E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Inoperable advanced cholangiocarcinomas |
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E.1.1.1 | Medical condition in easily understood language |
Inoperable advanced cholangiocarcinomas |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008594 |
E.1.2 | Term | Cholangiocarcinoma non-resectable |
E.1.2 | System Organ Class | 100000004864 |
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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 |
The phase I primary objective is to determine a tolerable dose and safety profile of Amphinex-induced PCI of gemcitabine followed by systemic gemcitabine/cisplatin chemotherapy in patients with advanced inoperable CCA.
The phase II primary objective is to make a preliminary assessment of the efficacy of Amphinex-induced PCI of gemcitabine followed by systemic gemcitabine/cisplatin chemotherapy in patients with advanced inoperable CCA. |
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E.2.2 | Secondary objectives of the trial |
The phase I secondary objectives are:
- To characterize the pharmacokinetic (PK) profiles of Amphinex and gemcitabine.
- To make a preliminary assessment of the efficacy of Amphinex-induced PCI of gemcitabine followed by systemic gemcitabine/cisplatin chemotherapy in patients with advanced inoperable CCA.
The phase II secondary objectives are:
- To characterize the PK profiles of Amphinex and gemcitabine in a limited number of patients.
- To further assess the safety profile of Amphinex-induced PCI of gemcitabine followed by the systemic gemcitabine/cisplatin combination. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histopathologically/cytologically (C5) verified adenocarcinoma consistent with advanced inoperable cholangiocarcinoma (hilar and extrahilar biliary duct region).
2. Adequate biliary drainage (either at least 50% of the liver volume, or at least two sectors), with no evidence of active uncontrolled infection (patients on antibiotics are eligible).
3. Age ≥ 18 years.
4. Performance status ECOG ≤ 2
5. Estimated life expectancy of at least 12 weeks.
6. Written informed consent. |
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E.4 | Principal exclusion criteria |
1. Any prior anti-cancer (either local or systemic) treatment for cholangiocarcinoma.
2. Patients with a severe visceral disease other than cholangiocarcinoma.
3. Patients with primary sclerosing cholangitis.
4. Patients with porphyria or hypersensibility to porphyrins.
5. Concomitant or prior malignant disease, with exception of adequately treated basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix.
6. Inability to undergo CT or MRI.
7. Current participation in any other interventional clinical trial.
8. Male patients not willing to use adequate contraception or female patients of childbearing potential not willing to use an effective form of contraception such as hormonal birth control, intrauterine device or double barrier method during PCI treatment and subsequent chemotherapy and for at least 6 months thereafter.
9. Breast feeding women or women with a positive pregnancy test at baseline.
10. Inadequate bone marrow function:
absolute Neutrophil Count (ANC): <1.5 x 10^9/L, or platelet count <100 x 10^9/L or haemoglobin <6 mmol/L (transfusion allowed).
11. Inadequate liver function, defined as:
Serum (total) bilirubin >1.5 x the Upper Limit of Normal (ULN) for the institution.
Aspartate Amino Transferase (AST) or Alanine Amino Transferase (ALT) >3.0 x ULN (>5 x ULN if liver metastases are present)
Alkaline phosphatase levels >5.0 x ULN.
12. Inadequate renal function, defined as:
Creatinine clearance <60ml/min
13. Planned surgery, endoscopic examination or dental treatment in the first 30 days after PCI treatment.
14. Co-existing ophthalmic disease likely to require slit-lamp examination within the first 90 days after PCI treatment.
15. Clinically significant and uncontrolled cardiac disease including unstable angina, acute myocardial infarction within six months prior to baseline, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities and controlled and well treated chronic atrial fibrillation.
16. Known allergy or sensitivity to photosensitisers.
17. Ataxia telangiectasia.
18. Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, physical examination or laboratory findings) that may interfere with the planned PCI treatment, affect patient compliance or place the patient at high risk from treatment-related complications.
19. Significant hearing impairment.
20. Patients concurrently receiving phenytoin. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I (safety)
Dose-limiting toxicities (DLT) and the safety profile (AEs, laboratory assessments and physical findings) of the Amphinex-induced PCI of gemcitabine followed by the gemcitabine/cisplatin combination.
Phase II (efficacy)
Progression Free Survival (PFS), defined as the time from randomization to documented disease progression (according to modified RECIST 1.1 criteria) or death from any cause. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
DLT - from start of treatment up to the end of cycle 1 of combination
chemotherapy for dose escalation patients only.
Safety profile - AEs/laboratory sampling from time of consent up to 30 days after the last administration of systemic chemotherapy. Physical examinations continue every 3 months for phase II patients (and phase I patients at the dose level selected for phase II) without disease progression or study discontinuation for any reason for up to 15 months after the end of treatment visit.
PFS - calculated from randomisation to documented disease progression (according to modified RECIST 1.1 criteria) or death from any cause. |
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E.5.2 | Secondary end point(s) |
Phase I
- PK profile of Amphinex and gemcitabine in plasma.
- PFS, defined as the time from registration to documented disease progression (according to modified RECIST 1.1 criteria) or death from any cause.
- Best Overall Response (BOR)
Phase II
- Overall Response Rate (ORR), calculated as the proportion of patients with a best overall response of confirmed Complete Response (CR) or Partial Response (PR).
- Disease Control Rate (DCR), defined as the proportion of patients with best overall response of confirmed CR, PR or Stable Disease (SD).
- Overall Survival (OS), calculated as the time from randomization to the date of death from any cause.
- Best Overall Response (BOR)
- PK profile of Amphinex and gemcitabine in plasma
- Safety profile (AEs, laboratory assessments and physical findings) of the Amphinex-induced PCI of gemcitabine followed by the gemcitabine/cisplatin combination, or the gemcitabine/cisplatin combination alone. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK Amphinex - pre-dose sample and 4 post-dosing samples over 24 hours, further samples at 6 days after dosing, 6 weeks after dosing and 3 months after dosing
PK Gemcitabine - pre-dose sample and 8 post-dosing samples over 24 hours.
PFS - calculated from randomisation to documented disease progression
or death from any cause.
ORR and DCR - post-treatment CT/MRI scans 3 months and 6 months after start of combination chemotherapy, then every 3 months until PD or death.
OS - from randomisation to the date of death from any cause.
Safety profile - AEs/laboratory sampling from time of consent up to 30 days after the last administration of systemic chemotherapy. Physical exam continue every 3 months for patients without disease progression for up to 15 months after the off-study visit. |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | No |
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 | Yes |
E.8.2.3.1 | Comparator description |
PCI procedure + combination chemotherapy vs combination chemotherapy alone |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
|
The date of the last study visit of the last patient undergoing the trial.
All patients will have a follow-up visit at 30 days after the last administration of systemic chemotherapy. Patients participating in phase II as well as patients in phase I from the dose cohort selected for phase II will have follow-up visits for 15 months or until progression or discontinuation for any other reason. Survival status will be documented until death for all patients in an extended follow up
phase. |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |