| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| urothelial cancer |
| carcinoma uroteliale |
|
| E.1.1.1 | Medical condition in easily understood language |
| urothelial cancer |
| carcinoma uroteliale |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077840 |
| E.1.2 | Term | Urothelial cancer of renal pelvis |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Primary objectives for Substudies 1, 3 and 4
•To evaluate the objective response rate (ORR) of single-agent derazantinib (in Cohorts 1, 3a, and 4a) and of derazantinib-atezolizumab in combination (in Cohorts 3b and 4b) in patients with mUC expressing FGFR1–3 GAs.
Primary objective for Substudy 2
•To determine the recommended Phase 2 dose (RP2D) of derazantinib in combination with atezolizumab.
|
Obiettivi primari per i sottostudi 1, 3 e 4
•Valutare il tasso di risposta obiettiva (ORR) di derazantinib come singolo agente (nelle Coorti 1, 3a e 4a) e di derazantinib-atezolizumab in combinazione (nelle Coorti 3b e 4b) in pazienti con mUC che esprime AG negli FGFR1-3.
Obiettivo primario per il sottostudio 2
•TDeterminare la dose raccomandata per la fase 2 (RP2D) di derazantinib in combinazione con atezolizumab. |
|
| E.2.2 | Secondary objectives of the trial |
Substudies 1, 3 and 4
•To evaluate the efficacy of the study drugs as measured by disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS)
•To assess the safety and tolerability of the study drugs
•To evaluate changes, and assess the minimally important difference, in health-related quality of life (HR-QoL) and symptom response from baseline using the EORTC QLQ C30, FACT-Bl, and EQ-5D (5L) visual analogue scale (VAS)
Substudy 2
•To evaluate the efficacy of the study drugs as measured by ORR, DCR, DOR, PFS and OS
•To assess the safety and tolerability profile of derazantinib in combination with atezolizumab
•To characterize the PK profile of derazantinib in combination with atezolizumab.
|
Sottostudi 1, 3 e 4
•Valutare l'efficacia dei farmaci in studio in base al tasso di controllo della malattia (DCR), alla durata della risposta (DOR), alla sopravvivenza senza progressione (PFS) e alla overall survival (OS).
•Valutare la sicurezza e la tollerabilità dei farmaci in studio.
•Valutare i cambiamenti, e valutare la differenza minima significativa, nella qualità della vita correlata alla salute (HR-QoL) e la risposta ai sintomi rispetto al basale utilizzando i questionari EORTC QLQ C30, FACT-Bl e la scala visuo-analogica (VAS) dell'EQ-5D (5L).
Sottostudio 2
•Valutare l'efficacia dei farmaci in studio come misurato da ORR, DCR, DOR, PFS e OS.
•Valutare il profilo di sicurezza e tollerabilità di derazantinib in combinazione con atezolizumab.
•Caratterizzare il profilo PK di derazantinib in combinazione con atezolizumab. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Other types of substudies
Specify title, date and version of each substudy with relative objectives: Translational Clinical Study:
A subset of patients within Substudies 1, 3, and 4 will undergo additional
assessments to analyze molecular and gene expression profiles, and
selection and/or pharmacodynamic biomarkers predictive of response
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and indicative of effective downregulation of the dependent signaling
pathway. For the TCS element, a subset of patients within Substudies 1,
3, and 4 will undergo additional assessments to analyze molecular
profiles and computed tomography (CT) or magnetic resonance imaging
(MRI) studies at baseline and over time. This subset of patients is
referred to as the TCS Group. These patients undergo up to two
additional paired tumor-liquid biopsies and CT/MRI studies, one in Cycle
2 and one at the Investigator's discretion at the time of Response
Evaluation Criteria In Solid Tumors (RECIST) 1.1 assessments scheduled
for confirming response, or at the time of clinical and/or (if applicable,
confirmed) radiographic progression.
2) Future Biomedical Research
Future biomedical research specimens will be stored to provide a
resource for future studies conducted by the Sponsor focused on the
study of biomarkers responsible for how a drug enters and is removed by
the human body, how a drug works, other pathways a drug may interact
with, or other aspects of disease. The specimens may be used for future
assay development and/or drug development.
|
Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Translational Clinical Study:
A subset of patients within Substudies 1, 3, and 4 will undergo additional
assessments to analyze molecular and gene expression profiles, and
selection and/or pharmacodynamic biomarkers predictive of response
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Page 14/29
and indicative of effective downregulation of the dependent signaling
pathway. For the TCS element, a subset of patients within Substudies 1,
3, and 4 will undergo additional assessments to analyze molecular
profiles and computed tomography (CT) or magnetic resonance imaging
(MRI) studies at baseline and over time. This subset of patients is
referred to as the TCS Group. These patients undergo up to two
additional paired tumor-liquid biopsies and CT/MRI studies, one in Cycle
2 and one at the Investigator's discretion at the time of Response
Evaluation Criteria In Solid Tumors (RECIST) 1.1 assessments scheduled
for confirming response, or at the time of clinical and/or (if applicable,
confirmed) radiographic progression.
2) Future Biomedical Research
Future biomedical research specimens will be stored to provide a
resource for future studies conducted by the Sponsor focused on the
study of biomarkers responsible for how a drug enters and is removed by
the human body, how a drug works, other pathways a drug may interact
with, or other aspects of disease. The specimens may be used for future
assay development and/or drug development.
|
|
| E.3 | Principal inclusion criteria |
1.ICF signed by the patient indicating that they understand the purpose of, and procedures required for, the study and are willing to participate in the study, prior to any study-related procedure. 2.Male or female aged = 18 years.
3.Histologically-confirmed transitional cell carcinoma of the urothelium of the upper or lower urinary tract (applicable to Substudies 1, 3 and 4) Note: Minor components (< 50% overall) of variant histology such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change, are acceptable.
4.Recurrent or progressing stage IV disease, or surgically unresectable, recurrent or progressing disease, as specified for each substudy:
•Substudy 1: Patients with mUC expressing specific FGFR1–3 GAs who have progressed on at least one standard chemotherapy and/or immune-checkpoint blockade and have not received prior FGFR inhibiting treatment.
•Substudy 2: Patients with any advanced solid tumor and any prior treatment (including FGFR inhibitor treatment), who have no standard treatment alternative (per multidisciplinary tumor board endorsement). •Substudy 3: First-line cisplatin-ineligible patients with patients with mUC expressing specific FGFR1–3 GAs and PD-L1 expression < 5% ('PDL1-
low'). Cisplatin-ineligibility as defined by any one of the following criteria: 1) grade = 2 peripheral neuropathy; 2) CLCR calculated by Cockcroft-Gault >30 mL/min but < 60 mL/min; 3) hearing impairment (measured by audiometry) of > 25 dB at two contiguous test frequencies in at least one ear; 4) comorbidity that precludes high-volume hydration. Note: For
atezolizumab, a low PD-L1 expression level is an ImmunoHistoChemistry Score of 1 using the polyclonal anti-PD-L1 rabbit antibody SP142 (Ventana, an FDA approved test), i.e., less than 5% of positive immune cells in the tumor microenvironment, which comprises tumor cells and tumor infiltrating immune cells (including macrophages, dendritic cells, and lymphocytes). •Substudy 4: Patients with FGFR inhibitor-resistant, mUC expressing specific FGFR1–3 GAs who have progressed on at least one standard regimen each of chemotherapy and immune-checkpoint blockade and have received FGFR inhibiting treatment (excluding derazantinib) Patients assessed as having progressed upon prior treatment with FGFR inhibitors must have received FGFR inhibitor treatment for at least 12 weeks and have undergone at least one on treatment tumor imaging assessment.
Prior treatment with immune-checkpoint blockade and FGFR inhibitor in combination are not allowed; prior treatment with either sequential immune-checkpoint blockade and FGFR inhibitor treatment or combinations of FGFR inhibitor and chemotherapy are allowed. •TCS Group: Patients enrolled in the TCS Group need to have disease that is safely amenable to repeated biopsies. 5.For enrollment into the study, patients for Substudies 1, 3 and 4 require positive tumor molecular FGFR1-3 status as detailed in Appendix 1, obtained from a plasma or tissue-based assay, using standard molecular protocols approved by the local IRB/IEC, Clinical Laboratory Improvement Amendments (CLIA), or other similar agency, or, where
applicable, US FDA-approved kits. For enrollment of patients in the EU, assays must be either fully CE-marked or CE-marked for analytical performance; tests manufactured by health institutions and used only on their own patients are exempt from the Medical Devices Regulation requirements, and do not have to be CE-marked.
6.Measurable disease, as defined by the Investigator using RECIST 1.1 criteria, documented within the 30 days prior to study drug administration.
7.ECOG PS of 0, 1 or 2
8.Adequate organ functions as indicated by the following Screening visit local laboratory values:
For the full list, please refer to the study Protocol |
1.ICF signed by the patient indicating that they understand the purpose of, and procedures required for, the study and are willing to participate in the study, prior to any study-related procedure. 2.Male or female aged = 18 years.
3.Histologically-confirmed transitional cell carcinoma of the urothelium of the upper or lower urinary tract (applicable to Substudies 1, 3 and 4) Note: Minor components (< 50% overall) of variant histology such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change, are acceptable.
4.Recurrent or progressing stage IV disease, or surgically unresectable, recurrent or progressing disease, as specified for each substudy:
•Substudy 1: Patients with mUC expressing specific FGFR1–3 GAs who have progressed on at least one standard chemotherapy and/or immune-checkpoint blockade and have not received prior FGFR inhibiting treatment.
•Substudy 2: Patients with any advanced solid tumor and any prior treatment (including FGFR inhibitor treatment), who have no standard treatment alternative (per multidisciplinary tumor board endorsement). •Substudy 3: First-line cisplatin-ineligible patients with patients with mUC expressing specific FGFR1–3 GAs and PD-L1 expression < 5% ('PDL1-
low'). Cisplatin-ineligibility as defined by any one of the following criteria: 1) grade = 2 peripheral neuropathy; 2) CLCR calculated by Cockcroft-Gault >30 mL/min but < 60 mL/min; 3) hearing impairment (measured by audiometry) of > 25 dB at two contiguous test frequencies in at least one ear; 4) comorbidity that precludes high-volume hydration. Note: For
atezolizumab, a low PD-L1 expression level is an ImmunoHistoChemistry Score of 1 using the polyclonal anti-PD-L1 rabbit antibody SP142 (Ventana, an FDA approved test), i.e., less than 5% of positive immune cells in the tumor microenvironment, which comprises tumor cells and tumor infiltrating immune cells (including macrophages, dendritic cells, and lymphocytes). •Substudy 4: Patients with FGFR inhibitor-resistant, mUC expressing specific FGFR1–3 GAs who have progressed on at least one standard regimen each of chemotherapy and immune-checkpoint blockade and have received FGFR inhibiting treatment (excluding derazantinib) Patients assessed as having progressed upon prior treatment with FGFR inhibitors must have received FGFR inhibitor treatment for at least 12 weeks and have undergone at least one on treatment tumor imaging assessment.
Prior treatment with immune-checkpoint blockade and FGFR inhibitor in combination are not allowed; prior treatment with either sequential immune-checkpoint blockade and FGFR inhibitor treatment or combinations of FGFR inhibitor and chemotherapy are allowed. •TCS Group: Patients enrolled in the TCS Group need to have disease that is safely amenable to repeated biopsies. 5.For enrollment into the study, patients for Substudies 1, 3 and 4 require positive tumor molecular FGFR1-3 status as detailed in Appendix 1, obtained from a plasma or tissue-based assay, using standard molecular protocols approved by the local IRB/IEC, Clinical Laboratory Improvement Amendments (CLIA), or other similar agency, or, where
applicable, US FDA-approved kits. For enrollment of patients in the EU, assays must be either fully CE-marked or CE-marked for analytical performance; tests manufactured by health institutions and used only on their own patients are exempt from the Medical Devices Regulation requirements, and do not have to be CE-marked.
6.Measurable disease, as defined by the Investigator using RECIST 1.1 criteria, documented within the 30 days prior to study drug administration.
7.ECOG PS of 0, 1 or 2
8.Adequate organ functions as indicated by the following Screening visit local laboratory values:
For the full list, please refer to the study Protocol |
|
| E.4 | Principal exclusion criteria |
Prior cancer treatment
1.Receipt of treatment before the first dose of study drug (Cycle 1 Day 1) within an interval shorter than the following, as applicable:
•One chemotherapy or biological (e.g., antibody) cycle interval•Five half-lives of any small molecule investigational or licensed medicinal product•Two weeks, for any investigational medicinal product (IMP) with an unknown half-life•Four weeks of curative radiotherapy •Seven days of palliative radiotherapy •12 months of neo-adjuvant or adjuvant chemotherapy or radiation (only applies to Substudy 3)
2.For Substudy 3 patients, any prior treatment with anti-PD-1 or anti-PD-L1-therapeutic antibody or pathway-targeting agents; 3.For Substudy 4 patients, prior treatment with FGFR inhibitor in combination with anti-PD-1 or anti-PD-L1 therapeutic antibody or pathway-targeting agents.Critical organ impairments 4.Concurrent evidence of corneal or retinal disorder, including but not limited to bullous/band keratopathy, keratoconjunctivitis, corneal abrasion (unless related to trauma), inflammation/ulceration, confirmed by ophthalmological examination. 5.History of clinically significant cardiac disorders:
•Myocardial infarction, or New York Heart Association Class II to IV congestive heart failure, within 6 months of the first dose of study drug.•Concurrent and clinically significant abnormalities on ECG at Screening, including TcF > 450 ms for males or > 460 ms for females. 6.Serum electrolyte abnormalities defined as follows:
•Hyperphosphatemia: serum phosphate > institutional ULN
•Hyperkalemia: serum potassium > institutional ULN
•Hypokalemia: serum potassium < institutional LLN
•Hypercalcemia: corrected serum calcium > 3.1 mmol/L (> 12.5 mg/dL)
•Hypocalcemia: corrected serum calcium < 1.75 mmol/L (< 7.0 mg/dL)
•Hypomagnesemia: < 0.4 mmol/L (< 0.9 mg/dL) 7.History of major thrombotic and clinically relevant bleeding event in the last 6 months before Screening which in the assessment of the Investigator puts the patient at high risk of bleeding during the study. 8.Uncontrolled tumor-related hypercalcemia.Medical history.9.Any unresolved (at the time of Screening) clinically significant CTCAE grade 2 or greater toxicity (except for alopecia and grade 2 platinum-therapy related neuropathy, anemia grade 2 from previous anti-tumor treatment and/or medical/surgical procedures/interventions).Grade 2 renal impairment per reduced CLCR by Cockcroft-Gault of 30– 60 mL/min is generally accepted for this population (see inclusion criterion 7)10.For Substudy 1, 3 or 4 patients, known CNS metastases. Patients with CNS metastases and CNS tumors are eligible for Substudy 2.11.Lack of recovery from major (e.g., open abdominal) surgery after 4 weeks, or major elective surgery is planned during the foreseeable duration of the study.12.Concurrent uncontrolled or active infection with either human immunodeficiency virus (known HIV 1/2 antibodies positive). 13.Active hepatitis B, or hepatitis C. Active Hepatitis B is defined as a
known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C antibody result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
14.Active tuberculosis.15.Severe bacterial, fungal, viral and/or parasitic infections on therapeutic oral or IV medication at the time of first dose of study drug administration
16.Significant gastrointestinal disorders that could, in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of derazantinib (e.g., Crohn’s disease, ulcerative colitis, diarrhea, extensive gastric resection, functionally relevant gastrointestinal obstruction, or vomiting) .
For full list please refer to protocol |
1. Precedente trattamento oncologico somministrato entro specifici intervalli di tempo (vedi Criterio di esclusione 1 nel corpo principale del protocollo).
2. Per i pazienti del sottostudio 3, precedente trattamento con anticorpi terapeutici anti-PD-1 o anti-PD-L1 o agenti che hanno come bersaglio i pathway;
3. Per i pazienti del sottostudio 4, precedente trattamento con inibitori degli FGFR in combinazione con anticorpi terapeutici anti-PD-1 o anti-PD-L1 o agenti che hanno come bersaglio i pathway;
4. Concomitanti evidenze di patologie corneali o retiniche tra cui, a titolo esemplificativo ma non esaustivo, cheratopatia bollosa/a banda, cheratocongiuntivite, abrasione corneale, infiammazione/ulcerazione, confermate da un esame oftalmologico.
5. Eventi pregressi di patologie cardiache clinicamente significative, tra cui infarto del miocardio o insufficienza cardiaca congestizia di classe II-IV secondo la New York Heart Association, entro 6 mesi dalla prima dose del farmaco in studio e/o anomalie concomitanti e clinicamente significative dell'elettrocardiogramma (ECG) allo screening, compreso QTcF >450 ms per gli uomini o >460 ms per le donne.
6.Anomalie degli elettroliti sierici definite come segue:
• Iperfosfatemia: fosfato sierico> ULN istituzionale
• Iperkaliemia: potassio sierico> ULN istituzionale
• Ipopotassiemia: potassio sierico <LLN istituzionale
• Ipercalcemia: calcio sierico corretto> 3,1 mmol / L (> 12,5 mg / dL)
• Ipocalcemia: calcio sierico corretto <1,75 mmol / L (<7,0 mg / dL)
• Ipomagnesemia: <0,4 mmol / L (<0,9 mg / dL)
8. Qualsiasi tossicità non risolta o clinicamente significativa di grado =21 secondo CTCAE (Criteri terminologici comuni per gli eventi avversi) (ad eccezione dell'alopecia, della neuropatia correlata alla terapia con platino di grado 2 secondo CTCAE e/o dell'anemia derivante da precedenti trattamenti antitumorali e/o procedure/interventi medici/chirurgici di grado 2 secondo CTCAE).
10. Per i pazienti del sottostudio 1, 3 o 4, metastasi note all'SNC. I pazienti con metastasi all'SNC e tumori del SNC sono idonei per il sottostudio 2.
11. Mancato recupero da un intervento chirurgico maggiore dopo 4 settimane o si prevede un intervento chirurgico elettivo maggiore nel corso della durata prevedibile dello studio.
12. Concomitante infezione non controllata o attiva da virus dell'immunodeficienza umana, (noti anticorpi HIV 1/2 positivi).
13. Epatite B attiva o epatite C. L'epatite B attiva è definita come a
risultato HBsAg positivo noto. L'epatite C attiva è definita da un noto
risultato positivo dell'anticorpo Hep C e risultati quantitativi noti di HCV RNA
maggiore dei limiti inferiori di rilevazione del dosaggio.
14. Tubercolosi attiva
L'elenco completo dei criteri di esclusione è reperibile nella sezione 4.4 del corpo principale del protocollo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint in Substudies 1, 3 and 4
•ORR, as measured by the proportion of patients with confirmed CR or PR by BICR.
Primary endpoint for Substudy 2
•RP2D of derazantinib-atezolizumab in combination, resulting from safety and tolerability of derazantinib-atezolizumab in combination according to DLT criteria and the aggregate of AE data, and considering PK and efficacy data.
DLTs within the DLT interval (i.e., the first 21 days of the first treatment cycle) will be analyzed in the first 6 patients enrolled to the initial dose level and – if applicable – further dose levels to determine if dose escalation is justified (or dose de-escalation is required) and if derazantinib in combination with atezolizumab is safe tolerable. The RP2D will be determined by a joint decision taken by the IDMC,
Investigators, and the Sponsor in reviewing the aggregate of DLT and AE data and considering pharmacokinetic and efficacy data. |
Per tutte le coorti dei sottostudi 1, 3 e 4, l'endpoint primario è rappresentato dall'ORR, misurato dalla percentuale di pazienti con risposta completa (CR)2 o risposta parziale (PR)3 confermata
mediante revisione centrale indipendente in cieco (BICR). Nel sottostudio 2, l'endpoint primario è l'RP2D di derazantinib-atezolizumab in combinazione, stimata in base alla sicurezza e alla tollerabilità secondo i criteri aggregati di tossicità dose-limitante (DLT) e i dati sugli eventi avversi (AE), e considerando ulteriori dati sulla PK e sull'efficacia della combinazione. Sarà il Comitato indipendente di monitoraggio dei dati (IDMC), gli sperimentatori e lo Sponsor a rivedere i dati aggregati relativi a DLT e AE e considerando ulteriori dati di PK e di efficacia della combinazione. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Analysis of primary endpoint of Substudies 1, 3, 4
The primary efficacy endpoint will be ORR, defined as the achievement of confirmed CR or PR using RECIST 1.1, as assessed by BICR. Point estimates and 2-sided 95% confidence intervals (CIs) will be provided.
For Substudy 2:
DLTs within the DLT interval (i.e., the first 21 days of the first treatment cycle) will be analyzed in the first 6 patients enrolled to the initial dose level and – if applicable – further dose levels to determine if dose escalation is justified (or dose de-escalation is required) and if derazantinib in combination with atezolizumab is safe and tolerable. The RP2D will be determined by the IDMC in reviewing the aggregate of DLT and AE data, and considering further PK and efficacy data of the combination. |
Analysis of primary endpoint of Substudies 1, 3, 4
The primary efficacy endpoint will be ORR, defined as the achievement of confirmed CR or PR using RECIST 1.1, as assessed by BICR. Point estimates and 2-sided 95% confidence intervals (CIs) will be provided.
For Substudy 2:
DLTs within the DLT interval (i.e., the first 21 days of the first treatment cycle) will be analyzed in the first 6 patients enrolled to the initial dose level and – if applicable – further dose levels to determine if dose escalation is justified (or dose de-escalation is required) and if derazantinib in combination with atezolizumab is safe and tolerable. The RP2D will be determined by the IDMC in reviewing the aggregate of DLT and AE data, and considering further PK and efficacy data of the combination. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints in Substudies 1, 3 and 4
•DCR, as measured by the proportion of patients with confirmed CR, PR or stable disease (SD) by BICR
•DOR, as calculated from the first date of documented tumor response to disease progression by BICR
•Median PFS and PFS at 6 months, as determined by BICR and measured from time of first dose to time of objective tumor progression or death, and the proportion of patients alive and free of objective tumor progression 6 months after cohort assignment, respectively
•Median OS and OS at 6 months, as measured from time of first dose until time of death and the proportion of patients alive 6 months after cohort assignment, respectively
•Safety and tolerability of study drugs as measured by the frequency and severity of AEs, clinical laboratory parameters, vital signs, ECOG PS, physical examinations (including eye examinations), and ECG parameters over time, and graded by CTCAE Version 5.0
•Changes in HR-QoL and symptom response, measured by global, functional and symptom scores obtained from patient reported outcome instruments (EORTC QLQ C30, FACT-Bl, and EQ-5D [5L] VAS) at baseline and over time
Secondary endpoints for Substudy 2
•ORR, as measured by the proportion of patients with CR or PR by BICR
•DCR, as measured by the proportion of patients with CR, PR or SD by BICR
•DOR, as calculated from the first date of documented tumor response to disease progression by BICR
•Median PFS and PFS at 6 months, as determined by BICR and measured from time of first dose to time of objective tumor progression or death, and the proportion of patients alive and free of objective tumor progression 6 months after cohort assignment, respectively
•Median OS and OS at 6 months, as measured from time of first dose until time of death and the proportion of patients alive 6 months after cohort assignment, respectively
•Safety and tolerability of study drugs, as measured by the frequency and severity of AEs, clinical laboratory parameters, vital signs, ECOG PS, physical examinations (including eye examinations), and ECG parameters over time, and graded by CTCAE Version 5.0
•Derazantinib (and – if applicable –derazantinib metabolites) plasma concentrations, Cmax, tmax, AUC0-24, AUClast assessed by measurements in blood
|
Secondary endpoints in Substudies 1, 3 and 4
•DCR, as measured by the proportion of patients with confirmed CR, PR or stable disease (SD) by BICR
•DOR, as calculated from the first date of documented tumor response to disease progression by BICR
•Median PFS and PFS at 6 months, as determined by BICR and measured from time of first dose to time of objective tumor progression or death, and the proportion of patients alive and free of objective tumor progression 6 months after cohort assignment, respectively
•Median OS and OS at 6 months, as measured from time of first dose until time of death and the proportion of patients alive 6 months after cohort assignment, respectively
•Safety and tolerability of study drugs as measured by the frequency and severity of AEs, clinical laboratory parameters, vital signs, ECOG PS, physical examinations (including eye examinations), and ECG parameters over time, and graded by CTCAE Version 5.0
•Changes in HR-QoL and symptom response, measured by global, functional and symptom scores obtained from patient reported outcome instruments (EORTC QLQ C30, FACT-Bl, and EQ-5D [5L] VAS) at baseline and over time
Secondary endpoints for Substudy 2
•ORR, as measured by the proportion of patients with CR or PR by BICR
•DCR, as measured by the proportion of patients with CR, PR or SD by BICR
•DOR, as calculated from the first date of documented tumor response to disease progression by BICR
•Median PFS and PFS at 6 months, as determined by BICR and measured from time of first dose to time of objective tumor progression or death, and the proportion of patients alive and free of objective tumor progression 6 months after cohort assignment, respectively
•Median OS and OS at 6 months, as measured from time of first dose until time of death and the proportion of patients alive 6 months after cohort assignment, respectively
•Safety and tolerability of study drugs, as measured by the frequency and severity of AEs, clinical laboratory parameters, vital signs, ECOG PS, physical examinations (including eye examinations), and ECG parameters over time, and graded by CTCAE Version 5.0
•Derazantinib (and – if applicable –derazantinib metabolites) plasma concentrations, Cmax, tmax, AUC0-24, AUClast assessed by measurements in blood |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
DCR (and ORR for Substudy 2) will be summarized in the same way as the primary endpoint.
DOR, PFS and OS analyses will be performed using KM methods. The analysis will be performed on the mITT population and repeated on the PP population.
Sensitivity analyses within Substudies 3 and 4 will be performed according to the stratification factor composite score and its variables.
|
DCR (and ORR for Substudy 2) will be summarized in the same way as the primary endpoint.
DOR, PFS and OS analyses will be performed using KM methods. The analysis will be performed on the mITT population and repeated on the PP population.
Sensitivity analyses within Substudies 3 and 4 will be performed according to the stratification factor composite score and its variables. |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
-Tolerability,
-To describe the type of FGFR1–3 GAs in responders and non-responders |
| -Tolerability,-To describe the type of FGFR1–3 GAs in responders and non-responders |
|
| 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 |
|
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| 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 | Information not present in EudraCT |
| 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 |
| Australia |
| Canada |
| Korea, Republic of |
| Singapore |
| United States |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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
|
| The study ends when the last patient completes the last study-related phone-call or visit, discontinues from the study or is lost to follow-up (i.e. the patient is unable to be contacted by the investigator). |
| Lo studio termina quando l'ultimo paziente completa l'ultima telefonata o visita correlata allo studio, interrompe lo studio o perde il follow-up (ovvero, il paziente non è in grado di essere contattato dallo sperimentatore). |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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