| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Breast Cancer Resistant or Refractory |
| Cancro al seno metastatico resistente o refrattario |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Cancer that is metastasic |
| Cancro avanzato che è metastatico |
|
| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| 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 | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The confirmed objective response rate (ORR) of ARX788 by blinded independent central review (BICR) based on RECIST v1.1 in subjects with metastatic HER2-positive breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens. |
| Tasso di risposta obiettiva (objective response rate, ORR) confermata di ARX788 mediante revisione centrale indipendente in cieco (blinded independent central review, BICR) in base ai criteri RECIST v1.1 in soggetti con carcinoma mammario HER2 positivo metastatico la cui malattia è resistente o refrattaria a regimi contenenti T-DM1 e/o T-DXd e/o tucatinib. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate duration of response (DOR), best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS)
- To evaluate the safety, tolerability, and immunogenicity profile of ARX788
- To determine the pharmacokinetics (PK) of ARX788, total anti-HER2 antibody, and pAF-AS269 |
•Valutare la durata della risposta (duration of response, DOR), la migliore risposta complessiva (best overall response, BOR), il tasso di controllo della malattia (disease control rate, DCR), la sopravvivenza libera da progressione (progression-free survival, PFS) e la sopravvivenza complessiva (overall survival, OS)
•Valutare la sicurezza, la tollerabilità e il profilo di immunogenicità di ARX788
•Determinare la farmacocinetica (pharmacokinetics, PK) di ARX788, anticorpi anti-HER2 totali e pAF-AS269 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age >= 18 years
2. Life expectancy > 3 months.
3. ECOG Performance Status <= 1
4. Metastatic breast cancer subjected previously treated with T-DM1, and/or T-DXd, and/or tucatinib-containing regimens. Subjects must have been previously treated with one (or more) of these regimens to be eligible. Subjects must have been treated with trastuzumab plus taxane. Subjects who received prior pertuzumab, lapatinib, neratinib, margetuximab, and/or other available and accessible HER2-directed therapies or investigational therapies are eligible.
5. Presence of at least one measurable lesion per RECIST v 1.1 as determined by BICR.
6. A tumor block or formalin-fixed paraffin-embedded (FFPE) tissue from tumor biopsies as 10 pre-cut unstained slides must be collected for the HER2 status evaluation and biomarker analysis based on most recent tumor tissue sample. If insufficient tissue, a fresh tumor biopsy must be collected. All tumor tissue (including the pathology report and methods of pathology laboratory's tissue preparation/testing) needs to be sourced for central laboratory for HER2 testing.
7. Central laboratory-confirmed HER2-positive expression (estrogen receptor/progesterone receptor positive subjects may be enrolled if they are HER2-positive) according to 2018 American Society of Clinical Oncology – College of American Pathologists (ASCO-CAP) guidelines. See Laboratory Manual for details.
8. Subjects whose brain metastases have been treated may participate provided they show radiographic stability (defined as 1 brain MR image, obtained at least four weeks after treatment to the brain metastases, shows no evidence of intracranial progression). In addition, any neurologic symptoms (including seizures) that developed either as a result of the brain metastases or their treatment must have returned to baseline or resolved. Any steroids administered as part of this therapy must be completed at least three days prior to study medication. After approximately 20 such subjects [20% of the first 100 subjects] have been enrolled, subsequent subjects with any current or past history of brain metastases will be excluded.
9. Acute toxicities from any prior therapy, surgery, or radiotherapy must have resolved to Grade 0 or 1 as per the NCI-CTCAE v 5.0, except alopecia.
10. Adequate bone marrow function defined by absolute neutrophil count of >= 1.5×109/L, platelet count of >= 100.0×109/L, and hemoglobin of >= 9.0 g/dL.
11. Adequate hepatic function, as defined by serum total bilirubin <= 1.5 × ULN, serum aspartate aminotransferase and alanine aminotransferase <= 2.5 × ULN. Subjects with known hepatic metastases or primary biliary
cancer may have serum total bilirubin <= 3.5 × ULN and transaminases <= 5 × ULN.
12. Adequate renal function, defined as creatinine clearance >= 30 mL/min, as calculated using the Cockcroft Gault equation: ([{140 -age in years} × {actual weight in kg}] divided by [{72 × serum creatinine in mg/dL}
multiplied by 0.85 if female]).
13. Adequate cardiac function as assessed by left ventricular ejection fraction >= 50% or institutional lower limit of normal; cumulative anthracycline dose < 360 mg/m2 doxorubicin or equivalent.
14. Willing and able to understand and sign an informed consent inform and to comply with all aspects of the protocol.
Please refer to the Protocol v2.0 dated 02Nov2021 for the full list. |
1. Età >= 18 anni
2. Aspettativa di vita >3 mesi
3. Stato dell’Eastern Cooperative Oncology Group <=1
4. Soggetti con carcinoma mammario metastatico precedentemente trattati con regimi contenenti T-DM1 e/o T-DXd e/o tucatinib. Per essere idonei, i soggetti devono essere stati precedentemente trattati con uno (o più) di questi regimi. I soggetti devono essere stati trattati con trastuzumab e un taxano. Sono idonei i soggetti che hanno ricevuto pertuzumab, lapatinib, neratinib, margetuximab e/o altre terapie dirette contro HER2 disponibili e accessibili o terapie sperimentali.
5. Presenza di almeno una lesione misurabile secondo i criteri RECIST v 1.1, come determinato dal BICR.
6. Un blocchetto di tessuto tumorale o tessuto fissato in formalina e incluso in paraffina (FFPE) prelevato da biopsie tumorali sotto forma di 10 vetrini pretagliati non colorati deve essere raccolto per la valutazione dello stato HER2 e l’analisi dei biomarcatori in base al campione di tessuto tumorale più recente. Se il tessuto è insufficiente, deve essere prelevata una biopsia tumorale fresca. Tutto il tessuto tumorale (incluso il referto patologico e i metodi di preparazione/analisi del tessuto del laboratorio di patologia) deve essere fornito per il laboratorio centrale per il test di HER2
7. Espressione di HER2 confermata dal laboratorio centrale (i soggetti positivi al recettore degli estrogeni/recettore del progesterone possono essere arruolati se sono HER2 positivi) secondo le linee guida 2018 dell’American Society of Clinical Oncology – College of American Pathologists (ASCO-CAP). Consultare il Manuale del laboratorio per i dettagli.
8. Possono partecipare i soggetti le cui metastasi cerebrali sono state trattate, a condizione che mostrino stabilità radiografica (definita come 1 immagine RM cerebrale, ottenuta almeno quattro settimane dopo il trattamento delle metastasi cerebrali, che non mostri alcuna evidenza di progressione intracranica). Inoltre, eventuali sintomi neurologici (comprese le crisi convulsive) che si sono sviluppati a seguito delle metastasi cerebrali o del loro trattamento devono essere tornati alla situazione basale o essersi risolti. Qualsiasi steroide somministrato nell’ambito di questa terapia deve essere completato almeno tre giorni prima del farmaco dello studio. Dopo l’arruolamento di circa 20 soggetti (20% dei primi 100 soggetti), saranno esclusi i soggetti successivi con qualsiasi anamnesi attuale o pregressa di metastasi cerebrali.
9. Le tossicità acute dovute a qualsiasi terapia, intervento chirurgico o radioterapia precedente devono essersi risolte a un grado <=1 secondo i criteri NCI-CTCAE v 5.0, fatta eccezione per l’alopecia.
10. Adeguata funzionalità del midollo osseo definita da una conta assoluta dei neutrofili >=1,5×109/L, conta piastrinica >=100,0×109/L ed emoglobina >=9,0 g/dL.
11. Funzione epatica adeguata, come definita da bilirubina sierica totale <=1,5 × ULN, aspartato aminotransferasi e alanina aminotransferasi sieriche <=2,5 × ULN. Soggetti con metastasi epatiche note o carcinoma biliare primitivo possono presentare livelli di bilirubina totale sierica <=3,5 x ULN e di transaminasi <=5 x ULN.
12. Funzionalità renale adeguata definita come clearance della creatinina >=30 mL/min, calcolata usando l’equazione di Cockroft-Gault:
([{140 - età in anni} × {peso effettivo in kg}] diviso per [{72 × creatinina sierica in mg/dL} moltiplicato per 0,85 se donna])
13. Funzione cardiaca adeguata valutata mediante frazione di eiezione ventricolare sinistra (left ventricular ejection fraction, FEVS) >=50% o limite inferiore della norma a livello istituzionale; dose cumulativa di antraciclina <360 mg/m2 di doxorubicina o equivalente.
14. Volontà e capacità di comprendere e firmare un modulo di consenso informato e rispettare tutti gli aspetti del protocollo.
Riferirsi al Protocollo v2.0 datato 02Nov2021 per la lista completa. |
|
| E.4 | Principal exclusion criteria |
1. History of allergic reactions to any component of ARX788.
2. Prior history of interstitial lung disease, pneumonitis, or other clinically significant lung disease within 12 months prior to screening, with the exception of directly attributable to the presence of lung metastases from their underlying cancer. Subjects with significant treatment-related lung injury, defined as any of the following, will be excluded:
a) Any prior history of drug-induced or immune-mediated pneumonitis.
b) Prior history of radiation therapy to the chest of > 18 Gy with residual sequelae considered clinically significant by Investigator assessment.
c) Radiographic evidence of radiation fibrosis involving > 15% of the lung parenchyma associated with clinical symptoms.
3. Any active ocular infections until resolved or any chronic corneal disorder unless approved by Medical Monitor. Keratopathy of grade <=1 due to prior treatment with anti-HER2 ADC or chemotherapy are allowed.
4. History of congestive heart failure, unstable angina pectoris, unstable atrial fibrillation, or cardiac arrhythmia within 12 months prior to enrollment. Medical history of myocardial infarction within 6 months prior to enrollment. Baseline QTc, averaged over 3 screening ECGs must be <= 470 msec (females) or <= 450 msec (males).
5. Grade 3 to 4 peripheral neuropathy (NCI CTCAE v 5.0). Patients with Grade 2 neuropathy can be enrolled at investigator’s discretion.
6. Non-manageable electrolyte imbalances including hypokalemia, hypocalcemia, or hypomagnesemia (Grade 2 or greater based on NCI-CTCAE v 5.0).
7. Any uncontrollable intercurrent illness, infection (including subjects with active, symptomatic Covid-19 infections), or other conditions that could limit study compliance or interfere with assessments.
8. Exposure to any other investigational or commercial anticancer agents or therapies administered with the intention to treat malignancy within 14 days before the first dose of ARX788. Anti-hormonal therapy may be administered up to 7 days prior to the first dose of ARX788.
9. Major surgical intervention within 21 days of the first dose of ARX788 or with ongoing post-operative complications.
10. Radiotherapy administered less than 21 days prior to the first dose of ARX788, or localized palliative radiotherapy administered less than 7 days prior to the first dose of ARX788, or radiotherapy-induced toxicity of Grade 2 or greater based on NCI-CTCAE v 5.0.
11. Pregnancy or breast feeding.
12. Known active HCV, HBV, and/or HIV infection. HIV testing is not required for the screening, unless required by the local Health Authorities. |
1. Anamnesi di reazioni allergiche a qualsiasi componente di ARX788.
2. Anamnesi pregressa di malattia polmonare interstiziale, polmonite o altra malattia polmonare clinicamente significativa nei 12 mesi precedenti lo screening, fatta eccezione se direttamente attribuibile alla presenza di metastasi polmonari dovute al tumore sottostante. Saranno esclusi i soggetti con lesione polmonare significativa correlata al trattamento, definita come una qualsiasi delle seguenti condizioni:
a) Qualsiasi anamnesi pregressa di polmonite indotta da farmaci o immuno-mediata.
b) Anamnesi pregressa di radioterapia al torace >18 Gy con sequele residue considerate clinicamente significative in base alla valutazione dello sperimentatore.
c) Evidenza radiografica di fibrosi da radiazioni che coinvolge >15% del parenchima polmonare con sintomi clinici associati.
3. Infezioni oculari attive fino a risoluzione oppure un qualsiasi disturbo cronico della cornea, salvo approvazione del responsabile del monitoraggio medico. La cheratopatia di grado =1 dovuta a precedente trattamento con coniugati anticorpo-farmaco (antibody-drug conjugates, ADC) anti-HER2 o chemioterapia è ammissibile.
4. Anamnesi di insufficienza cardiaca congestizia, angina pectoris instabile, fibrillazione atriale instabile o aritmia cardiaca nei 12 mesi precedenti l’arruolamento. Anamnesi medica di infarto miocardico nei 6 mesi precedenti l’arruolamento. Il QTc al basale, calcolato sulla media di 3 ECG di screening, deve essere =470 msec (donne) o =450 msec (uomini).
5. Neuropatia periferica di grado da 3 a 4 (NCI-CTCAE v 5.0). Pazienti con neuropatia di grado 2 possono essere arruolati a discrezione dello sperimentatore.
6. Squilibri elettrolitici non gestibili, tra cui ipopotassiemia, ipocalcemia o ipomagnesemia (Grado 2 o superiore in base ai criteri NCI-CTCAE v 5.0).
7. Qualsiasi malattia intercorrente incontrollabile, infezione (compresi i soggetti con infezioni sintomatiche attive da Covid-19) o altre condizioni che potrebbero limitare la conformità allo studio o interferire con le valutazioni.
8. Esposizione a qualsiasi altro agente antitumorale sperimentale o disponibile in commercio o terapie somministrate con l’intento di trattare il tumore maligno nei 14 giorni precedenti la prima dose di ARX788. La terapia antiormonale può essere somministrata fino a 7 giorni prima della prima dose di ARX788.
9. Intervento chirurgico maggiore nei 21 giorni precedenti la prima dose di ARX788 o con complicanze postoperatorie in corso.
10. Radioterapia somministrata meno di 21 giorni prima della prima dose di ARX788 o radioterapia palliativa localizzata somministrata meno di 7 giorni prima della prima dose di ARX788 o tossicità indotta da radioterapia di grado 2 o superiore in base ai criteri NCI-CTCAE v 5.0.
11. Gravidanza o allattamento al seno.
12. Infezione attiva nota da HCV, HBV e/o HIV. Il test dell’HIV non è richiesto per lo screening, a meno che non sia richiesto dalle autorità sanitarie locali. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (ORR) by blinded independent central review (BICR). |
| Tasso di risposta obiettiva (objective response rate, ORR) mediante revisione centrale indipendente in cieco (blinded independent central review, BICR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study. |
| Monitorato durante lo studio. |
|
| E.5.2 | Secondary end point(s) |
- Efficacy: Anticancer activity of ARX788, including:
o Duration of response (DOR)
o Best overall response (BOR) (CR, PR, SD, or progressive disease)
o Disease control rate o Progression-free survival (PFS)
o Overall survival (OS)
- Safety: The safety, tolerability, and immunogenicity profile assessed by AE, vital signs, ECG, LVEF, clinical laboratory tests, ADA assays, physical examination, medical history and prior and concomitant medication, and where applicable, changes from baseline .
- Pharmacokinetics: Serum concentrations of ARX788, total antibody, and metabolite pAF-AS269 will. PK and PDx characteristics of ARX788 and its major metabolites
- Immunogenicity: Presence of ADA and neutralizing ADA and their potential impact on the PK, efficacy, and safety of ARX788. |
-Efficacia: attività antitumorale di ARX788, tra cui:
o Valutare la durata della risposta (duration of response, DOR)
o La migliore risposta complessiva (best overall response, BOR) (CR, PR, SD, o malattia progressiva)
o Il tasso di controllo della malattia (disease control rate, DCR) o la sopravvivenza libera da progressione (progression-free survival, PFS)
o La sopravvivenza complessiva (overall survival, OS)
- Sicurezza: Valutare la sicurezza, la tollerabilità e il profilo di immunogenicità da AE, segni vitali, ECG, LVEF, test clinici di laboratorio, test ADA, esame obiettivo, anamnesi e farmaci precedenti e concomitanti e, ove applicabile, cambiamenti rispetto al basale.
- Farmacocinetica: Le concentrazioni sieriche di ARX788, anticorpi totali e del metabolita pAF-AS269 lo faranno. Caratteristiche PK e PDx di ARX788 e dei suoi principali metaboliti
- Immunogenicità: presenza di ADA e ADA neutralizzante e loro potenziale impatto su farmacocinetica, efficacia e sicurezza di ARX788. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study. |
| Monitorato durante lo studio. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | 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 | 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| 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 |
| Hong Kong |
| Belgium |
| Brazil |
| Canada |
| Czechia |
| Germany |
| Italy |
| Korea, Republic of |
| Portugal |
| Spain |
| Switzerland |
| Taiwan |
| United States |
| France |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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