Clinical trial to investigate the efficacy of treatment combination with gemcitabine and pazopanib in patients with inoperable locally advanced or metastatic gallbladder and bile duct cancer

Phase 1

• Conditions: Inoperable locally advanced or metastatic cancer of the biliary tree (cholangiocarcinoma and gallbladder carcinoma); MedDRA version: 14.1Level: LLTClassification code 10017620Term: Gallbladder carcinomaSystem Organ Class: 100000004864; MedDRA version: 14.1Level: LLTClassification code 10008593Term: CholangiocarcinomaSystem Organ Class: 100000004864; MedDRA version: 14.1Level: LLTClassification code 10004655Term: Biliary carcinomaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2012-001705-24-GR
• Lead Sponsor: Hellenic Cooperative Oncology Group

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2013-02-26
• Last Update Posted: 22 October 2018

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

1. Subjects must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to comply with treatment and follow up. Procedures conducted as part of the subject’s routine clinical management (e.g., blood count, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol.
2. Age = 18 years
3. Histologically confirmed diagnosis of inoperable, locally advanced or metastatic cholangiocarcinoma (adenocarcinoma of intrahepatic, proximal extrahepatic, distal extrahepatic, gallbladder adenocarcinoma and periampullary bile duct adenocarcinoma). During the recruitment phase of the study, it will be ensured that gallbladder Ca patients will consist no more than 25% of the total study population.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Measurable disease criteria per RECIST v1.1.
6. No prior chemotherapy or treatment with targeted therapy
7. Formalin-fixed paraffin-embedded tumour and whole blood/plasma samples at diagnosis/study enrollment for biomarker studies.
8. Adequate organ system function:
Absolute neutrophil count >=1.5 x 109/L, Hemoglobin >=9 g/dL, platelets >=100 x 109/L, INR <=1.2 x ULN, aPTT <=1.2 x ULN, Total bilirubin (stenting allowed) <=1.5 x ULN, ALT and AST <=2.5 X ULN, Serum creatinine <=1.5 mg/dL (133 µmol/L) Or, if >1.5 mg/dL: Calculated creatinine clearance (ClCR) >=50 mL/min, Urine Protein to Creatinine Ratio <1 Or 24-hr urine protein <1g

9. Female patients are allowed to participate provided they consent to avoid pregnancy throughout the course of the trial and 1 month after the last administration of the drug, if they are surgically sterilized or menopausal. All female patients of child-bearing potential must undergo a pregnancy test (serum or urine) < 2weeks prior to first administration of the drug and consent to use effective contraception throughout the course of the trial.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 30
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 16

Exclusion Criteria

1. Prior malignancy. Subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma or indolent prostate cancer are eligible (even if they are receiving anti-hormonal therapy).
2. Central nervous system (CNS) metastases at baseline, with the exception of those subjects who have previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) are asymptomatic and have no requirement for steroids or enzyme-inducing anticonvulsants (phenyntoin, carbamazepine, phenobarbital, oxcarbazepine) in the past 6 months.
3. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, such as active peptic ulcer disease, known intraluminal metastatic lesion/s with risk of bleeding, inflammatory bowel disease with increased risk of perforation, or history of abdominal fistula or intra-abdominal abcess 28 days prior to study treatment initiation.
4. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including malabsorption syndrome, major resection of the stomach
5. Corrected QT interval (QTc) > 480 msecs using Bazett’s formula
6. History of myocardial infarction, unstable angina, symptomatic peripheral vascular disease or Class II, III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) or cardiac angioplasty or stenting within the past 6 months
7. Newly-diagnosed hypertension or history of poorly controlled hypertension [defined as systolic blood pressure (SBP) of =140 mmHg or diastolic blood pressure (DBP) of = 90mmHg].
8. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible
9. Major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
10. Evidence of active bleeding or bleeding diathesis.
11. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage
12. Recent hemoptysis (= ½ teaspoon of red blood within 8 weeks of first dose of study drug).
13. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures.
14. Unable or unwilling to discontinue use of prohibited medications listed in Appendix C Section of the protocol for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study
15. Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazopanib
16. Administration of any non-oncologic investigational study drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment.
17. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia.
18. Pregnancy or lactation. Female patients must be surgically sterilised, menopausal, or must consent to use effective contraception throughout the course of the trial. All

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess the efficacy of pazopanib combination with gemcitabine (measured as Objective Response Rate) in patients with inoperable locally advanced or metastatic biliary tree carcinoma. ;Secondary Objective: • To estimate progression-free survival (PFS) <br>• To estimate 6-month progression-free survival rate (6-month PFS rate)<br>• To assess overall survival (OS)<br>• To assess safety and tolerability of the combination<br>• To measure treatment effect on patients’ Quality of Life<br>• To evaluate potential prognostic and/or predictive biomarkers in tumor/blood samples<br>;Primary end point(s): Objective Response rate (ORR) defined as the percentage of subjects who achieved either a confirmed complete response (CR) or partial response (PR) using radiological assessment using standard Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ;Timepoint(s) of evaluation of this end point: Imaging evaluation for the determination of response to treatment will be performed every 8 weeks

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Progression Free Survival (PFS)<br>2. 6-month Progression Free Survival rate (6-month PFS rate) <br>3. Overall survival (OS)<br>4. Safety <br>5. Quality of Life (QoL) evaluation <br>6. To evaluate potential prognostic and/or predictive biomarkers in tumor/blood samples<br>;Timepoint(s) of evaluation of this end point: 1. Defined as the time from treatment initiation to the first date of disease progression, or death from any cause without prior confirmed disease progression. <br>2. 6 months<br>3. Defined as the time from treatment initiation to the date of death from any cause. <br>4. Evaluation of Adverse Events (??s) will be performed every 21 days (per treatment cycle) throughout the course of treatment<br>5. Quality of Life Questionnaire will be filled out before treatment initiation, every 8 weeks and at the end of treatment. <br>6. At study initiation