Clinical Trials Register

Summary
EudraCT Number:	2020-002820-35
Sponsor's Protocol Code Number:	KRT-232-103
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2022-04-21
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2020-002820-35

A.3

Full title of the trial

A Phase 1b/2, Open-Label Study Evaluating the Safety and Efficacy of KRT-232 in Patients with p53 Wild Type (p53WT) Merkel Cell Carcinoma (MCC) Who Have Failed Anti-PD-1 or Anti-PD-L1 Immunotherapy, or in Combination with Avelumab in MCC Patients who are Anti-PD-1 or Anti-PD-L1 Treatment Naïve

Estudio de fase Ib/II abierto para evaluar la seguridad y la eficacia de KRT-232 en pacientes con carcinoma de células de Merkel (CCM) que expresan p53 de tipo natural (p53WT) en los que ha fracasado la inmunoterapia con anti-PD-1 o anti-PD-L1, o en combinación con avelumab en pacientes con CCM que no han recibido tratamiento con anti-PD-1 o anti-PD-L1.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study Evaluating the Safety and Efficacy of KRT-232 in Patients with p53 Wild-Type (p53WT) Merkel Cell Carcinoma (MCC) Who Have Failed Anti-PD-1 or Anti-PD-L1 Immunotherapy, or in Combination with Avelumab in MCC Patients who are Anti-PD-1 or Anti-PD-L1 Treatment Naïve

A.4.1

Sponsor's protocol code number

KRT-232-103

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03787602

A.5.4

Other Identifiers

Name:

IND Number

Number:

115894

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Kartos Therapeutics, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Kartos Therapeutics, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Kartos Therapeutics, Inc.
B.5.2	Functional name of contact point	Clinical Operations- Josh Martino
B.5.3	Address:
B.5.3.1	Street Address	275 Shoreline Drive
B.5.3.2	Town/ city	Redwood City
B.5.3.3	Post code	CA 94065
B.5.3.4	Country	United States
B.5.4	Telephone number	+16505420136
B.5.6	E-mail	jmartino@kartosthera.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	KRT-232
D.3.2	Product code	KRT-232 (formerly AMG-232)
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	KRT-232
D.3.9.2	Current sponsor code	KRT-232
D.3.9.3	Other descriptive name	AMG 232
D.3.9.4	EV Substance Code	SUB123933
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	KRT-232
D.3.2	Product code	KRT-232 (formerly AMG-232)
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	KRT-232
D.3.9.2	Current sponsor code	KRT-232
D.3.9.3	Other descriptive name	AMG 232
D.3.9.4	EV Substance Code	SUB123933
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Bavencio
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Bavencio (Avelumab)
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AVELUMAB
D.3.9.1	CAS number	1537032-82-8
D.3.9.4	EV Substance Code	SUB180078
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

p53 Wild-Type (p53WT) Merkel Cell Carcinoma (MCC)

p53 Wild-Type (p53WT) Merkel Cell Carcinoma (MCC

E.1.1.1

Medical condition in easily understood language

Merkel Cell Carcinoma (MCC)

carcinoma de células de Merkel (CCM) p53WT

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.1.3

Condition being studied is a rare disease

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

- Cohorte 1 Parte 1: Para determinar la dosis recomendada de KRT-232 de fase 2 (RP2D)
- Cohorte 1 Parte 2: Determinar la tasa de respuesta objetiva (ORR) en sujetos con p53WT MCC que han fallado en la inmunoterapia anti-PD-1 o anti-PD-L1
- Cohorte 2 Parte 1: Determinar el KRT-232 RP2D en combinación con avelumab
- Cohorte 2 Parte 2: Determinar la tasa de respuesta objetiva (ORR) en sujetos sin tratamiento previo con p53WT MCC

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

- Para determinar la duración de la respuesta (DoR)- Para determinar la supervivencia libre de progresión (SLP)- Para determinar la supervivencia general (OS)- Para determinar la seguridad y tolerabilidad de KRT-232- Para determinar el perfil farmacocinético / farmacodinámico (PK / PD) de KRT-232

E.2.3

Trial contains a sub-study

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. Para la cohorte 1, los sujetos con CCM metastásico deben haber recibido sin éxito tratamiento con al menos un inhibidor de PD-1 o un inhibidor de PD-L1.
2. Para la cohorte 2, los sujetos no deben haber recibido ningún tratamiento con anti-PD-1 o anti-PD-L1 para el CCM metastásico.
3. Adultos de al menos 18 años.
4. Estado funcional del ECOG de 0 o 1.
5. CCM confirmado mediante histología. La enfermedad debe ser mensurable y tener como mínimo una lesión mensurable conforme a los criterios RECIST, versión 1.1 (Eisenhauer 2009, Apéndice 3).
6. CCM que expresa p53WT tomando como base cualquier análisis aprobado por la CLIA o la FDA.
7. Se debe contar con tejido tumoral en fresco o de archivo para la evaluación de los biomarcadores. Las muestras tisulares de archivo deben haberse obtenido de una biopsia realizada ≤2 años antes de la fecha de firma del consentimiento informado para este estudio.
8. Función hematológica, hepática y renal adecuada en los 14 días anteriores la primera dosis de KRT-232
9. Acceder a cumplir con los requisitos de anticoncepción como se define con más detalle en el protocolo

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. Para la Cohorte 2, los sujetos no deben tener enfermedad autoinmune, condiciones médicas que requieran inmunosupresión sistémica, trasplante previo de células madre o infección activa con VHB o VHC2. Tratamiento concomitante contra el cáncer, como quimioterapia, terapia citorreductora, inmunoterapia o terapia con citocinas dentro de los 28 días o aproximadamente 5 vidas medias, lo que sea más corto, antes de la primera dosis de KRT-2323. Radioterapia dentro de las 2 semanas previas a la primera dosis de KRT-2324. Toxicidad de la radioterapia previa que no se resolvió según los Criterios de terminología común del Instituto Nacional del Cáncer para eventos adversos (NCI-CTCAE) Grado 0 o Grado 1 (con la excepción de la alopecia de grado 2)5. Participación en otro ensayo clínico intervencionista dentro de las últimas 4 semanas de la primera dosis de KRT 232 (se permite la participación en estudios observacionales)6. Pacientes tratados previamente con terapias antagonistas de MDM2 o terapias dirigidas a p537. Mujeres embarazadas o en periodo de lactancia.8. Historia del trasplante de órganos mayores.9. Sujetos con metástasis conocidas del sistema nervioso central (SNC) que no fueron tratadas previamente10. Enfermedad intercurrente no controlada que incluye, entre otras, hepatitis A aguda; historia conocida del virus de inmunodeficiencia humana (VIH) positivo; enfermedad cardíaca clínicamente significativa (New York Heart Association Clase III o IV); insuficiencia cardíaca congestiva sintomática; angina de pecho inestable; arritmia ventricular; o enfermedades psiquiátricas / situaciones sociales que limitarían el cumplimiento de los requisitos del estudio11. Sujetos con infección bacteriana, fúngica, parasitaria o viral clínicamente significativa que requiere terapia. Los sujetos con infecciones bacterianas agudas que requieren el uso de antibióticos deben retrasar la detección / inscripción hasta que se haya completado el curso de la terapia con antibióticos.12. Otra neoplasia maligna en los últimos 3 años, que no sea leucemia linfocítica crónica (CLL), curativamentecáncer de piel de células basales o de células escamosas tratado, carcinoma in situ del cuello uterino, confinado a órganos ocáncer de próstata no metastásico tratado con antígeno prostático específico normal, carcinoma de mama in situ después de resección quirúrgica completa o carcinoma de vejiga de células transicionales superficiales. Los pacientes con CLL no deben, en opinión del investigador, requerir o recibir ningún tratamiento para su CLL para ser elegibles.13. Prolongación QTc de grado 2 o superior (> 480 milisegundos según los criterios de NCI-CTCAE, versión 5.0)

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

Cohorte 1, parte 1: determinar la DRF2 de KRT-232
Cohorte 1, parte 2: determinar la tasa de respuesta objetiva (TRO) en sujetos con CCM p53WT en quienes ha fracasado la inmunoterapia con anti-PD-1 o anti-PD-L1.
Cohorte 2, parte 1: determinar la DRF2 de KRT-232 en combinación con avelumab.
Cohorte 2, parte 2: determinar la tasa de respuesta objetiva (TRO) en sujetos aquejados de CCM p53WT sin tratamiento previo.

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.

Evaluación de la respuesta: el investigador determinará la respuesta al tratamiento KRT-232 de acuerdo con los criterios RECIST versión 1.1. Las lesiones objetivo y no objetivo se evaluarán en el cribado y se seguirán durante todo el estudio en los puntos de tiempo especificados por el protocolo. Las evaluaciones de respuesta se realizarán en la semana 5, semana 10, semana 15, semana 20 y posteriormente cada 5 semanas hasta la progresión de la enfermedad. Las evaluaciones de respuesta deben realizarse en los puntos de tiempo especificados, independientemente de la visita al ciclo o las modificaciones del tratamiento.

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)

- Mediana DoR (estimación de Kaplan-Meier) entre los sujetos que logran una respuesta desde la primera observación de respuesta a la progresión de la enfermedad o la muerte.- Tiempo medio desde la primera dosis del estudio hasta la progresión de la enfermedad o la muerte y la tasa histórica de SLP (%) (estimación de Kaplan-Meier)- Tiempo medio desde la primera dosis del estudio hasta la muerte (estimación de Kaplan-Meier) y tasa de supervivencia histórica (%)- Los análisis de los puntos finales de seguridad incluirán las siguientes mediciones o evaluaciones: físicasexámenes, pruebas de laboratorio y EA que condujeron a reducciones de dosis de KRT-232, interrupciones o interrupciones, EA, EA graves (SAE), ECG, signos vitales- Parámetros PK de KRT-232 y metabolito de acil glucurónido (M1), que incluyen, entre otros, máximoconcentración observada (Cmax), concentración mínima observada (Cmin), área bajo la curva de concentración plasmática-tiempo (AUC) y semivida de eliminación terminal (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 Triplicate: 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

DdR: tiempo desde la documentación de la respuesta hasta la progresión de la enfermedad
SSP: tiempo desde el tratamiento inicial hasta la progresión de la enfermedad
SG: tiempo desde el tratamiento inicial hasta la muerteSignos vitales: día 1 de cada cicloEstado de rendimiento de ECOG: Día 1 de cada ciclo según la escala de estado de rendimiento de ECOGTriplicado de ECG: Ciclo 1 Día 1, Ciclo 3 Día 1, Ciclo 6 Día 1, Ciclo 9 Día 1, y cada 3er ciclo a partir de entonces (Ciclo 21 D)Triplicado de ECG: Ciclo 1 Día 1, Ciclo 3 Día 1, Ciclo 6 Día 1, y cada 3er ciclo a partir de entonces (Ciclo 28 D)Hematología: ciclo 1, 2 y 3: días 1, 8, 15, 22 (para el ciclo 28 D); Ciclo 4 y más allá en el día 1 de cada cicloEA: cada visitaSangre para PK: en los puntos de tiempo especificados en el Apéndice I

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

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

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase 1b/2

Fase 1b/2

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

estudio abierto/Fase Ib/2

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

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

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.

El estudio se considerará completo 1 año después de que el último sujeto se haya inscrito en el estudio, momento en el cual se evaluará la elegibilidad de los sujetos que permanecen en el tratamiento del estudio para inscribirse en un estudio de reinversión.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

104

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subjects who achieve a response (CR or PR by RECIST criteria version 1.1) will be followed until disease progression, regardless of whether they are on study drug treatment or not. Subjects who stop KRT-232 and start on a new anti-MCC therapy will no longer be followed for efficacy outcomes and will enter long-term follow-up for survival only.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-12-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-16

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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