MK-3475 in Melanoma and NSCLC Patients With Brain Metastases
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ClinicalTrials.gov Identifier: NCT02085070 |
Recruitment Status :
Completed
First Posted : March 12, 2014
Results First Posted : March 24, 2021
Last Update Posted : March 24, 2021
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Tracking Information | ||||
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First Submitted Date ICMJE | March 10, 2014 | |||
First Posted Date ICMJE | March 12, 2014 | |||
Results First Submitted Date ICMJE | February 23, 2021 | |||
Results First Posted Date ICMJE | March 24, 2021 | |||
Last Update Posted Date | March 24, 2021 | |||
Study Start Date ICMJE | March 2014 | |||
Actual Primary Completion Date | February 27, 2020 (Final data collection date for primary outcome measure) | |||
Current Primary Outcome Measures ICMJE |
Overall Response in the Brain by mRECIST [ Time Frame: 8 weeks ] 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
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Original Primary Outcome Measures ICMJE |
Response will be evaluated after systemic therapy [ Time Frame: 8 weeks ] Response will be evaluated after 8 weeks of systemic therapy and then every 8 weeks thereafter. The purpose of the 4 weeks scans is to determine safety. If sysmptoms develop or clinical deterioration occurs, patients may be imaged prior to the pre-specified time points for imaging. All responses must be confirmed by repeat imaging at least 4 weeks following initial documentation of objective response.
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Change History | ||||
Current Secondary Outcome Measures ICMJE | Not Provided | |||
Original Secondary Outcome Measures ICMJE |
Brain metastases response assessment [ Time Frame: 28 days ] RECIST criteria v1.1 will be modified to account for differences in measuring the response of clinically evaluable brain lesions as opposed to systemic lesions (modified RECIST, or mRECIST). Size is considered the tumor's largest diameter. Measurements from multiple lesions are summed to calculate the sum of the diameters (SD). The SD calculated on a baseline scan performed within 28 days of study drug initiation will be used as a reference to determine the objective response of the clinically evaluable lesions. All responses must be confirmed at 4 weeks with an equivalent or better response. Please refer to the original RECIST criteria if further reference is necessary.
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Current Other Pre-specified Outcome Measures | Not Provided | |||
Original Other Pre-specified Outcome Measures | Not Provided | |||
Descriptive Information | ||||
Brief Title ICMJE | MK-3475 in Melanoma and NSCLC Patients With Brain Metastases | |||
Official Title ICMJE | A Phase 2 Study of MK-3475 in Patients With Metastatic Melanoma and Non-Small Cell Lung Cancer With Untreated Brain Metastases | |||
Brief Summary | 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). |
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Study Type ICMJE | Interventional | |||
Study Phase ICMJE | Phase 2 | |||
Study Design ICMJE | Allocation: Non-Randomized Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment |
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Condition ICMJE |
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Intervention ICMJE | Drug: MK-3475
IV MK-3475
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Study Arms ICMJE |
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Publications * |
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | ||||
Recruitment Status ICMJE | Completed | |||
Actual Enrollment ICMJE |
65 | |||
Original Estimated Enrollment ICMJE |
64 | |||
Actual Study Completion Date ICMJE | February 27, 2020 | |||
Actual Primary Completion Date | February 27, 2020 (Final data collection date for primary outcome measure) | |||
Eligibility Criteria ICMJE | Inclusion Criteria:
Exclusion Criteria:
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years to 99 Years (Adult, Older Adult) | |||
Accepts Healthy Volunteers ICMJE | No | |||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | |||
Listed Location Countries ICMJE | United States | |||
Removed Location Countries | ||||
Administrative Information | ||||
NCT Number ICMJE | NCT02085070 | |||
Other Study ID Numbers ICMJE | 1401013290 IND 121564 ( Other Identifier: FDA ) |
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Has Data Monitoring Committee | Yes | |||
U.S. FDA-regulated Product | Not Provided | |||
IPD Sharing Statement ICMJE |
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Current Responsible Party | Harriet Kluger, Yale University | |||
Original Responsible Party | Same as current | |||
Current Study Sponsor ICMJE | Yale University | |||
Original Study Sponsor ICMJE | Same as current | |||
Collaborators ICMJE | Not Provided | |||
Investigators ICMJE |
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PRS Account | Yale University | |||
Verification Date | February 2021 | |||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |