| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced non-resectable intrahepatic cholangiocarcinoma with positively confirmed FGFR2 fusion/rearrangements via NGS-Analysis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced and inoperable intrahepatic bile duct cancer with positively confirmed FGFR2 genetic alterations |
|
| 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 | 27.0 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008594 |
| E.1.2 | Term | Cholangiocarcinoma non-resectable |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10073077 |
| E.1.2 | Term | Intrahepatic cholangiocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077846 |
| E.1.2 | Term | Cholangiocarcinoma metastatic |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary efficacy objective of the study is to assess the efficacy of atezolizumab in combination with derazantinib by ORR (Objective Response Rate) after 9 months of study treatment as assessed by the local investigator according to RECIST 1.1 criteria. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of atezolizumab in combination with derazantinib by ORR (Objective Response Rate) at EOT (End Of Treatment), PFSR (Progression Free Survival Rate) at 6, 8 and 10 months, PFS (Progression Free Survival) and OS (Overall Survival)
- To evaluate the safety and tolerability of atezolizumab in combination with derazantinib
- To evaluate biomarkers in tumor tissue and blood samples for their predictive and prognostic potential |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria to be eligible for the study:
1. Fully informed written consent and locally required authorization (European Union [EU] Data Privacy Directive in the EU) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
2. Patients*, age ≥ 18 years at the time of signing the Informed Consent Form.
3. Histologically documented diagnosis of non-resectable iCCA with positively confirmed FGFR2 fusion/rearrangement via NGS-Analysis.
Note: Only CE-IVD marked NGS-tests are applicable which cover FGFR2 fusions and rearrangements.
4. Performance status (PS) ≤ 2 (ECOG scale).
5. At maximum one previous line of systemic anti-cancer therapy, (chemotherapy, hormonal, targeted therapy, experimental therapy) for which treatment was discontinued at least 4 weeks before the first dose of study treatment, or five half-lives of the respective anti-cancer therapy, whichever is the longer period.
Note: For mABs in previous therapy the restriction to five half-lives does not apply.
6. No prior treatment with any FGFR or immune checkpoint inhibitor (including but not limited to antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies) apart from Durvalumab as PD-L1 inhibitor in first line therapy.
7. Body weight > 30 kg AND BMI ≥ 15.
8. At least one measurable site of disease as defined by RECIST 1.1 criteria.
9. Adequate bone marrow and renal function including the following:
Hemoglobin ≥ 9.0 g/dL (previous transfusion permitted); Absolute neutrophil count (ANC) ≥ 1.500 per µL (1.5×109/L); Platelet count ≥ 75,000 per µL (75 × 109/L);International normalized ratio (INR) between 0.8 × ULN to 1.0 × ULN OR ≤ 3 × ULN for subjects receving anticoagulant therapy
Creatinine ≤ 1.5 × ULN OR CLCR ≥ 50 mL/min (as calculated by the Cockcroft-Gault formula);serum phosphate ≤ ULN;corrected serum calcium ≥ 1.75 mmol/L (≥ 7.0 mg/dL) AND ≤ 3.1 mmol/L (≤ 12.5 mg/dL); serum sodium ≥ LLN.
10. Adequate hepatic function (with stenting for any obstruction, if required) including the following:Total bilirubin ≤ 2 × ULN; AST or ALT ≤ 3 × ULN (or ≤ 5 × ULN for subjects with liver metastases); Prothrombin time ≥ 60%; Albumin ≥ 2.8 g/dL.
11. For patients with active hepatitis B virus (HBV):
HBV DNA ≤ 500 IU/mL obtained within 28 days prior to initiation of study treatment, AND Anti-HBV treatment (per local standard of care; e.g., entecavir) prior to study entry and willingness to continue treatment for the length of the study.
12. For patients with active hepatitis C virus (HCV):
• Patients positive for hepatitis C virus (HCV) antibody are eligible, also if polymerase chain reaction testing is positive for HCV ribonucleic acid (RNA).
• However, anti-viral therapy against HCV is only allowed prior to trial but not during the trial.
13. Negative HIV test.
14. Negative pregnancy test within 72 h prior to dosing.
15. Females of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 5 months or for a period of at least 5 half-lives of the respective drug/IMP (whichever is longer) after the last study treatment. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (has not had ≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
16. With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of 1% per year from screening to 5 months after the last dose of combination therapy or for a period of at least 5 half-lives of the respective drug/IMP after the last dose of combination therapy (whichever is longer). Men must refrain from donating sperm during this same period. Men with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy to avoid exposing the embryo.
17. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
18. Must have a life expectancy of at least 12 weeks. |
|
| E.4 | Principal exclusion criteria |
1. Mixed CCA and HCC.
2. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) study or a study without a medical intervention (specifically the PLATON registry [ClinicalTrials.gov identifier: NCT04484636] is allowed).
3. Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into the study; patients must have recovered from effects of any major surgery.
4. Uncontrolled intercurrent illness (as described in the study protocol).
5. History of another primary malignancy (with a few exceptions, as described in the study protocol).
6. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 5 months after the last dose of combination therapy or for a period of at least 5 half-lives of the respective drug/IMP after the last dose of combination therapy (whichever is longer).
7. Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the product.
8. Any co-existing medical condition that in the investigator’s judgement will substantially increase the risk associated with the patient’s participation in the study.
9. Active or History of autoimmune disease including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
10. History of non-infectious pneumonitis requiring steroids, or patients with Grade ≥ 2 pneumonitis.
11. History of active primary immunodeficiency.
12. History of allogeneic bone marrow transplantation or prior solid organ transplantation.
13. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment (with two exceptions, as described in the study protocol).
14. Administration of a live, attenuated vaccine within four weeks or for a period of at least 5 half-lives of the respective drug/IMP (whichever is longer) prior to start of enrollment, or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after the last dose of atezolizumab.
15. Significant cardiovascular disease, such as cardiac disease (New York Heart Association Class II or greater), myocardial infarction or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmias, unstable angina, and/or concurrent and clinically significant abnormalities on electrocardiogram (ECG) at Screening, including QTcF > 450 ms for males or > 460 ms for females.
16. Clinically significant valvular defect.
17. Unable or unwilling to swallow the complete daily dose of derazantinib capsules.
18. Clinically unstable central nervous system (CNS) metastases (to be eligible, subjects must have stable disease > 3 months, confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and/or have CNS metastases well controlled by low-dose steroids, anti-epileptics, or other symptom-relieving medications).
19. Current evidence of clinically significant corneal or retinal disorder, including but not limited to bullous/band keratopathy, keratoconjunctivitis (except for keratoconjunctivits sicca), corneal abrasion (except if related to trauma), inflammation/ulceration, confirmed by ophthalmologic examination.
20. Significant gastrointestinal disorder(s) that could, in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of derazantinib and/or atezolizumab (e.g., Crohn’s disease, ulcerative colitis, extensive gastric resection).
21. Active tuberculosis.
22. Co-infection with hepatitis B and hepatitis C. Patients who are negative for HCV RNA will be considered non-infected for HCV.
23. Severe bacterial, fungal, viral and/or parasitic infections on therapeutic oral or IV medication at the time of first dose of study drug administration.
24. Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study treatment, including rifampin (and its analogues) or St. John's wort.
25. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
26. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot make a rational/informed decision after receiving the study information [§ 40 Abs. 1 S. 3 Nr. 3a AMG]. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Response Rate (ORR) assessed every 8 weeks according to investigator-based RECIST 1.1 assessment, defined as the proportion of allocated subjects with best response of complete or partial response within 9 months after the date of first administration of study treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- ORR (Objective Response Rate) at EOT (End of Treatment)
- PFSR (Progression Free Survival Rate) at 6, 8 and 10 months
- PFS (Progression Free Survival)
- OS (Overall Survival)
- Safety endpoints: incidence of adverse events, serious adverse events and adverse events of special interest; severity of adverse events by CTCAE v5.0 grade; relationship of adverse events to atezolizumab and/ or derazantinib; frequency of clinically significant abnormal laboratory parameters
- Serum Tumor Markers (CA19-9, CEA) as efficacy measurements
- Exploratory endpoints: fecal samples for microbiom analysis and blood samples for accompanying research project |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- End of study
- Safety will be evaluated continuously and after end of study |
|
| 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 | Yes |
| 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 | 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 | No |
| 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 | 20 |
| 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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