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Trial to Evaluate Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC (PANGEA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03025880
Recruitment Status : Active, not recruiting
First Posted : January 20, 2017
Last Update Posted : August 14, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Spanish Breast Cancer Research Group

Brief Summary:

Study Design and Treatment:

This is a multicenter phase II trial, with an initial exploratory run-in-phase, to evaluate the efficacy and safety of pembrolizumab in combination with gemcitabine in patients with HER2-negative ABC that have previously received anthracyclines and taxanes (unless clinically contraindicated). In hormone receptor positive patients, previous treatment with 2 or more lines of hormone therapy will also be required. Patients must have at least one measurable lesion that can be accurately assessed at baseline and is suitable for repeated assessment by CT, MRI or plan X-ray. Approximately 53 patients (up to a maximum of 65 patients depending on the results of the run-in-phase) will be included in this trial.


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

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter Phase II Trial to Evaluate the Efficacy and Safety of Pembrolizumab and Gemcitabine in Patients With HER2-negative Advanced Breast Cancer (ABC) "PANGEA-Breast"
Actual Study Start Date : June 28, 2017
Actual Primary Completion Date : June 3, 2019
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Single arm

Eligible patients will be enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 or 1,000mg/m2 (this dose will be explored in combination with P in the initial exploratory run-in-phase if necessary) as a IV infusion on day 1 and 8 of each 21-day cycle.

Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.

Drug: Pembrolizumab
Pembrolizumab at a dose of 200mg as an intravenous (IV) 30 minutes infusion on day 1 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. Patients completing 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication will stop pembrolizumab treatment (though may continue with gemcitabine). Subjects who stop pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab treatment if they progress after stopping it.
Other Name: Keytruda

Drug: Gemcitabine
Gemcitabine at a dose of 1,250mg/m2 as an intravenous (IV) 60 minutes infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.
Other Name: Gemzar




Primary Outcome Measures :
  1. Incidence rate of Dose Limiting Toxicity (DLT) within the first cycle [ Time Frame: Up to cycle 1 ]
    DLT is defined as the occurrence of any of the following adverse events (AE) or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for AE (CTCAE) version 4.0), assessed as possibly, probably or definitively related to study drug/medication, occurring within the first cycle of study treatment: any Grade 4 thrombocytopenia or neutropenia lasting > 7 days; episcleritis, uveitis, or iritis of Grade 2 or higher, any Grade 4 toxicity, any Grade 3 toxicity EXCLUDING: nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours, grade 3 rash in the absence of desquamation, no mucosal involvement, does not require steroids, and resolves to Grade 1 by the next scheduled dose of pembrolizumab, transient Grade 3 Aspartate Transaminase (AST) or Alanine Transaminase (ALT) elevation, defined as no more than 3 days with or without steroid use, discontinuation or delay of more than 2 weeks of any study drug/medication due to treatment-related AE.

  2. Recommended Phase II Dose (RP2D) of gemcitabine in combination with pembrolizumab [ Time Frame: Up to cycle 1 ]
    The RP2D will be decided by the internal committee taken into consideration the information obtained in the study and based on the DLT.

  3. Objective Response Rate (ORR) [ Time Frame: Through study treatment ]
    Tumor response will be assessed using RECIST 1.1 criteria. ORR is defined as the percentage of patients with a complete or partial response out of the Efficacy population


Secondary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: Through study treatment ]
    PFS is defined as the time from enrollment to the first documented progressive disease, using RECIST version 1.1, or death from any cause, whichever occurs first.

  2. Clinical Benefit Rate (CBR) [ Time Frame: Through study treatment ]
    CBR is defined as complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks according to the RECIST version 1.1.

  3. Response Duration (RD) [ Time Frame: Through study treatment ]
    RD is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documented progressive disease using RECIST version 1.1, or to death due to any cause, whichever occurs first.

  4. Overall Survival (OS). [ Time Frame: Through study treatment ]
    OS is defined as the time from the date of enrollment to the date of death from any cause.

  5. The Number of Participants Who Experienced Adverse Events (AE) [ Time Frame: Through study treatment up to 1 month after discontinuation ]
    Safety assessments to be performed at baseline and during the study: Vital signs assessments will include blood pressure, pulse and body temperature. A baseline standard 12-lead electrocardiogram (ECG) is mandatory. Safety laboratory assessments will be performed: hemoglobin, platelet count, White Blood Cell (WBC), Absolute Neutrophil Count (ANC) and Absolute Lymphocyte Count (ALC), albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, serum creatinine, creatinine clearance (for patients with creatinine levels > 1.5 x ULN), glucose and urea, International Normalized Ratio (INR)/ Prothrombin time (PT) and activated partial thromboplastin time (aPTT), total or free triiodothyronine (T3 or FT3), free thyroxine (FT4) and Thyroid-stimulating hormone (TSH), Urinalysis. AEs will be graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.0.



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
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. The patient has signed and dated the informed consent document and it has been obtained before conducting any procedure specifically for the study.
  2. Female ≥ 18 years of age on day of signing informed consent.
  3. Histological/cytological confirmation of breast cancer with evidence of advanced disease, not amenable to resection or radiation therapy with curative intent.
  4. Documented luminal A, luminal B (HER2-negative) or triple negative disease by immunohistochemistry (IHQ) and/or in situ hybridization (FISH/CISH/SISH) based on local testing on the most recent tumour biopsy defined as follows:

    Luminal A: tumour with positive oestrogen receptor (ER) status (≥1% of tumour cells with ER expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ hybridization defined as a HER2/chromosome enumeration probe 17 (CEP17) ratio < 2 or for single probe assessment a HER2 copy number < 4) and high progesterone receptor (PgR) (≥ 20% of tumour cells with PgR expression) and low Ki67 (< 14%).

    Luminal B (HER2-negative): tumour with positive ER status (≥1% of tumour cells with ER expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ hybridization defined as a HER2/CEP17 ratio < 2 or for single probe assessment a HER2 copy number < 4) and either low or negative PgR (< 20% of tumour cells with PgR expression) and/or high Ki67 (≥ 14%).

    Triple negative: tumour with negative hormone receptor status (<1% of tumour cells with ER and PgR expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ hybridization defined as a HER2/CEP17 ratio < 2 or for single probe assessment a HER2 copy number < 4).

  5. Have at least one unidimensionally measurable lesion by RECIST 1.1.
  6. Patient agrees to the collection of a metastatic tumor sample (biopsy) at the time of inclusion and at progression (whenever possible).
  7. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
  8. Demonstrate adequate organ function as follows (all screening labs should be performed within 7 days of study treatment initiation):

    Bone marrow:

    Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/l) Platelets ≥ 100,000/mm3 (100x109/l) Hemoglobin ≥ 9g/dl or ≥ 5.6 mmol/l without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)

    Hepatic:

    Serum total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) Alkaline Phosphatase ≤ 2.5 x ULN Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN for patients with liver metastases Albumin ≥ 2.5 g/dl

    Renal:

    Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 ml/min for patients with creatinine levels > 1.5 x ULN

    Coagulation:

    International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 xULN unless patient 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 patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.

  9. Prior treatment with anthracyclines and taxanes (unless clinically contraindicated) and two or more prior lines of hormone therapy in hormone receptor positive disease.
  10. At least 3 months life expectancy.
  11. Patient of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study drug/medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  12. Patients of childbearing potential (see section 4.4. for definition) must be willing to use an adequate method of contraception as outlined in Section 4.4. - Contraception, for the course of the study through 120 days after the last dose of study medication.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

  13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

  1. HER2-positive disease by immunohistochemistry or in situ hybridation (FISH-SISH-CISH).
  2. Patient is currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug/medication.
  3. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 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.

    • Note: Patients with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    • Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  5. Has received prior therapy with an anti-Programmed death-1 (PD), anti-PD-L1, or anti-PD-L2 agent.
  6. Has received a live vaccine within 30 days of planned start of study therapy.

    o 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.

  7. Has hypersensitivity to pembrolizumab, gemcitabine or any of theirs excipients.
  8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and all neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  9. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug/medication.
  10. Has an 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.
  11. Has a current or prior malignancy within the previous 5 years (other than breast cancer or adequately treated basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix).
  12. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  13. Has an active infection requiring systemic therapy.
  14. Has a known history of active Tuberculosis Bacillus (TB) or Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or a known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected).
  15. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
  16. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  17. Patient is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the baseline visit through 120 days after the last dose of trial treatment.

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): NCT03025880


Locations
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Spain
Institut Català d'Oncologia. Hospital Universitario Germans Trias i Pujol
Badalona, Barcelona, Spain, 08916
Hospital Universitario de Canarias
La Laguna, Canarias, Spain, 38320
Hospital Universitario Virgen de la Arrixaca
El Palmar, Murcia, Spain, 30120
Clínica Universitaria de Navarra
Pamplona, Navarra, Spain, 31008
Centro Oncológico de Galicia
A Coruña, Spain, 15009
Hospital Universitario Ramón y Cajal
Madrid, Spain, 28034
Hospital Clínico Universitario San Carlos
Madrid, Spain, 28040
Hospital Universitario Virgen de la Macarena
Sevilla, Spain, 41009
Hospital Clínico Universitario de Zaragoza "Lozano Blesa"
Zaragoza, Spain, 50009
Sponsors and Collaborators
Spanish Breast Cancer Research Group
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Study Director Hospital Universitario Virgen Macarena

Additional Information:
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Responsible Party: Spanish Breast Cancer Research Group
ClinicalTrials.gov Identifier: NCT03025880     History of Changes
Other Study ID Numbers: GEICAM/2015-04
2016-001779-54 ( EudraCT Number )
First Posted: January 20, 2017    Key Record Dates
Last Update Posted: August 14, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Spanish Breast Cancer Research Group:
Advanced Breast Cancer
Pembrolizumab
HER2-negative
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Gemcitabine
Pembrolizumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological