| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Male and female participants at least 18 years of age who have unresectable and/or metastatic cholangiocarcinoma with FGFR2 rearrangement |
|
| E.1.1.1 | Medical condition in easily understood language |
| Participants with advanced cholangiocarcinoma |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008593 |
| E.1.2 | Term | Cholangiocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| Evaluate the efficacy of pemigatinib versus gemcitabine plus cisplatin in the first-line treatment of participants with cholangiocarcinoma with FGFR2 rearrangement. |
|
| E.2.2 | Secondary objectives of the trial |
- Evaluate the efficacy of pemigatinib versus gemcitabine plus cisplatin in the first-line treatment of participants with cholangiocarcinoma with FGFR2 rearrangement.
- Safety and tolerability of pemigatinib.
- Quality of Life impact. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability to comprehend and willingness to sign a written ICF for the study.
2. Male and female participants at least 18 years of age at the time of signing the ICF; a legally minor participant from Japan needs written parental consent.
3. Histologically or cytologically confirmed cholangiocarcinoma that is previously untreated and considered unresectable and/or metastatic (Stage IV per the AJCC Cancer Staging Manual [AJCC 2010]).
4. Radiographically measurable or evaluable disease by CT or MRI per RECIST v1.1 criteria.
5. ECOG performance status 0 to 1.
6. Documented FGFR2 rearrangement. |
|
| E.4 | Principal exclusion criteria |
1. Received prior anticancer systemic therapy for unresectable and/or metastatic disease (not including adjuvant/neo-adjuvant treatment completed at least 6 months prior to enrollment, and participants that have received treatment for locally advanced disease with trans-arterial chemoembolization or selective internal radiation therapy, if clear evidence of radiological progression is observed before enrollment, or enrolled as of Amendment 6 and the participant received 1 cycle of gemcitabine plus cisplatin [the start of study drug {Cycle 1 Day 1} must be at least 14 days and ≤ 4 weeks {28days} from the last dose of gemcitabine plus cisplatin.] ).
2. In participants with liver cirrhosis, Child-Pugh B and C (Note: Ascites attributed to cholangiocarcinoma rather than liver disfunction (e.g.in the presence of peritoneal metastases) should not be taken into consideration when scoring)
3. Toxicities related to prior therapy(ies) must be CTCAE v5.0 ≤ Grade 1 at the time of screening.
4. Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumor embolization), other than the therapies being tested in this study.
5. Participant is a candidate for potentially curative surgery.
6. Current evidence of clinically significant corneal (including but not limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, and keratoconjunctivitis) or retinal disorder (including but not limited to central serous retinopathy, macular/retinal degeneration, diabetic retinopathy, retinal detachment) as confirmed by ophthalmologic examination.
7. Radiation therapy administered within 4 weeks of enrollment/randomization/ first dose of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Evidence of fibrosis within a radiation field from prior radiotherapy is permitted with medical monitor approval. A 2-week washout is permitted for palliative radiation to non-CNS disease.
8. Known CNS metastases or history of uncontrolled seizures. Participants with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period, and they are on stable or decreasing dose of corticosteroids for at least 1 week.
9. Known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS: defined as the time from date of randomization until date of disease progression (according to RECIST v1.1 and assessed by an ICR) or death, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The schedule for assessments will be performed according to the schedule of activities reported in the protocol.
The schedule for efficacy assessments will be at screening (this will be considered the baseline scan), every 9 weeks (every 3 cycles) and then at EOT (if applicable). Imaging should continue in 9-week intervals regardless of delays in cycle starts. |
|
| E.5.2 | Secondary end point(s) |
• ORR (CR + PR): defined as the proportion of participants with best overall response of CR or PR per RECIST v1.1 as assessed by an ICR.
• OS: defined as the time from date of randomization until death due to any cause.
• DOR: defined as the time from the date of the first assessment of CR or PR until the date of the first disease progression by an ICR per RECIST v1.1 or death, whichever occurs first.
• DCR (CR + PR + SD): defined as the proportion of participants who achieved best overall response of CR, PR, or SD per RECIST v1.1 as assessed by an ICR.
• Occurrence of TEAEs and treatment-related AEs according to NCI CTCAE v5.0, physical findings, and vital sign, laboratory, and ECG changes.
• QoL questionnaire data (EQ-5D, EORTC QLQ-30, and BIL-21). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The schedule for assessments will be performed according to the schedule of activities reported in the protocol.
The schedule for efficacy assessments will be at screening (this will be considered the baseline scan), every 9 weeks (every 3 cycles) and then at EOT (if applicable). Imaging should continue in 9-week intervals regardless of delays in cycle starts.
Adverse events will be monitored from the time the participant signs the ICF until at least 30 days after the last dose of study treatment or until the start of new anticancer therapy, whichever occurs first.
|
|
| 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 | No |
| 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 | No |
| 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) | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 21 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 104 |
| 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 |
| Switzerland |
| Israel |
| Japan |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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