposed to systemic lesions (modified RECIST, or mRECIST). Size was considered the tumor's largest diameter. Measurements from multiple lesions were summed to calculate the sum of the diameters (SD). The SD calculated on a baseline scan performed within 28 days of study drug initiation was used as a reference to determine the objective response of the clinically evaluable lesions. mRECIST differ from RECIST v1.0 in allowing lesions measuring 5mm or less for response evaluation, provided that the MRI slice thickness was no more than 2.5mm. Seeing that the primary trial endpoint was brain metastasis response, up to 5 lesions were used for evaluation. Complete response (CR) constitutes complete disappearance of all target lesions, partial response (PR) constitutes >= 30% decrease in the sum of the sum of the largest diameter of target


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Yale University

Last Updated

March 24, 2021