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Ph II Study of Pembrolizumab & Eribulin in Patients With HR+/HER2- MBC Previously Treated With Anthracyclines & Taxanes (KELLY)

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ClinicalTrials.gov Identifier: NCT03222856
Recruitment Status : Recruiting
First Posted : July 19, 2017
Last Update Posted : January 18, 2018
Sponsor:
Information provided by (Responsible Party):
MedSIR

Brief Summary:

This a multicenter, open-label, phase II clinical trial to assess the efficacy of pembrolizumab in combination with eribulin in female patients older than 18 years old with hormone receptor-(HR)positive/HER2-negative metastatic breast cancer (MBC) previously treated with at least one, but not more than two, prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease. Prior therapy must have included an anthracycline and a taxane and prior anti-hormonal therapy is mandatory.

The number of patients to be included is 44 patients at 11 sites. All eligible patients will be treated with MK3475 (pembrolizumab) 200 mg on day 1 of each 21-day cycle and eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) on days 1 and 8 of every 21-day cycle.


Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Pembrolizumab Drug: Eribulin Phase 2

Detailed Description:

This a multicenter, open-label, phase II clinical trial to assess the efficacy of pembrolizumab in combination with eribulin in female patients older than 18 years old with hormone receptor-(HR)positive/HER2-negative metastatic breast cancer (MBC) previously treated with at least one, but not more than two, prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease. Prior therapy must have included an anthracycline and a taxane in any combination or order and either in the early or metastatic disease setting unless contraindicated for a given patient. Prior anti-hormonal therapy is mandatory.

The number of patients to be included is 44 patients at 11 sites. The primary objective is to assess the efficacy -as determined by the clinical benefit rate (CBR) (total number of objective responses plus stable disease for at least 24 weeks) based on RECIST v.1.1- of MK3475 (pembrolizumab) in combination with eribulin.

Primary endpoint is CBR based on RECIST v.1.1. All eligible patients will be treated with MK3475 (pembrolizumab) 200 mg on day 1 of each 21-day cycle and eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) on days 1 and 8 of every 21-day cycle. Treatment with MK3475 (pembrolizumab) and eribulin will continue based on physician criteria. No maximum duration of treatment is specified. Study follow-up will be performed 12 months after last study dose.

Available tumor tissue for PD-L1 biomarker analysis from a newly obtained core or excisional biopsy since last progression of a metastatic tumor lesion not previously irradiated is requested for this study.

Translational research of this protocol involves the collection, processing, temporary storage, and shipment of samples from consenting patients enrolled in centers selected for participation in the study. The study plan includes collection and initial processing of tumor tissues and blood samples to the central laboratory of Institut Hospital del Mar d‟Investigacions Mèdiques (IMIM), that will be used to identify dynamic biomarkers that may be predictive of response to MK3475 (pembrolizumab) and eribulin treatment.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Intervention Model: Single Group Assignment
Intervention Model Description: A phase II, multicenter, open-label study of pembrolizumab and eribulin in patients with HR- positive/HER2-negative metastatic breast cancer previously treated with anthracyclines and taxanes.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Pembrolizumab and Eribulin in Patients With HR-positive/HER2-negative Metastatic Breast Cancer Previously Treated With Anthracyclines and Taxanes
Actual Study Start Date : December 14, 2017
Estimated Primary Completion Date : August 31, 2019
Estimated Study Completion Date : August 31, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab + eribulin
All eligible patients will be treated with MK3475 (pembrolizumab) 200 mg on day 1 of each 21-day cycle and eribulin 1.23 mg/m2 (equivalent to eribulin mesylate at 1.4 mg/m2) on days 1 and 8 of every 21-day cycle. Treatment with MK3475 (pembrolizumab) and eribulin will continue based on physician criteria. No maximum duration of treatment is specified. Study follow-up will be performed 12 months after last study dose.
Drug: Pembrolizumab
MK3475 (pembrolizumab) will be supplied directly as a solution for infusion in a single-use vial. Each vial contains 100 mg of MK3475 (pembrolizumab) in 4 ml of solution.
Other Names:
  • Keytruda
  • MK3475

Drug: Eribulin
Eribulin will be supplied as a clear and colourless aqueous solution for injection provided in glass vials containing 2 ml. Each 2 ml vial contains eribulin mesylate equivalent to 0.88 mg eribulin.
Other Name: Halaven




Primary Outcome Measures :
  1. Efficacy of pembrolizumab in combination with eribulin. [ Time Frame: At least 24 weeks ]
    The efficacy -as determined by the clinical benefit rate (CBR) (total number of objective responses plus stable disease for at least 24 weeks) based on RECIST v.1.1- of MK3475 (pembrolizumab) in combination with eribulin in patients with HR-positive/HER2-negative MBC who have previously received an anthracycline and a taxane (for either early or advanced disease), unless contraindicated, and between one to two lines of chemotherapy in the metastatic setting.


Secondary Outcome Measures :
  1. The CBR in subjects with programmed death ligand-1 (PD-L1) positive tumors. [ Time Frame: 24 months ]
    CBR based on RECIST v.1.1 in subjects with PD-L1 positive tumors.

  2. The progression-free survival (PFS) [ Time Frame: 24 months ]
    PFS based on RECIST v.1.1.

  3. The PFS in subjects with PD-L1 positive tumors. [ Time Frame: 24 months ]
    PFS based on RECIST v.1.1 in subjects with PD-L1 positive tumors.

  4. The overall survival OS [ Time Frame: 24 months ]
    OS (OS will be determined at the end of the study).

  5. The OS in subjects with PD-L1 positive tumors. [ Time Frame: 24 months ]
    OS in subjects with PD-L1 positive tumors.

  6. The overall response rate (ORR) [ Time Frame: 24 months ]
    ORR based on RECIST v.1.1.

  7. The ORR in subjects with PD-L1 positive tumors. [ Time Frame: 24 months ]
    ORR based on RECIST v.1.1 in subjects with PD-L1 positive tumors.

  8. The duration of response (DoR) [ Time Frame: 24 months ]
    DoR based on RECIST v.1.1.

  9. The DoR in subjects with PD-L1 positive tumors. [ Time Frame: 24 months ]
    DoR based on RECIST v.1.1 in subjects with PD-L1 positive tumors.

  10. Safety and tolerability of pembrolizumab in combination with eribulin [ Time Frame: 24 months ]
    The safety and tolerability of MK3475 (pembrolizumab) in combination with eribulin according to the US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3.


Other Outcome Measures:
  1. The PFS based on Immune-Related Response Evaluation Criteria In Solid Tumors (irRECIST). [ Time Frame: 24 months ]
    PFS based on irRECIST.

  2. The ORR based on irRECIST. [ Time Frame: 24 months ]
    Endpoint: ORR based on irRECIST.

  3. Gene signature predictive of MK3475 (pembrolizumab) and eribulin therapy benefit. [ Time Frame: 24 months ]
    New predictive factors of response to MK3475 (pembrolizumab) and eribulin

  4. The link between mutational load and response to MK3475 (pembrolizumab) and eribulin. [ Time Frame: 24 months ]
    New predictive factors of response to MK3475 (pembrolizumab) and eribulin

  5. PD-L1 expression in circulating tumor cells (CTCs) and its correlation with response to MK3475 (pembrolizumab) and eribulin. [ Time Frame: 24 months ]
    New predictive factors of response to MK3475 (pembrolizumab) and eribulin



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Female patients age ≥ 18 years with advanced HR-positive/HER2- negative breast cancer previously treated with anthracyclines and taxanes.
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent prior to beginning specific protocol procedures.
  2. Female patients ≥18 years of age.
  3. Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 which the Investigator believes is stable at the time of screening.
  4. Life expectancy ≥ 12 weeks.
  5. Patients have a histologically and/or cytologically confirmed diagnosis of breast cancer.
  6. Patients have radiologic evidence of inoperable locally recurrent or MBC.
  7. Patients have HER2-negative breast cancer (based on most recently analyzed biopsy) defined as a negative in situ hybridization (ISH) test or an immunohistochemistry (IHC) status of 0, 1+, or 2+ (if IHC 2+, a negative ISH test is required) by local laboratory testing.
  8. Patients have HR-positive breast cancer defined as estrogen receptor (ER) and/or progesterone receptor (PR) with >1% of tumor cells positive for ER and/or PR by IHC irrespective of staining intensity.
  9. Available tumor tissue for PD-L1 biomarker analysis from a newly obtained core or excisional biopsy since last progression of a metastatic tumor lesion not previously irradiated.

    Note: Subjects for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor or subject safety concern) may submit an archived metastatic tumor specimen only upon agreement from the Sponsor.

  10. Patients have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 as assessed by site Investigator and local radiology review.
  11. Patients have received at least one, but not more than two, prior chemotherapeutic regimens for locally recurrent and/or metastatic disease. Prior therapy must have included an anthracycline and a taxane in any combination or order and either in the early or metastatic disease setting unless contraindicated for a given patient. Prior anti-hormonal therapy is mandatory.
  12. Patients have adequate bone marrow and organ function as defined by the following laboratory values:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L.
    • Platelets ≥ 100 x 10^9/L.
    • Hemoglobin ≥ 9 g/dL.
    • Potassium, calcium (corrected for serum albumin), and magnesium within normal limits for the institution.
    • Serum creatinine ≤ 1.5 x upper limit of normal (ULN).
    • Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 2.5 x ULN (or ≤ 5.0 x ULN if liver metastases are present).
    • Total serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present). Patients with known Gilbert disease who have serum bilirubin ≤ 3 x ULN may be enrolled.
  13. Patients must be accessible for treatment and follow-up.

