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Pembrolizumab in Biliary Tract Cancer

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03260712
Recruitment Status : Recruiting
First Posted : August 24, 2017
Last Update Posted : January 31, 2020
Sponsor:
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Brief Summary:

This is a single-arm, multi-centre, phase II study in biliary tract cancer (BTC) patients. The main objective is to detect an increase in progression-free survival rate at 6 months (according to RECIST version 1.1) from 60% in patients with BTC treated with standard chemotherapy (CT) approach to 75% when treated with CT combined with pembrolizumab.

Secondary objectives are:

  • Assess the treatment efficacy in terms of overall survival, immune related progression-free survival, response rate (according to RECIST version 1.1), safety, symptom control and quality of life (QoL) (according to EORTC QoL C30 and BIL 21)
  • Exploratory objectives include assessment of immunological response (cytokines, lymphocyte phenotype, immunoglobulins), and evaluation of pathological and clinical predictive factors for response/toxicity
  • Translational research will focus on biomarkers for prediction of response and toxicity.

Condition or disease Intervention/treatment Phase
Biliary Tract Cancer Metastatic Cancer Advanced Cancer Gallbladder Cancer Drug: Pembrolizumab Drug: Cisplatin Drug: Gemcitabine Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-label First Line, Single-arm Phase II Study of CisGem Combined With Pembrolizumab in Patients With Advanced or Metastatic Biliary Tract Cancer
Actual Study Start Date : January 7, 2020
Estimated Primary Completion Date : November 1, 2022
Estimated Study Completion Date : June 1, 2023


Arm Intervention/treatment
Experimental: CisGem + pembrolizumab
Patients will be enrolled in the experimental arm and will receive CisGem [25mg/m2 cisplatin + 1000mg/m2 gemcitabine, on days 1 and 8 of a 21 day cycle] plus 200 mg pembrolizumab (fixed dose) on day 1 of a 21 day cycle.
Drug: Pembrolizumab
The dose of pembrolizumab in this trial is 200 mg Q3W.
Other Name: Anti-PD-1

Drug: Cisplatin
25mg/m2 cisplatin on days 1 and 8 of a 21 day cycle

Drug: Gemcitabine
1000mg/m2 gemcitabine on days 1 and 8 of a 21 day cycle




Primary Outcome Measures :
  1. Detection of progression-free survival (PFS) rate at 6 months defined according to RECIST 1.1. [ Time Frame: At 6 months ]
    The main objective is to detect an increase in progression-free survival (PFS) rate at 6 months (according to RECIST version 1.1) from 60% in patients with BTC treated with standard chemotherapy approach to 75% when treated with CT combined with pembrolizumab.


Secondary Outcome Measures :
  1. Best overall response rate (according to RECIST 1.1) and overall response [ Time Frame: Up to 120 days after last administration of Pembrolizumab ]
    Assessing both short term and long term outcome of patients receiving this combined treatment

  2. Toxicity (according to CTCAE 4.03) [ Time Frame: Up to 120 days after last administration of Pembrolizumab ]
    Establishing the safety of standard chemotherapy combined with pembrolizumab in these patients

  3. Progression free survival rate at 6 months according to iRECIST [ Time Frame: At 6 months ]

Other Outcome Measures:
  1. Immunological response (cytokines, lymphocyte phenotype, immunoglobulins) [ Time Frame: Up to 2 years after start of study treatment ]
    Assessment of immunological responses (cytokines, lymphocyte phenotype, immunoglobulins)

  2. Pathological predictive factors for response and toxicity (TCR Sequencing, FACs, RNASeq, nanostring) [ Time Frame: Up to 2 years after start of study treatment ]
    Evaluation of pathological predictive factors for response and toxicity

  3. Clinical predictive factors for response and toxicity (TCR Sequencing, FACs, RNASeq, nanostring) [ Time Frame: Up to 2 years after start of study treatment ]
    Evaluation of clinical predictive factors for response and toxicity

  4. Biomarkers predictive of response and toxicity (protein profiling, HLA typing) [ Time Frame: Up to 2 years after start of study treatment ]
    Evaluation of biomarkers for prediction of response and toxicity



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A histopathological / cytological diagnosis of non-resectable or recurrent / metastatic biliary tract carcinoma (intra- or extra-hepatic) or gallbladder
  • Availability of archival FFPE tumor tissue for biobanking
  • Measurable disease by CT/MRI (RECIST 1.1) within 28 days of enrollment
  • ECOG performance status 0, 1
  • Age ≥ 18 with estimated life expectancy >3 months
  • Adequate hematological function: screening labs should be performed within 14 days (± 3 days) prior to enrollment:
  • Hemoglobin ≥ 10 g/dl* (prior transfusions for patients with low hemoglobin are allowed)
  • White blood cell (WBC) ≥ 3.0 x 109/L
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Platelet count ≥ 100 x 109/L
  • Adequate liver function: screening labs should be performed within 14 days (± 3 days) prior to enrollment:
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
  • ALT and/or AST & alkaline phosphatase ≤ 5 x ULN
  • Adequate renal function: screening labs should be performed within 14 days (± 3 days) prior to enrollment:
  • Serum creatinine < 1.5 x ULN
  • and a calculated GFR ≥ 45 mL/min (using Cockcroft-Gault formula). If the calculated GFR is below 45 mL/min, isotope EDTA confirmation of adequate renal function is required (see Appendix F). If isotope EDTA methods are not available, then a 24-hour urine creatinine clearance can be used.
  • Adequate coagulation: screening labs should be performed within 14 days (± 3 days) prior to enrollment:
  • International Normalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5xULN unless patient is receiving anticoagulant therapy as long as PT or Partial Thromboplastin Time (PTT) is within therapeutic range of intended use of anticoagulants
  • Adequate biliary drainage with C-reactive protein (CRP) levels in normal ranges (based on institution's standard): screening labs should be performed within 14 days (± 3 days) prior to enrollment
  • Patient is not currently participating and receiving study therapy or has not participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks prior to enrollment
  • Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 72 hours prior to the first dose of study treatment.
  • Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:
  • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
  • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
  • Intrauterine device (IUD)
  • Intrauterine hormone-releasing system (IUS)
  • Bilateral tubal occlusion
  • Vasectomised partner
  • Sexual abstinence. Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard.
  • Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 120 days after the last study treatment.
  • Before patient enrollment, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

