| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| p53 Wild-Type (p53WT) Merkel Cell Carcinoma (MCC) |
| carcinoma a cellule di Merkel (MCC) p53 wildtype (p53WT) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Merkel Cell Carcinoma (MCC) |
| carcinoma a cellule di Merkel (MCC) |
|
| 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 | 10064025 |
| E.1.2 | Term | Merkel cell carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10064025 |
| E.1.2 | Term | Merkel cell carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10064025 |
| E.1.2 | Term | Merkel cell carcinoma |
| 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 |
- Cohort 1 Part 1: To determine the KRT-232 recommended phase 2 dose (RP2D)
- Cohort 1 Part 2: To determine the objective response rate (ORR) in subjects with p53WT MCC who have failed anti-PD-1 or anti-PD-L1 immunotherapy
- Cohort 2 Part 1: To determine the KRT-232 RP2D in combination with avelumab
- Cohort 2 Part 2: To determine the objective response rate (ORR) in treatment-naïve subjects with p53WT MCC |
-Parte 1 della Coorte 1: determinare la dose raccomandata per la fase 2 (RP2D) di KRT-232
-Parte 2 della Coorte 1: determinare il tasso di risposta obiettiva (ORR) in soggetti con MCC p53WT che non hanno risposto all’immunoterapia con anti-PD-1 o anti-PD-L1
-Parte 1 della Coorte 2: determinare la RP2D di KRT-232 in combinazione con avelumab
-Parte 2 della Coorte 2: determinare il tasso di risposta obiettiva (ORR) in soggetti affetti da MCC con p53WT naïve al trattamento |
|
| E.2.2 | Secondary objectives of the trial |
- To determine duration of response (DoR)
- To determine progression-free survival (PFS)
- To determine overall survival (OS)
- To determine KRT-232 safety and tolerability
- To determine the pharmacokinetic/pharmacodynamic (PK/PD) profile of KRT-232 |
-Determinare la durata della risposta (DoR)
-Determinare la sopravvivenza libera da progressione (PFS)
-Determinare il tasso di sopravvivenza globale (OS)
-Determinare la sicurezza e la tollerabilità di KRT-232
-Determinare il profilo farmacocinetico/farmacodinamico (PK/PD) di KRT-232 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. For Cohort 1, subjects must have failed treatment with at least one PD-1 inhibitor or PD-L1 inhibitor for metastatic MCC
2. For Cohort 2, subjects must not have received any anti-PD-1 or anti-PD-L1 treatments for metastatic MCC
3. Adults = 18 years of age
4. ECOG performance status of 0 to 1
5. Histologically confirmed MCC. Disease must be measurable, with at least 1 measurable lesion by RECIST criteria, version 1.1
6. MCC expressing p53WT based on any CLIA or FDA approved test
7. Fresh or archival tumor tissue must be submitted for biomarker assessment. Archival tissue samples must have been obtained from biopsy performed = 2 years before the date of signing the informed consent for this study
8. Adequate hematological, hepatic, and renal function within 14 days prior to the first dose of KRT-232 as defined in more detail in the protocol
9. Agree to comply with contraception requirements as defined in more detail in the protocol |
1. Per la Coorte 1, il requisito è che i soggetti non abbiano risposto al trattamento con almeno un
inibitore di PD-1 o di PD-L1 per MCC metastatico
2. Per la Coorte 2, il requisito è che i soggetti non abbiano ricevuto alcun trattamento anti-PD-1 o
anti-PD-L1 per MCC metastatico
3. Adulti di età = 18 anni
4. Stato di validità secondo l’ECOG (Gruppo cooperativo orientale di oncologia) da 0 a 1.
5. MCC confermato istologicamente. La malattia deve essere misurabile, con almeno una lesione misurabile secondo i criteri RECIST, versione 1.1
6. MCC che esprime p53WT in base a un test approvato da CLIA o FDA
7. Presentazione di tessuto tumorale fresco o di archivio per la valutazione dei biomarcatori. I campioni di tessuto di archivio devono essere stati ottenuti da una biopsia eseguita = 2 anni prima della data della firma del consenso informato per questo studio
8. Funzione ematologica, epatica e renale adeguata nei 14 giorni che precedono la prima dose di KRT-232 come definito in modo più dettagliato nel protocollo
9. Accordo di rispettare i requisiti contraccettivi definiti in modo più dettagliato nel protocollo |
|
| E.4 | Principal exclusion criteria |
1. For Cohort 2, subjects must not have autoimmune disease, medical conditions requiring systemic immunosuppression, prior stem cell transplant, or active infection with HBV or HCV
2. Concurrent anticancer treatment such as chemotherapy, cytoreductive therapy, immune therapy, or cytokine therapy within 28 days or approximately 5 half-lives, whichever is shorter, prior to the first dose of KRT-232
3. Radiation therapy within 2 weeks prior to the first dose of KRT-232
4. Toxicity from prior radiation therapy that has not resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 0 or Grade 1 (with the exception of Grade 2 alopecia)
5. Participation in another interventional clinical trial within the past 4 weeks of the first dose of KRT 232 (participation in observational studies is permitted)
6. Patients previously treated with MDM2 antagonist therapies or p53-directed therapies
7. Women who are pregnant or breastfeeding
8. History of major organ transplant
9. Subjects with known central nervous system (CNS) metastases that are previously untreated
10. Uncontrolled intercurrent illness including, but not limited to, acute hepatitis A; known history of human immunodeficiency virus (HIV)-positive; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
11. Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute bacterial infections requiring antibiotic use should delay screening/ enrollment until the course of antibiotic therapy has been completed.
12. Other malignancy within the last 3 years, other than chronic lymphocytic leukemia (CLL), curatively
treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or
treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma. Patients with CLL must not in the opinion of the investigator require or be receiving any treatment for their CLL in order to be eligible.
13. Grade 2 or higher QTc prolongation (>480 milliseconds per NCI-CTCAE criteria, version 5.0) |
1. Per la Coorte 2, i soggetti non devono avere malattie autoimmuni, condizioni mediche che
richiedano l’immunosoppressione sistemica, precedente trapianto di cellule staminali o
infezione attiva da HBV o HCV
2. Terapia antitumorale concomitante come chemioterapia, terapia citoriduttiva,
immunoterapia o terapia con citochine entro 28 giorni o circa 5 emivite, a seconda del periodo
più breve, che precedono la prima dose di KRT-232
3. Radioterapia nelle 2 settimane che precedono la prima dose di KRT-232
4. Tossicità da precedente radioterapia non risolta di grado 0 o grado 1 secondo i Criteri
terminologici comuni per gli eventi avversi del National Cancer Institute (NCI-CTCAE) (ad eccezione dell’alopecia di grado 2)
5. Partecipazione a un altro studio clinico interventistico nelle ultime 4 settimane dalla
prima dose di KRT-232 (è consentita la partecipazione a studi osservazionali)
6. Pazienti precedentemente trattati con terapie antagoniste di MDM2 o terapie dirette contro
p53
7. Donne in gravidanza o in allattamento
8. Precedente trapianto di un organo maggiore
9. Soggetti con metastasi note al sistema nervoso
centrale (SNC) non trattate precedentemente
10. Malattia intercorrente non controllata tra cui, a
titolo esemplificativo: epatite A acuta;
anamnesi nota di positività al virus
dell’immunodeficienza umana (HIV); malattia
cardiaca clinicamente significativa (Classe III o
IV secondo la New York Heart Association);
insufficienza cardiaca congestizia sintomatica;
angina pectoris instabile; aritmia ventricolare; o
malattie psichiatriche/situazioni sociali che
limiterebbero il rispetto dei requisiti dello
studio
11. Soggetti con infezione batterica, fungina,
parassitaria o virale clinicamente significativa
che richieda terapia. I soggetti con infezioni
batteriche acute che richiedono l’uso di
antibiotici devono ritardare lo
screening/l’arruolamento fino al
completamento del corso della terapia
antibiotica.
12. Altra neoplasia negli ultimi 3 anni, diversa da
leucemia linfatica cronica (LLC), carcinoma
cutaneo a cellule basali o squamose trattato con
intento curativo, carcinoma in situ del collo
dell’utero, carcinoma prostatico non
metastatico confinato all’organo o trattato con
livelli normali di antigene prostatico specifico,carcinoma mammario in situ dopo completa
resezione chirurgica o carcinoma vescicale
superficiale a cellule transizionali. Per essere
idonei, i pazienti con LLC non devono,
secondo il parere dello sperimentatore,
richiedere alcun trattamento per la LLC o
essere al momento sottoposti a trattamento.
13. Prolungamento dell’intervallo QTc di grado 2 o superiore (>480 millisecondi, secondo la
versione 5.0 dei Criteri NCI-CTCAE) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Cohort 1 Part 1: Safety Review Committee (SRC) will determine recommended phase 2 dose (RP2D) for expansion based on safety and tolerability of each arm.
- Cohort 1 Part 2: Objective Response Rate (ORR) as assessed per RECIST criteria version 1.1
- Cohort 2 Part 1: Dose Limiting toxicity (DLT) will be used to establish the Maximum Tolerated Dose (MTD) of KRT-232 in combination with avelumab. SRC will determine the RP2D based on the safety of combination of KRT-232 with avelumab.
- Cohort 2 Part 2: ORR will be assessed per RECIST criteria version 1.1 |
-Parte 1 della Coorte 1: L’SRC determinerà la RP2D per l’espansione in base alla sicurezza e alla tollerabilità di ciascun braccio
-Parte 2 della Coorte 1:L’ORR sarà valutato secondo i criteri RECIST versione 1.1
-Parte 1 della Coorte 2: I casi di DLT saranno usati per stabilire la MTD di KRT-232 in combinazione con avelumab. L’SRC determinerà la RP2D in base alla sicurezza di KRT-232 in combinazione con avelumab
-Parte 2 della Coorte 2: L’ORR sarà valutato secondo i criteri RECIST versione 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Response Assessment: Response to KRT-232 treatment will be determined by the investigator according to RECIST criteria version 1.1. Target and non-target lesions will be assessed at Screening and followed throughout the study at protocol-specified time points. Response assessments will be performed at Week 5, Week 10, Week 15, Week 20, and thereafter every 5 weeks until disease progression. Response assessments should be performed at the specified time points independent of cycle visit or treatment modifications. |
| Valutazione della risposta: la risposta al trattamento con KRT-232 sarà determinata dallo sperimentatore secondo i criteri RECIST versione 1.1. Le lesioni target e non target saranno valutate allo Screening e seguite durante lo studio a intervalli di tempo specificati dal protocollo. Le valutazioni della risposta verranno eseguite alla Settimana 5, Settimana 10, Settimana 15, Settimana 20 e successivamente ogni 5 settimane fino alla progressione della malattia. Le valutazioni della risposta devono essere eseguite nei momenti specificati indipendentemente dalla cycle visit o dalle modifiche del trattamento. |
|
| E.5.2 | Secondary end point(s) |
- Median DoR (Kaplan-Meier estimate) among subjects who achieve a response from the first observation of response to disease progression or death.
- Median time from the first study dose to disease progression or death and landmark PFS rate (%)(Kaplan- Meier estimate)
- Median time from the first study dose to death (Kaplan-Meier estimate) and landmark survival rate (%)
- Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, and AEs that led to KRT-232 dose reductions, interruptions or discontinuations, AEs, serious AEs (SAEs), ECGs, vital signs
- KRT-232 and acyl glucuronide metabolite (M1) PK parameters, including but not limited to, maximum observed concentration (Cmax), minimum observed concentration (Cmin), area under the plasma concentration-time curve (AUC), and terminal elimination half-life (t1/2z) |
-DoR mediana (stima di Kaplan-Meier) tra i soggetti che raggiungono una risposta dalla prima
osservazione della risposta alla progressione della malattia o alla morte
-Tempo mediano fino alla progressione della malattia o alla morte e tasso di PFS limite (%)
(stima di Kaplan-Meier)
-Tempo mediano dalla prima dose dello studio alla morte (stima di Kaplan-Meier) e tasso di
sopravvivenza limite (%)
-Le analisi degli endpoint di sicurezza includeranno le seguenti misurazioni o valutazioni: esami obiettivi, analisi di laboratorio ed eventi avversi (EA) che portano a riduzioni della dose di KRT-232, interruzioni o sospensioni, EA, EA gravi (SAE), elettrocardiogrammi (ECG), parametri vitali
-Parametri PK di KRT-232 e del metabolita acil glucuronide (M1), compresi ma non limitati alla, concentrazione massima osservata (Cmax), concentrazione minima osservata (Cmin), area sotto la curva concentrazione plasmatica-tempo (AUC) ed emivita di eliminazione terminale (t1/2z) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
DoR: Time from documentation of response until disease progression
PFS: Time from initial treatment until disease progression
OS: Time from initial treatment until death
Vital signs: Day 1 of each cycle
ECOG performance status: Day 1 of each cycle as per ECOG performance status scale
ECG Triplicate: Cycle 1 Day 1, Cycle 3 Day 1, Cycle 6 Day 1, Cycle 9 Day 1, and every 3rd cycle thereafter (21 D Cycle)
ECG Trilplicate: Cycle 1 Day 1, Cycle 3 Day 1, Cycle 6 Day 1, and every 3rd cycle thereafter (28 D Cycle)
Hematology: Cycle 1, 2, and 3: Days 1, 8, 15, 22 (for 28 D Cycle); Cycle 4 and beyond on Day 1 of each cycle
AEs: Every visit
Blood for PK: At time points specified in Appendix I of protocol |
DoR: Time from documentation of response until disease progression
PFS: Time from initial treatment until disease progression
OS: Time from initial treatment until death
Vital signs: Day 1 of each cycle
ECOG performance status: Day 1 of each cycle as per ECOG performance status scale
ECG Triplicate: Cycle 1 Day 1, Cycle 3 Day 1, Cycle 6 Day 1, Cycle 9 Day 1, and every 3rd cycle thereafter (21 D Cycle)
ECG Trilplicate: Cycle 1 Day 1, Cycle 3 Day 1, Cycle 6 Day 1, and every 3rd cycle thereafter (28 D Cycle)
Hematology: Cycle 1, 2, and 3: Days 1, 8, 15, 22 (for 28 D Cycle); Cycle 4 and beyond on Day 1 of each cycle
AEs: Every visit
Blood for PK: At time points specified in Appendix I of protocol |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Studio di fase 1b/2 in aperto |
| Phase 1b/2, Open-Label Study |
|
| 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 | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| United States |
| France |
| Germany |
| Italy |
| Spain |
|
| 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 study will be considered complete 1 year after the last subject is enrolled in the study, at which time subjects who remain on study treatment will be evaluated for eligibility to enroll in a rollover study. |
Lo studio sarà considerato completo 1 anno dopo l’arruolamento dell’ultimo soggetto nello studio,
momento in cui i soggetti che proseguono il trattamento dello studio saranno valutati per l’idoneità ad arruolarsi in uno studio di rollover. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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