Exclusion Criteria:

  1. Patients have received previous treatment with eribulin and an/or anti-PD1 or anti-PD-L1 agents.
  2. Patients have a known hypersensitivity to any of the excipients of MK3475 (pembrolizumab) or eribulin.
  3. Patients who have received chemotherapy, targeted small molecule therapy, or radiotherapy within two weeks of first dose of study treatment.
  4. Patients who have received monoclonal antibodies for direct antineoplastic treatment or an investigational agent/device within four weeks of first dose of study treatment.
  5. Patients have known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

    Note: Known brain metastases are considered active, if any of the following criteria is applicable:

    1. Brain imaging during screening demonstrates progression of existing metastases and/or appearance of new lesions compared to brain imaging performed at least four weeks earlier.
    2. Neurological symptoms attributed to brain metastases have not returned to baseline.
    3. Steroids were used for brain metastases within 28 days of first dose of study treatment.
  6. Patients have peripheral neuropathy grade 2 or more.
  7. Patients have a concurrent malignancy or malignancy within five years of study enrollment (with the exception of adequately treated, basal or squamous cell skin carcinoma or curatively resected cervical cancer).
  8. Patients have not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy.
  9. Patients have had a major surgical procedure within 28 days prior to starting study drug.
  10. Patients have an active cardiac disease or a history of cardiac dysfunction including any of the following:

    • Unstable angina pectoris or documented myocardial infarction within six months prior to study entry.
    • Symptomatic pericarditis.
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV).
    • Patients have a left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO).
  11. Patients have any of the following cardiac conduction abnormalities:

    • Ventricular arrhythmias except for benign premature ventricular contractions.
    • Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication.
    • Conduction abnormality requiring a pacemaker.
    • Other cardiac arrhythmia not controlled with medication.
  12. Uncontrolled hyper/hypothyroidism or type 1 diabetes mellitus (T1DM). Patients with hypothyroidism stable on hormone replacement will not be excluded from the trial. Patients with controlled T1DM on a stable insulin regimen may be eligible for this study.
  13. Active autoimmune disease or a documented history of autoimmune disease, or a syndrome that has required systemic treatment (steroids or immunosuppressive agents) in the past two years.

    Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic steroid replacement therapy (≤ 10 mg prednisone daily) for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

  14. Prior allogenic stem cell or solid organ transplantation.
  15. Active/history of pneumonitis requiring treatment with steroids or active/history of interstitial lung disease.
  16. Active uncontrolled infection at the time of screening
  17. Active tuberculosis.
  18. Current known infection with HIV.
  19. Active hepatitis B (HBV) [patients with negative hepatitis B surface antigen (HBsAg) test and a positive antibody to HBsAg (anti-HBsAg) test at screening are eligible] or hepatitis C (HCV) [patients with a positive antibody to hepatitis C (anti-HCV) are eligible only if polymerase chain reaction (PCR) is negative for virus hepatitis C RNA].
  20. Patients have any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment contraindicate patient participation in the clinical study.
  21. Treatment with systemic steroids (standard premedication for chemotherapy/contrast reactions, inhaled steroids, and local applications are allowed) or another immunosuppressive agent within seven days prior to study treatment initiation.
  22. Has received live vaccines within 30 days prior to first dose of study treatment.
  23. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study unless they are using highly effective methods of contraception during dosing and up to 120 days after study drugs discontinuation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03222856


Contacts
Contact: Maria Sió, MsC +34 932 214 135 maria.sio@medsir.org
Contact: Anna Gibernau, PhD +34 932 214 135 anna.gibernau@medsir.org

Locations
Spain
Corporació Sanitaria Sanitari Parc Taulí Not yet recruiting
Sabadell, Barcelona, Spain
Contact: Miguel A Seguí, PhD         
Hospital de Navarra Not yet recruiting
Pamplona, Navarra, Spain
Contact: Susana de la Cruz         
Complejo Hospitalario Universitario A Coruña (CHUAC) Not yet recruiting
A Coruña, Spain
Contact: Lourdes Calvo, PhD         
Hospital Clínic de Barcelona Not yet recruiting
Barcelona, Spain
Contact: Aleix Prat, PhD         
Instituto Oncológico Baselga - Hospital Quirónsalud Barcelona Not yet recruiting
Barcelona, Spain
Contact: José Pérez, PhD         
Hospital Universitario Ramón y Cajal Not yet recruiting
Madrid, Spain
Contact: Esther Holgado, PhD         
MD Anderson Not yet recruiting
Madrid, Spain
Contact: Raúl Márquez, PhD         
Hospital Clínico Universitario Virgen de la Arrixaca Not yet recruiting
Murcia, Spain
Contact: José L Alonso, PhD         
Hospital Universitario Virgen del Rocío Not yet recruiting
Sevilla, Spain
Contact: Manuel Ruiz, PhD         
Hospital Arnau de Vilanova de Valencia Recruiting
Valencia, Spain
Contact: Vicente Carañana, PhD         
Hospital Clínico de Valencia Not yet recruiting
Valencia, Spain
Contact: Begoña Bermejo, PhD         
Sponsors and Collaborators
MedSIR
Investigators
Principal Investigator: Javier Cortés, PhD MedSIR

Responsible Party: MedSIR
ClinicalTrials.gov Identifier: NCT03222856     History of Changes
Other Study ID Numbers: MedOPP127
First Posted: July 19, 2017    Key Record Dates
Last Update Posted: January 18, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Pembrolizumab
Taxane
Antineoplastic Agents