| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced or metastatic solid tumours and haematological malignancies |
| Tumores sólidos avanzados o metastásicos y neoplasias malignas |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced or metastatic (spread from a part of the body to another) solid tumours (abnormal malignant mass of tissue) and haematological malignancies (blood cancer) |
tumores sólidos (masas de tejido anormal maligno) avanzados o
metastásicos (se extienden de una parte del cuerpo a otra) y neoplasias malignas (cáncer sanguíneo) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066476 |
| E.1.2 | Term | Haematological malignancy |
| 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 |
Phase I, Part A - Dose Escalation
• determine the MTD or RP2D of CB-103 as a single agent when administered orally and with repeat dosing to adult patients with advanced or metastatic solid tumours and haematological malignancies, who have progressed despite curative therapy or for whom no curative therapy exists
Phase IIA, Part B - Expansion
• assess preliminary anti-tumour, anti-lymphoma and anti-myeloma activity of single agent CB-103 when administered orally and with repeat dosing in the different expansion arms across the different indications |
Fase I, Parte A — Escalamiento de la dosis:
•Determinar la dosis máxima tolerada (MTD, por sus siglas en inglés) o
la dosis de fase 2 recomendada (RP2D, por sus siglas en inglés) de CB-
103 como agente único cuando se administra por vía oral y con dosis
repetidas a pacientes adultos con tumores sólidos avanzados o
metastásicos y neoplasias hematológicas, que han progresado a pesar
del tratamiento curativo o para quienes no existe tratamiento curativo.
Fase IIA, Parte B — Expansión:
•Evaluar la actividad preliminar antitumoral, antilinfoma y antimieloma
del agente único CB-103 cuando se administra por vía oral y con dosis
repetidas en los diferentes grupos de expansión en las distintas
indicaciones |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives - part A&B
• characterise the PK characteristics of CB-103 in patients after single and repeated administration at various dose levels
Secondary objectives - Part A only
• characterise safety and tolerability of the MTD/RP2D of CB-103 in patients with selected solid tumours and haematological malignancies
• assess preliminary anti-tumour, anti-lymphoma and anti-myeloma activity of single agent CB-103 when administered orally and with repeat dosing
Secondary objectives - part B only
• characterise safety and tolerability of the MTD/RP2D of CB-103 in patients with selected solid tumours and haematological malignancies, stratified into separate expansion arms for the respective indications and with tumours characterised by genetic alterations and activation of the NOTCH pathway
Exloratory objectives
• explore potential correlations of PK, biomarkers, PD (genes/proteins) with safety and efficacy parameters in tissue samples (tumour, blood, hair follicles) |
•Solo la Parte A:
oCaracterizar la seguridad y tolerabilidad de la MTD/RP2D de CB-103 en
los pacientes con tumores sólidos y neoplasias hematológicas
seleccionados.
oEvaluar la actividad antitumoral, antilinfoma y antimieloma preliminar
del agente único CB-103 cuando se administra por vía oral y con dosis
repetidas.
•Solo la Parte B:
oCaracterizar la seguridad y tolerabilidad de la MTD/RP2D de CB-103 en
los pacientes con tumores sólidos y neoplasias hematológicas
seleccionados, clasificados en grupos de expansión separados para las
indicaciones respectivas y con tumores caracterizados por alteraciones
genéticas y activación de la señalización NOTCH.
Objetivos exploratorios
• explorar las posibles correlaciones de PC, biomarcadores, PD
(genes/proteínas) con parámetros de seguridad y efectividad en
muestras de tejido (tumor, sangre, folículos pilosos) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Disease
a.Patients with histologically or cytologically confirmed solid tumours that are surgically unresectable, locally advanced, or metastatic and whose disease has progressed on at least one line of systemic therapy and for whom no standard curative therapy exists
b.The following solid tumour indications are allowed to be enrolled into Part A:
•Breast cancer (TNBC, ER+/-, HER2+/-), gastrointestinal (GI) cancers (colorectal cancer, CCC, gastric cancer), ovarian cancer, cervical cancer, prostate cancer, NSCLC (lung adenocarcinoma), melanoma, sarcomas (osteosarcoma, liposarcoma, rhabdomyosarcoma, fibrosarcoma), desmoid tumours, adenoid cystic carcinoma, and glioblastoma multiforme (GBM)
c.Patients with histologically or cytologically confirmed, advanced haematological malignancies whose disease has relapsed or progressed upon standard therapy and for whom at that point no standard therapy exists:
•Hodgkin lymphoma (HL)
•Non-Hodgkin lymphomas (NHL): Follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma, marginal zone B-cell lymphoma (MZCL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma MCL), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), CNS lymphoma
•Multiple myeloma (MM)
Specific criteria per type of lymphoma:
•HL: relapsed/refractory to at least two lines of treatment, among which includes brentuximab vedotin
•B-cell NHL: relapsed/refractory upon at least one line of chemo-immunotherapy, no standard therapy available
•T-cell NHL: relapsed/refractory upon at least one line of chemotherapy, no standard curative therapy available
Specific criteria for multiple myeloma:
•Relapsed/refractory to at least two lines of therapy, including both a proteasome inhibitor and an immunomodulatory agent (IMiD), and no standard alternative therapy available
d.Solid tumours: ≥1 measurable lesion according to RECIST v1.1 guideline for solid tumours
e.Lymphomas: ≥1 measurable lesion according to The Lugano Classification
f.Multiple myeloma: must have measurable disease (serum M-protein ≥ 10 g/L or urine M-protein ≥ 200 mg/24 hours or abnormal free light chain (FLC) ratio with involved FLC > 100 mg/L) or proven plasmacytoma by biopsy)
g.Patients in Part B: must have tumours characterised by activation of the NOTCH signalling pathway. All patients should have sufficient archival biopsy tissue not older than 6 months prior to pre-screening (or if not available-a fresh tumour biopsy must be taken)
h.Patients in Part B: willing to provide a fresh pre-dose and, if feasible, on-treatment and an EOT tumour biopsy
i.Patients in Part A: must have sufficient archival tumour tissue samples not older than 6 months prior to screening (or if not available a fresh pre-dose tumour biopsy)
2.Demography
a.Men and women ≥ 18 years old on the day of signing informed consent
b.ECOG performance status 0 or 1
c.Patients able and willing to swallow capsules
3.Organ function and laboratory results
Patients must have the following laboratory values (obtained within 14d of enrolment):
a.ANC ≥ 1.5x10^9/L (solid tumour indications) or ≥ 1.0x10^9/L (haematological malignancies)
b.Haemoglobin (Hgb) ≥ 10 g/dL (≥ 100 g/L)
c.Platelet count ≥ 75 x 109/L (no platelet transfusion or growth factor support in the preceding 7d)
d.Total serum bilirubin ≤ 1.5xULN
e.ALP, AST/SGOT and ALT/SGPT ≤ 2.5xULN (if abnormalities are due to the underlying malignancy and known hepatic metastases, AST and ALT must be ≤ 5xULN)
f.Serum creatinine ≤ 1.5xULN (if serum creatinine > 1.5xULN, then serum creatinine clearance (CrCl) ≥ 50 mL/min
g to j: Potassium, Total calcium (corrected for serum albumin), Magnesium and Phosphorus levels: within normal limits or correctable with supplements
k.Serum albumin concentration ≥ 30 g/L
l.Serum amylase and serum lipase ≤ ULN
m.PTT ≤ 1.5 x ULN and INR ≤ 1.3 (unless receiving therapeutic anticoagulants)
4.Contraceptive measures
a.Women of childbearing potential (serum or urine pregnancy test performed within 7d before start of treatment, negative result must be documented)
b.Women of childbearing potential and men must agree to use at least two highly effective forms of contraception throughout the entire clinical trial period and for 90d post-treatment completion
c.Men whose partners could be of childbearing potential must routinely use a condom throughout the clinical trial period and for 90d post-treatment completion. The partner should also use a reliable form of contraception
d.Azoospermic males and females with sterilisation are exempt
e.Women who are continuously not heterosexually active are exempt (must still undergo pregnancy testing)
5.Informed consent
a.Ability to understand the patient information and ICF and comply with the protocol-related procedures
b.Signed and dated written informed consent obtained prior to performing any study-related procedure, including pre-screening (part B only) and screening |
| Enfermedad:Pacientes con tumores sólidos confirmados histológica o citológicamente que no pueden extirparse mediante cirugía,son localmente avanzados o metastásicos y cuya enfermedad ha progresado en por lo menos una línea de tratamiento sistémico y para quienes no existe un tratamiento curativo estándar.Se permite incorporar las siguientes indicaciones de tumores sólidos en la ParteA de este estudio:Cáncer de mamaTNBC,ER+/-,HER2+/-,GI(cáncer colorrectal,CCC)cáncer gástrico,cáncer de ovario,cáncer de cuello de útero,cáncer de próstata,NSCLC;adenocarcinoma de pulmón,melanoma,sarcomas(osteosarcoma,liposarcoma,rabdomiosarcoma, fibrosarcoma)tumores desmoides,carcinoma adenoide quístico y GBM.Pacientes con neoplasias hematológicas avanzadas,confirmadas histológica o citológicamente)cuya enfermedad ha recaído o progresado con el tratamiento estándar y para quienes no existe tratamiento estándar en dicho punto:HL,NHL,FL,DLBCL,linfoma de Burkitt,MZCL,SMZL,MCL,PTCL,ALCL,linfoma del SNC,MM.Criterios específicos por tipo de linfoma:HL:en recaída/refractario a por lo menos dos líneas de tratamiento,entre los que se incluye brentuximab vedotin.NHL de Cél-B:en recaída/refractario con por lo menos una línea de quimioinmunoterapia,sin tratamiento estándar disponible.NHL de Cél-T:en recaída/refractario con por lo menos una línea de quimioterapia,sin tratamiento curativo estándar disponible.Criterios específicos para mieloma múltiple:En recaída/refractario a por lo menos dos líneas de tratamiento,incluido tanto un IMiD,y sin tratamiento alternativo estándar disponible.Los pacientes con tumores sólidos deben tener al menos una lesión mensurable(al menos1cm de diámetro)de acuerdo con la pauta de RECIST,v1.1 para tumores sólidos.Los pacientes con linfomas deben tener al menos una lesión mensurable(al menos1,5cm de diámetro)de acuerdo con la“Clasificación de Lugano”para los linfomas.Los pacientes con mieloma múltiple deben tener una enfermedad mensurable(proteína M sérica≥10g/l o proteína M en orina≥200 mg/24h o relación anormal de la FLC,con FLC>100 mg/l involucrado)o plasmocitoma probado mediante biopsia).Solo para los pacientes de la ParteB:los pacientes deben tener tumores caracterizados por la activación de la vía de señalización NOTCH.Todos los pacientes deben tener suficiente tejido de biopsia archivado que no tengan más de 6meses de antigüedad antes de la preselección(o,si no está disponible,se debe tomar una nueva biopsia del tumor).Solo para los pacientes de la ParteB:dispuestos a proporcionar una nueva biopsia del tumor previa a la dosis y,si fuese factible, en el tto y al FdT.Los pacientes de la ParteA deben tener suficientes muestras de tejido tumoral archivadas que no tengan más de 6 meses de antigüedad antes de la selección o,si no estuviesen disponibles, una nueva biopsia del tumor previa a la dosis.Demografía:Hombres y mujeres≥18 años de edad a la fecha de firmar el consentimiento informado-Calidad de vida del paciente según el ECOG,0 o 1.Pacientes capaces y dispuestos a tragar cápsulas.Función de los órganos y resultados de laboratorio:Los pacientes deben tener los siguientes valores de laboratorio (obtenidos dentro de los 14 días de la incorporación):RAN≥1,5x109/l(indicaciones de tumores sólidos)y ≥1,0x109/l(neoplasias hematológicas).Hgb≥10 g/dl(≥100g/l).RP≥75x109/l(sin transfusión de plaquetas ni soporte del factor de crecimiento en los 7 días anteriores).Bilirrubina sérica total≤1,5xULN.ALP,AST/SGOT y ALT/SGPT≥2,5xULN.CS≥1,5xULN;o si la CS≥5xULN,entonces el CrCl≥50 ml/min.Niveles de K,Ca(corregidos en función de la albúmina sérica),niveles de Mg y P dentro de los límites normales o corregibles con suplementos. [albúmina sérica]≥30g/l.Amilasa sérica y lipasa sérica≤ULN.PTT≤1,5xULN e INR≤1,3(a menos que el paciente esté recibiendo anticoagulantes terapéuticos).Medidas anticonceptivas:Las mujeres en edad fértil deben someterse a una prueba de embarazo en suero u orina dentro de un máximo de 7 días antes del inicio del tratamiento, y un resultado negativo debe documentarse antes del inicio del tratamiento.Las mujeres en edad fértil y los hombres deben aceptar usar al menos dos formas anticonceptivas altamente eficaces durante 90 días después del tratamiento.Los hombres cuyas parejas puedan estar en edad fértil deben utilizar rutinariamente un condón durante todo el período del ensayo clínico y durante 90 días después de la finalización del tratamiento.La pareja también debe utilizar una forma confiable de anticoncepción.Los hombres y mujeres azoospérmicos con esterilización están exentos de los requisitos anticonceptivos.Las mujeres capaces de quedar embarazadas que no sean continua ni heterosexualmente activas están exentas.CI:Capacidad para entender la información del paciente y e ICF y cumplir con los procedimientos relacionados con el protocolo.CI por escrito, firmado y fechado, obtenido antes de realizar cualquier procedimiento relacionado con el estudio, incluidas la preselección(solo parteB)y la selección |
|
| E.4 | Principal exclusion criteria |
1.Medical History
a.Patients with symptomatic CNS metastases (neurologically unstable or requiring increasing doses of steroids to control their CNS disease)
b.Hypersensitivity to any of the excipients of CB-103
c.Patients with unresolved nausea, vomiting, or diarrhoea of CTCAE grade > 1
d.Impairment of GI function or presence of GI disease that may significantly alter the absorption of CB-103
e.History of second or other primary cancer with the exception of
•Curatively treated non-melanomatous skin cancer
•Curatively treated cervical cancer or breast carcinoma in situ
•Other primary solid tumour treated with curative intent and no known active disease present and no treatment administered during the last 2 years
2.Exclusionary concurrent medical conditions
a.Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
1.Clinically significant cardiac disease including congestive heart failure (NYHA class III or IV), arrhythmia or conduction abnormality requiring medication, or cardiomyopathy
2.Clinically uncontrolled hypertension (blood pressure > 160/110 mmHg)
3.Complete left bundle branch block
4.Right bundle branch block + left anterior hemiblock
5.Mandatory use of a cardiac pacemaker
6.Congenital long QT syndrome
7.History or presence of sustained or symptomatic ventricular tachyarrhythmia
8.Presence of unstable atrial fibrillation (ventricular response > 110 bpm)
9.Clinically significant resting bradycardia (< 50 bpm)
10.Corrected QTcF > 450 ms for males and > 470 ms for females at the screening ECG
11.QRS ≥ 110 ms
12.History of symptomatic congestive heart failure
13.LVEF < 50%. History of absolute decrease in LVEF of ≥ 15 absolute %, or ≥ 10 absolute % and crossing from > LLN to < LLN on prior anti-HER2 therapy, even if asymptomatic
14.Angina pectoris ≤ 6 months prior to starting CB-103
15.Acute myocardial infarction ≤ 6 months prior to starting CB-103
b.General conditions or other clinically significant diseases, including any one of the following:
1.Haemorrhagic, embolic, or thrombotic stroke within 6 months prior to the first planned CB-103 infusion
2.Prior allogeneic bone marrow/haematopoietic stem cell transplant
3.Autologous haematopoietic stem cell transplant ≤ 6 months prior to starting study drug
4.Known infection with HIV or hepatitis B or C requiring treatment
5.Any active infection requiring the use of parenteral anti-microbial agents or > Grade 2
6.Non-malignant interstitial lung disease or pneumonitis
7.Dyspnoea of any cause requiring supplemental oxygen therapy and dyspnoea at rest due to complications of advanced malignancy and co-morbidities
8.Significant traumatic injury or major surgery within 14d of scheduled dosing day 1
9.Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol
3.Prior Therapy
a.Cytotoxic chemotherapy within 3 weeks (6 weeks for nitrosoureas and mitomycin C) of scheduled first dose of CB-103 on day 1
b.Prior cumulative doxorubicin exposure of ≥ 450 mg/m2
c.Prior cumulative epirubicin exposure of ≥ 900 mg/m2
d.Any investigational treatment within 4 weeks of scheduled CB-103 dosing day 1.
e.Prior treatment with any NOTCH signalling inhibitor compound
f.Concurrent enrolment in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo
g.Radiation therapy within 2 weeks of scheduled CB-103 dosing day 1, unless the radiation comprised a limited field to non-visceral structures
h.Immunotherapy (including interferons, interleukins, immune-conjugates, immune checkpoint inhibitors), biological therapies (including monoclonal antibodies, antibody drug conjugates or other engineered proteins), targeted small molecules (including but not limited to kinase inhibitors), hormonal therapies within 3 weeks of scheduled CB-103 dosing day 1
i.Unresolved toxicity CTCAE grade > 1 from previous anti-cancer therapy or radiotherapy (excluding neurotoxicity, alopecia, ototoxicity, lymphopenia), or incomplete recovery from previous surgery, unless agreed by Cellestia and the Principal Investigator and documented
4.Current medications
a.Drugs which prolong QT interval
b.Acid reducing agents
c.Patients receiving warfarin and phenytoin that cannot be discontinued at least one week prior to start of treatment with CB-103 and for the duration of the study
d.Anticoagulants: Patients receiving coumarin-type anticoagulants who cannot discontinue at least one week prior to start of treatment and for the duration of the study. Low molecular weight heparin and direct oral anticoagulants are permitted
5.Demography
a.Patients who are pregnant or breast feeding
6.Others
a.Patients who are unable or unwilling to comply with all study requirements for clinical visits, examinations, tests, and procedures |
| Antec.médicos:Pacientes con metástasis sintomáticas del SNC que están neurológicamente inestables o que requieren dosis crecientes de esteroides para controlar su enf.del SNC.Hipersensibilidad a alguno de los excipientes del fármaco terminado CB-103.Pacientes con náuseas,vómitos o diarrea no resueltos de los CTCAE grado>1.Deterioro de la función GI o presencia de enf.GI que puede alterar significativamente la absorción de CB-103.Antec.del2ºu otro cáncer primario con la excepción de:C.de piel no melanomatoso tratado con curación,C.de cuello uterino o carcinoma de mama in situ tratados con curación,Otros tumores sólidos primarios tratados con intención curativa y sin enf.activa conocida presente y sin tto administrado durante los últimos2años.Afecciones médicas concurrentes de exclusión:Func.ardíaca deteriorada o enf.cardíacas clínicamente significativas,incluidas cualquiera de las siguientes:Enf.cardíaca clínicamente significativa que incluye insuficiencia cardíaca congestiva(claseIII o IV de la NYHA)arritmia o anormalidad de conducción que requieren medicamentos,o cardiomiopatía.Hipertensión clínicamente no controlada(PA>160/110mmHg)Bloqueo completo de la rama izq.del haz.Bloqueo de la rama der.del haz+hemibloqueo anterior izquierdo.Uso obligatorio de un marcapasos cardíaco.Sínd.congénito del QT largo.Antec. o presencia de taquiarritmia ventricular sostenida o sintomática.Presencia de FA inestable(respuesta ventricular>110latidos bpm)Bradicardia en reposo clínicamente significativa(<50bpm)IntervaloQT corregido con la F.de Fridericia(QTcF)>450ms para los hombres y >470ms para las mujeres en el ECG de selección.QRS≥110ms.Antec.de ICC sintomática.LVEF<50%.Antec. de disminución absoluta de la LVEF≥15puntos%absolutos,o ≥10puntos%absolutos y cruce de>LLN a<LLN en el tto previo anti-HER2,incluso si es asintomático.Angina de pecho≤6meses antes de iniciar el fármaco del estudio.MI≤6meses antes de iniciar el fármaco del estudio.Afecciones generales u otras enf.clínicamente significativas,que incluyen alguna de las siguientes:AVC hemorrágico,embólico o trombótico dentro de los 6meses previos a la1ªinfusión deCB-103planificada.Trasplante alógeno previo de médula ósea/cél.madre hematopoyéticas.Trasplante autógeno de cél.madre hematopoyéticas≤6meses antes de iniciar el fármaco del estudio.Infección conocida por el VIH;o,hepatitisBoC que requiere tto.Cualquier infección activa que requiere el uso de Ag.antimicrobianos parenterales o que es>Grado2.Enf.pulmonar intersticial no maligna o neumonitis.Disnea de cualquier causa que requiera oxigenoterapia complementaria y disnea en reposo debido a complicaciones de neoplasias malignas avanzadas y comorbilidades.Lesiones traumáticas significativas o cirugía mayor dentro de los 14 días del Día1 de la pauta posológicas.Otras afecciones médicas graves o incontroladas simultáneas que puedan causar riesgos de seguridad inaceptables o comprometer el cumplimiento del protocolo.Tto previo:Quimio citotóxica dentro de las 3semanas(6semanas para nitrosoureas y mitomicinaC)de la1ªpauta posológica de CB-103 el Día1.Exposición acumulada previa a doxorrubicina≥450mg/m2.Exposición acumulada previa a epirubicina≥900mg/m2.Cualquier tto de investigación dentro de las 4semanas de la posología de CB-103 el Día1.Tto previo con algún compuesto inhibidor de señalización NOTCH.Incorporación simultánea en otro ensayo clínico terapéutico que implique un tto continuo con cualquier producto en investigación o comercializado o placebo.Radio dentro de las 2semanas de la posología de CB-103 el Día1,a menos que la radiación incluyera un campo limitado a estructuras no viscerales (ej.metástasis ósea en extremidad).Inmunoterapia(incluye interferones,ILs,inmunoconjugados, inhibidores de puntos de control inmunes),terapias biológicas (incluyen Ac monoclonales, conjugados Ac-fármaco u otras proteínas modificadas),moléculas pequeñas dirigidas (que incluyen por ejemplo, inhibidores de quinasa),terapias hormonales dentro de las 3 semanas de la pauta posológica de CB-103 el Día1.CTCAE de toxicidad no resuelta grado>1 del tto anticáncer o radio previos (que excluyen neurotoxicidad, alopecia,ototoxicidad,linfopenia), o recuperación incompleta de una cirugía anterior, a menos que lo acuerden Cellestia y el IP y se documente.Medicamentos actuales:Fármacos que prolongan el intervalo QT.Agentes reductores de ácidos.Pacientes que reciben warfarina y fenitoína que no pueden interrumpirseal menos una semana antes del inicio del tto con CB-103 y durante el período del estudio.Anticoagulantes: Pacientes que reciben anticoagulantes de tipo cumarínico que no pueden interrumpir al menos una semana antes del inicio del tto y durante el período del estudio.Se permiten heparina de BPM y anticoagulantes orales directos.Demografía:Pacientes que están embarazadas o amamantando.Otros:Pacientes que no pueden o no están dispuestos a cumplir con todos los requisitos del estudio para las visitas clínicas,los exámenes,análisis y procedimientos |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I, Part A
• The number of patients experiencing dose-limiting toxicity (DLT) during the first 28 day cycle of CB-103 treatment
Phase IIA, Part B
• To assess tumour response rates in each expansion arm:
‒ For solid tumour indications: to assess best overall response rate (complete response [CR] + partial response [PR]), assessed by Response Evaluation Criteria in Solid Tumours (RECIST 1.1)
‒ For Hodgkin and non-Hodgkin lymphomas: to assess best overall response rate (CR + PR), assessed by Lugano Lymphoma classification
‒ For multiple myeloma: to assess best overall response rate (stringent complete response [sCR] + CR + very good partial remission [VGPR] + PR), assessed by International Myeloma Working Group (IMWG) uniform response criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I, Part A
Cyc1 d1, 2, 3, 8, 9, 15 & 22
Phase IIA, Part B
baseline, Cyc2 d15, after cycle 2 every 8 weeks until EOT or disease progression/overall survival, EoT |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints - part A and B:
• The incidence rate, severity and relationship to CB-103 of adverse drug reactions and serious drug reactions according to common terminology criteria for adverse events (CTCAE) V4.03, safety laboratory, vital signs, ECG and ECHO/MUGA assessments in each dose group and expansion arm.
• CB-103 plasma concentrations, PK parameters: Cmax, tmax, area under the curve (AUC) during 8 and 24 hours (AUC0 8, AUC0 24), AUC from time 0 extrapolated to infinite time (AUC0-∞), apparent volume of distribution (Vd/F), apparent volume of distribution at steady (Vss/F), apparent clearance after oral administration (CL/F), t1/2 and AR.
Secondary endpoints - part A:
• to assess tumour response rates
‒ For solid tumour indications: to assess best overall response rate (CR + PR), assessed by RECIST 1.1.
‒ For Hodgkin and non-Hodgkin lymphomas: to assess best overall response rate (CR + PR), assessed by Lugano Lymphoma classification
‒ For multiple myeloma: to assess best overall response rate (sCR + CR + VGPR + PR), assessed by IMWG uniform response criteria
• To assess clinical benefit rate
‒ For solid tumour indications: clinical benefit rate (CR + PR + SD), assessed by RECIST 1.1.
‒ For Hodgkin and non-Hodgkin lymphomas: clinical benefit rate (CR + PR + SD), assessed by Lugano Lymphoma classification
‒ For multiple myeloma: clinical benefit rate (sCR + CR + VGPR + PR + SD), assessed by IMWG uniform response criteria
• Duration of response (DOR), time to response, progression-free survival (PFS), OS.
Exploratory endpoints:
• To assess plasma levels and PK parameters (Cmax, tmax, AUC0-8, AUC0-24, AUC0–∞, t1/2 and AR) of metabolite(s) when feasible
• To evaluate the relationship between CB-103 plasma concentrations and/or PK parameters (eg, Cmax and AUC0-24) and safety, efficacy and PD parameters
• To assess changes in the expression of NOTCH and NOTCH target genes (NOTCH1 4 receptors, NOTCH ligands, NICD1-4 and NOTCH target genes) assessed by Nanostring expression analysis from pre- to post- CB-103 treatment in tumour tissue samples, whole blood, plasma and hair follicles to determine on-target effects of CB-103.
• To assess NOTCH and NOTCH target genes expression (NOTCH1-4 receptors, NOTCH ligands, NICD1-4 and NOTCH target genes) assessed by Nanostring expression analysis in pre- and post-treatment tumour tissue samples, whole blood / plasma samples and hair follicles and assess relation to clinical activity of CB-103.
• To assess certain genotypes (e.g. cytochrome P450 enzymes or NAT) and assess relation to PK outcome data
• To assess NOTCH genetic aberrations in pre- and post-treatment tumour tissue samples, whole blood and hair follicles and assess relation to clinical activity of CB 103
• To assess NOTCH1-4 NICD expression assessed by IHC staining or by Western Blot in pre- and post-treatment tumour tissue samples and to assess relation to clinical activity of CB-103
• To assess genetic aberrations on DNA derived from blood samples (liquid biopsy with circulating tumour DNA and blood cell-derived DNA) and to assess relation to results from corresponding tumour tissue samples.
• To assess NOTCH mutations by genomic mutation analysis in tumour tissue samples and to assess relation to clinical activity of CB-103 treatment
• To assess change from baseline cardiac intervals versus increasing plasma CB 103 concentrations |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary
safety assess. incl. AE/SAEs: Scr., Baseline, Cyc1 d1, 2, 3, 8, 9, 15 & 22 (d2,3 part A only), Cyc2+ d1 a 15, week 24, EoT, safety FU, unsched. visit
ECOG perf and physic exam.: Scr., Baseline, Cyc1 d2, 3, 8, 15 & 22 (d2,3 part A only), Cyc2+ d1 & 15, EoT, safety FU (only ECOG) and unsched. visit
ECG: Scr., Cyc1 d1, 8, 15 & 22, Cyc2 d1 & 15 (d15 part A only), Cyc3+ d1, EoT and unsched. visit
ECHO/MUGA: Baseline, Cyc1 d8, Cyc3 d1, EoT
plasma, pk: Cycle 1 days 1, 2, 3, 8, 9, 15 & 22, Cyc2+ d1 & 15
tumour assess.: Baseline, Cyc2 d15, after cycle 2, every 8 weeks until EOT or disease progress./OS, EoT
pfs: week 24, EoT, safety FU
Exploratory
Whole blood, plasma & hair follicles: baseline, Cyc2+ d1
Tumour biopsy: same as tumor assess.
Liquid biopsy: baseline, Cyc2+ d1 |
|
| 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 | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Netherlands |
| Spain |
| Switzerland |
|
| 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 end-of-study is reached when the last patient in Part B of the study has been on study treatment for up to 12 cycles plus the safety follow-up period of 28 days after the first dose of CB-103. In case the study is stopped before any patient was treated for 12 months, the end-of-study is reached 28 days after the last patient in Part B of the study has received his/her last dose of CB-103 |
El final del estudio se produce cuando el último paciente de la Parte B
del estudio ha estado en el tratamiento del estudio durante hasta 12
ciclos más el período de seguimiento de seguridad de 28 días
posteriores a la primera dosis de CB-103. En caso de que el estudio se
interrumpa antes de que algún paciente haya sido tratado durante 12
meses, el final del estudio se produce 28 días después de que el último
paciente en la Parte B del estudio haya recibido su última dosis de CB-
103 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
Print
