Pembrolizumab in Biliary Tract Cancer
Pembrolizumab, Cisplatin, Gemcitabine
Indikation (Clinical Trials):
Biliary Tract Neoplasms, Gallbladder Neoplasms
European Organisation for Research and Treatment of Cancer - EORTC
Johannes Gutenberg Universitaetskliniken - Mainz University Medical Center
Phone: +32 2 774 16 94
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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.
- 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
- 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,
- 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.
- 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.
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.
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)
- Pembrolizumab (Anti-PD-1):
The dose of pembrolizumab in this trial is 200 mg Q3W.
25mg/m2 cisplatin on days 1 and 8 of a 21 day cycle
1000mg/m2 gemcitabine on days 1 and 8 of a 21 day cycle
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