  • Patients with ascites grade 2 or higher
  • Child Pugh B or C hepatic impairment
  • Incomplete recovery from previous surgery or unresolved biliary tract obstruction
  • Active infection requiring therapy. Antibiotic treatment should have been completed 5 days before enrollment
  • Patients who are candidates for curative surgery
  • History of (non-infectious) pneumonitis that required steroids or current pneumonitis. No history of or current interstitial lung disease
  • Active autoimmune disease that has required systemic treatment in 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
  • Diagnosis of immunodeficiency, systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
  • Known history of human immunodeficiency virus (HIV), active Hepatitis B or Hepatitis C
  • Patients with hyperthyroidism or hypothyroidism unless stable on hormone replacement
  • History of another malignancy or a concurrent malignancy. Exceptions include patients who have been disease-free for 5 years, or patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ.
  • Patients who received treatment with live vaccines within 30 days prior to the first dose of study medication. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, seasonal flu, H1N1 flu, rabies, BCG and typhoid vaccine.
  • Prior treatment with any anti-CTLA4 monoclonal antibody or anti-PD-1, or PD-L1 or PD-L2 agent. Examples of PD-1 inhibitors (include, but are not limited to): pembrolizumab (Merck); Nivolumab (also known as BMS-936558, MDX-1106, ONO-4538) (Bristol-Myers Squibb); Pidilizumab (CT-11) (Cure-Tech/Teva); and AMP-224 (Amplimmune). Examples of PD-L1 inhibitors (include, but are not limited to): BMS-936559 (also known as MDX-1105) (Bristol-Myers Squibb); MPDL3280A (also known as RG7446) (Roche Genentech); and MEDI4736 (MedImmune).
  • Prior systemic chemotherapy for locally advanced or metastatic disease.
  • Prior adjuvant chemotherapy is allowed if the last treatment was completed at least 6 months before trial entry and neither gemcitabine nor cisplatin were given. Also the following treatment modalities are allowed within the rules described (provided there has been a full recovery):
  • Surgery - patients may have undergone a non-curative operation (i.e. R2 resection [with macroscopic residual disease] or palliative bypass surgery only). Patients who have previously undergone curative surgery, must have evidence of non-resectable disease relapse requiring systemic chemotherapy prior to study entry.
  • Radiotherapy - patients may have received prior radiotherapy (with or without radiosensitising low-dose chemotherapy) for localised disease. However, there must be clear evidence of disease progression prior to inclusion in this study.
  • Photodynamic therapy (PDT) for localized disease only with no evidence of metastatic disease - patients may have received prior PDT, provided the patient has fully recovered and at least 28 days have elapsed since the PDT and there is clear evidence of disease progression at the local site or disease or at a new metastatic site.
  • PDT for localised disease to relieve biliary obstruction in the presence of metastatic disease - patients may have received prior PDT provided the patient has fully recovered and at least 28 days have elapsed since the PDT. Patients may enter trial provided the non-PDT treated lesion(s) only are followed for response assessment.
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before enrollment in the trial.

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): NCT03260712


Contacts
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Contact: Christophe Verstegen +32 2 774 16 94 christophe.verstegen@eortc.org
Contact: Ionela Stanciu ionela.stanciu@eortc.org

Locations
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Spain
Vall d'Hebron Institut Oncologia Recruiting
Barcelona, Spain
Contact: Teresa Macarulla         
Hospital Universitario 12 De Octubre Recruiting
Madrid, Spain
Contact: Jorge Adeva Alonso         
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Investigators
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Study Chair: Markus Moehler, Prof. Dr. Johannes Gutenberg Universitaetskliniken - Mainz University Medical Center
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Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT03260712    
Other Study ID Numbers: EORTC-1607-GITCG / ABC-09
First Posted: August 24, 2017    Key Record Dates
Last Update Posted: January 31, 2020
Last Verified: November 2019

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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.: Yes
Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
biliary tract cancer
metastitic cancer
advanced cancer
pembrolizumab
cisplatin
gemcitabine
gallbladder cancer
Additional relevant MeSH terms:
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Biliary Tract Neoplasms
Gallbladder Neoplasms
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Biliary Tract Diseases
Digestive System Diseases
Gallbladder Diseases
Gemcitabine
Pembrolizumab
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological