| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastatic cholangiocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cholangiocarcinoma is cancer of the biliary tract system, involving the bile ducts which connect the liver and gall bladder to the small bowel. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the efficacy of gemcitabine and nab-paclitaxel in patients with advanced CCA as measured by improvement in 6-month Progression Free Survival . |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
1. Evaluate clinical efficacy by assessment of median OS, PFS, TTP as well as best ORR and disease control rate (DCR).
2. Describe the safety and toxicity profile of nab-paclitaxel and gemcitabine.
3. Correlate change in CA 19-9 with ORR, DCR, median PFS, TTP and OS.
Exploratory Objectives:
1. Correlate change in Circulating Tumor Cells (CTCs) to ORR, DCR and median PFS, TTP and OS. Perform targeted gene expression analysis on CTCs and correlate with CCA pathology, PFS, TTP, ORR and OS.
2. Correlate stromal SPARC (high versus low) expression and fibrosis (low, intermediate and high) by trichrome staining with ORR, DCR and median PFS, TTP and OS.
3. Correlate CDA (high versus low) and hENT1 (high versus low) expression with ORR, DCR and median PFS, TTP and OS.
4. Optional specimen banking of patient blood specimens and fixed left-over tissue specimens when available for possible future molecular, pharmacogenomic, and/or proteomic testing. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must have a histologically-confirmed diagnosis of cholangiocarcinoma American Joint Committee on Cancer (AJCC) Stage II, III, or IV CCA (intra-hepatic, extra-hepatic and perihilar) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed histology are not allowed.
2. Must have radiographically measurable disease (RECIST Version 1.1) in at least one site not previously treated with radiation, chemoembolization, radioembolization, or other local ablative procedures (i.e. must have at least one measurable target lesion, either within the liver or in a measurable metastatic site); a new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is acceptable. Appropriate imaging should have been completed ≤ 4 weeks prior to registration.
3. May have received prior radiation, chemoembolization, radioembolization, or other local ablative therapies, or hepatic resection if completed ≥ 4 weeks prior to registration AND if patient has recovered to ≤ grade 1 toxicity.
NOTE: Measurable disease (as required above) must still be present.
4. May have received prior radiation for bone or brain metastases if patient is now asymptomatic and has completed all radiation and steroid therapy (if applicable) ≥ 2 weeks prior to registration.
5. Age ≥ 18 years.
6. Child-Pugh score of A or B with ≤ 7 points (Appendix I of protocol).
7. ECOG performance status of 0-1 (Appendix II) of protocol).
8. Ability to understand and willingness to sign IRB-approved informed consent.
9. Willing to provide archived tissue, if available, from a previous diagnostic biopsy.
10. Must be able to tolerate CT and/or MRI with contrast.
11. Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to registration:
• Absolute Neutrophil Count (ANC) ≥ 1500/mm3
• Hemoglobin ˃9.0 g/dL
• Platelets ˃100,000/mm3
• Serum Creatinine ≤ 1.5x Upper Limit Normal (ULN)
• Creatinine Clearance ≥ 50 mL/min
• Albumin ≥ 2.8 g/dL
• Total Bilirubin ≤ 1.5 mg/dL or ≤ 1.5x ULN
• AST/ALT ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)
• INR <1.5x the ULN [INR ≥ 1.5 is allowed if anticoagulation is used. Patient must be on a stable dose of anticoagulant (i.e. Coumadin) for ≥ 2 weeks at time of randomization.]
|
|
| E.4 | Principal exclusion criteria |
1. Women must not be pregnant or breastfeeding since nab-paclitaxel and/or gemcitabine may harm the fetus or child. All females of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a blood test to rule out pregnancy within 2 weeks prior to registration.
2. Women of child-bearing potential and men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 3 months following completion of study therapy. Method of contraception must be documented.
NOTE: Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
3. Must not have received prior systemic cytotoxic chemotherapy or targeted therapy for this cancer.
NOTE: Prior systemic cytotoxic therapy for other diagnoses is permitted if the last dose was >6 months prior, any prior toxicity has recovered to ≤ grade 1, and treatment was not discontinued for toxicity.
4. Must not be receiving treatment with other investigational agents and must not have received any other investigational agent’s ≤ 4 weeks prior to registration.
5. Must not have a pre-existing >grade 2 peripheral neuropathy.
6. Must not be receiving immunosuppressive medications, including systemic corticosteroids, aside from the following exceptions: used for adrenal replacement, appetite stimulation, acute therapy for asthma or bronchitis exacerbation (≤ 2 weeks), or anti-emesis.
7. No known Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) seropositivity. The risk for potential toxicities secondary to Hepatitis B, Hepatitis C or HIV (e.g., increased risk for fatal opportunistic infection) may confound the toxicity profile of the chemotherapy regimen. Testing is not required in absence of clinical suspicion.
8. Must not have undergone liver transplantation.
9. Must not have symptomatic brain or bone metastases (Section 3.4 for additional requirements).
10. Must not have serious non-healing wound, ulcer, bone fracture, or abscess.
11. Must not have undergone a major surgical procedure <4 weeks prior to registration.
12. Must not have possible histories of pneumonitis or pneumonitis risk factors (Section 5.3.5).
13. Must not have an active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ.
NOTE: Patients with history of malignancy are not considered to have a “currently active” malignancy if they have completed therapy and are now considered by their physician to be at less than 30% risk for relapse.
14. Must have no ongoing or active, uncontrolled infections (afebrile for ≥ 48 hours off antibiotics).
15. Must have no evidence of significant, uncontrolled concomitant diseases including, but not limited to: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, myocardial infarction within preceding 12 months, uncontrolled peripheral vascular disease, cerebrovascular accident within preceding 12 months, pulmonary disease impairing functional status or requiring oxygen, connective tissue disease including lupus.
16. Must not have any history of allergic reaction(s) attributed to compounds of similar composition to nab-paclitaxel or gemcitabine.
17. Must not require prohibited medications with the potential for serious interactions with protocol therapy, and who cannot have therapeutic substitution (Section 5.4).
18. Must not have a psychiatric illness, other significant medical illness, or social situation which, in the investigator’s opinion, would limit compliance or ability to comply with study requirements.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS at 6 months will be calculated in months from date of first dose of protocol therapy to date of documented disease progression or death from any cause, whichever comes first. PFS will be censored at the date of study discontinuation for evaluable patients other than progression or death. Eligible patients who receive at least one dose of nab-paclitaxel and gemcitabine will be included in the analysis of PFS. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 6 months and censored at the date of study discontinuation for evaluable patients other than progression or death. |
|
| E.5.2 | Secondary end point(s) |
Overall Survival (OS) is defined as the time from enrollment until death or last patient contact, whichever comes first.
Clinical Efficacy Endpoints:
Stable disease (SD), complete response (CR), partial response (PR) and progressive disease (PD) will be defined as per the response evaluation criteria in solid tumors (RECIST) Version 1.1 guidelines to calculate ORR (PR + CR) and DCR (SD + PR + CR).
Safety Endpoints:
A patient will be considered for safety endpoints if the patient is eligible and one of the following occurs: (1) receives one dose of protocol therapy; (2) death on protocol therapy for a reason considered possibly, probably or likely related to protocol therapy; or (3) are removed from protocol therapy because of an adverse experience possibly, probably or likely related to one of the agents. Review will be performed by Data Safety and Monitoring Board (DSMB) approximately every 6 months.
Exploratory Endpoints:
-Immunohistochemical staining of CCA tumors will be performed for SPARC, CDA and hENT1.
-Tumor Fibrosis Evaluation: Available tissue will be stained with trichrome to evaluate for fibrosis.
-Optional Specimens for Testing and Banking: Blood specimens (whole blood) will be requested from the patient to test for Circulating Tumor Cells [CTCs]. Correlation of change in CTCs to ORR, DCR and median PFS, TTP and OS will be completed. Targeted gene expression analysis will be performed on CTCs for correlation with CCA pathology, PFS, TTP, ORR and OS.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall Survival: at death or last patient contact, whichever comes first.
Clinical efficacy: Radiographic assessments will be performed every 8 weeks to evaluate response to treatment.
Safety: Will be assessed every study visit until 30 days after last dose of study medication.
Exploratory:
-Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or surgery. Formalin-Fixed Paraffin-Embedded (FFPE) blocks or up to 15 FFPE slides plus H&E slide will be required. Procurement of tissue will be mandatory for enrollment, but if additional tissue from initial biopsy is not available, repeat biopsy will not be required.
-Optional blood specimens will be collected at Cycle 1, Day 1, Cycle 1 Day 8, Cycle 3, Day 1 (only) and at Off Treatment. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
Print
