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Biliary Tract CancerPhase 2NCT03260712

Pembrolizumab in Biliary Tract Cancer

A Phase 2 study testing Pembrolizumab, Cisplatin and Gemcitabine in people with Biliary Tract Cancer and Metastatic Cancer, run by European Organisation for Research and Treatment of Cancer - EORTC at 7 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Pembrolizumab, Cisplatin and Gemcitabine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
50 participants
Where
7 sitesin 3 countries
Study dates
7 Jan 2020to 31 Aug 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
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  • 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.

Who cannot join

  • 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
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  • 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.

Trial locations and contacts

7 sites in 3 countries.

7 sites in 3 countries

United Kingdom3 sites

  • University College London Hospitals NHS Foundation Trust - University College Hospital

    London, NW1 2PG

  • The Christie NHS Foundation Trust

    Manchester, M20 4BX

  • Nottingham University Hospitals NHS Trust - City Hospital

    Nottingham, NG5 1PB

Other trials in United Kingdom

Germany2 sites

  • Universitaetsklinikum Leipzig UCCL-Krebszentrum

    Leipzig, 04103

  • Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz-University Medical Center

    Mainz, 55131

Other trials in Germany

Spain2 sites

  • Vall d'Hebron Institut Oncologia

    Barcelona

  • Hospital Universitario 12 De Octubre

    Madrid

Other trials in Spain

About this study

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

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.

Read the detailed description

Primary endpoint: PFS rate at 6 months according to RECIST 1.1.

Secondary endpoints:

  • Best overall response rate (according to RECIST 1.1 and iRECIST)
  • Response duration and stable disease duration (according to RECIST 1.1 and iRECIST)
  • PFS rate at 6 months according to iRECIST
  • PFS according to RECIST 1.1 and iRECIST
  • Overall survival (OS)
  • Toxicity of treatment (Common Toxicity Criteria CTCAE 5.0)
  • Safety analysis: A safety analysis will be done when at least 10 patients have completed at least one cycle of the three- drug combination.

Events of clinical interest for this safety analysis are the following:

  • At least Grade 2 or higher CTCAE 5.0 signs of acute renal failure
  • Grade 3 or 4 liver dysfunction defined as elevation of liver transaminases (AST and ALT) and alkaline phosphatase, increased bilirubin
  • Grade 3 or 4 gastrointestinal disorders specifically colitis, diarrhea and stomatitis
  • Grade 3 or 4 dyspnea, dry cough and pneumonia
  • Grade 3 or 4 sepsis
  • Grade 3 or 4 skin toxicity If 4 out of these 10 patients experience any of the above, this will trigger an IDMC review. This cut-off is based on: 1) previous ABC-02 study where 57% of patients experienced a grade 3 or 4 toxicity at 12 weeks of treatment; and 2) KEYNOTE 028 where 17% of patients experienced grade 3 or 4 toxicity The primary analysis of efficacy endpoints will be performed in the protocol population.
  • PFS rate at 6 months will be estimated using Kaplan Meier estimate at the time point of interest. The lower bound of the one-sided 90% confidence interval (CI) will be calculated by Greenwood's estimation of the standard deviation. If the lower bound of the one-sided 90% CI is above 60%, it will be concluded that the new treatment is effective enough to warrant further evaluation in a phase III trial. Assuming exponential distributions for both PFS and for the risk of drop-out, power with a total sample size of 50 patients when the primary test is performed using Kaplan Meier analyses will be around 82% for a drop-out rate of 5% at 6 months and still above 80% for a drop-out rate of 10% at 6 months. The one-sided type I error will be respectively 9.33% and 9.02%.
  • PFS rate at 6 months according to iRECIST will be estimated using Kaplan Meier estimate and the one-sided 90% confidence interval (CI) will be calculated by Greenwood's estimation of the standard deviation.
  • BOR rate according to RECIST 1.1 and iBOR rate according to iRECIST will be displayed (point estimate) with their exact two-sided 95% confidence intervals. Response duration and stable disease duration according to RECIST 1.1 and iRECIST will be graphically displayed using swimmer plots and bar charts.
  • Progression free survival according to RECIST 1.1 and iRECIST and overall survival curves will be estimated using the Kaplan-Meier technique. The safety analyses will be performed in the Safety population. The worst toxicity grade per patient over the treatment period according to the CTCAE criteria version 5.0 will be displayed.
Keywords
biliary tract cancer, metastitic cancer, advanced cancer, pembrolizumab, cisplatin, gemcitabine, gallbladder cancer
Medical subject headings
Biliary Tract Neoplasms, Neoplasm Metastasis, Gallbladder Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PembrolizumabDrug

    Also called Anti-PD-1

    The dose of pembrolizumab in this trial is 200 mg Q3W.

  • CisplatinDrug

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

  • GemcitabineDrug

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

Study groups in NCT03260712
Study groupRoleWhat they receive
CisGem + pembrolizumabExperimentalPatients 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.
Receives: Drug: Pembrolizumab; Drug: Cisplatin; Drug: Gemcitabine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Detection of progression-free survival (PFS) rate at 6 months defined according to RECIST 1.1.

    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.

    Measured: At 6 months

Secondary outcomes (3)

  1. Best overall response rate (according to RECIST 1.1) and overall response

    Assessing both short term and long term outcome of patients receiving this combined treatment

    Measured: Up to 120 days after last administration of Pembrolizumab

  2. Toxicity (according to CTCAE 4.03)

    Establishing the safety of standard chemotherapy combined with pembrolizumab in these patients

    Measured: Up to 120 days after last administration of Pembrolizumab

  3. Progression free survival rate at 6 months according to iRECIST

    Measured: At 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Aug 2017
  2. Study start7 Jan 2020
  3. Primary completion27 Apr 2023
  4. Study completion31 Aug 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
50 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03260712
Sponsor's protocol ID
EORTC-1607-GITCG / ABC-09
Status last verified
Nov 2023
First submitted
8 Aug 2017
Last updated
3 Nov 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pembrolizumab, Cisplatin and Gemcitabine in people with Biliary Tract Cancer and Metastatic Cancer, run by European Organisation for Research and Treatment of Cancer - EORTC at 7 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 31 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United Kingdom, Germany, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Detection of progression-free survival (PFS) rate at 6 months defined according to RECIST 1.1. (time frame: At 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03260712.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Nov 2023.

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