| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Solid Tumors |
| Tumori solidi |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid Tumors |
| Tumori solidi |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| 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 |
Part 1:
- Determination of MTD/MRD and tolerability
- Evaluation of adverse events (AEs) and dose limiting toxicities (DLT)
Part 2:
Primary Safety End Point:
- To characterize the safety and tolerability of MCLA-128
- Frequency and nature of AEs
Primary Efficacy End Point:
- To explore the relationships between the anti-tumor activity of MCLA-128 and disease-related biomarkers
- Overall response rate (ORR), DOR, CBR (defined as the proportion of patients in whom a CR or PR is observed, or SD of a minimum duration of 12 weeks) per RECIST 1.1 as per local investigator's assessment. The relationship between anti-tumor activity and biomarkers including expression of HER2, HER3, and heregulin will be explored, and serum biomarkers such as CA-125 (ovarian) and CA-19-9 (gastric). |
Parte 1
-Determinazione della dose massima tollerata (MTD) e/o della dose massima consigliata (MRD) di MCLA-128.
-Valutazione degli eventi avversi (EA) e delle tossicità limitanti la dose (DLT).
Parte 2
End Point primario di Sicurezza:
-Descrivere il profilo di sicurezza e tollerabilità di MCLA-128.
-Frequenza e natura degli EA.
End Point primario di Efficacia:
-Analizzare le relazioni tra attività antitumorale di MCLA-128 e biomarcatori correlati alla patologia
-Tasso di risposta globale (ORR), DOR, CBR (definito come la percentuale di pazienti in cui si è osservata remissione completa (CR) o risposta parziale (PR) o malattia stabile (SD) di durata minima di 12 settimane) come da criteri di valutazione della risposta nei tumori solidi (RECIST) versione 1.1 secondo valutazione dello sperimentatore locale. Verrà studiata la relazione tra attività antitumorale e biomarcatori, inclusa l’espressione di HER2, HER3 ed eregulina, e biomarcatori sierici come CA-125 (ovaie) e CA-19-9 (gastrico |
|
| E.2.2 | Secondary objectives of the trial |
Part 1:
- safety and tolerability of MCLA-128
- PK profile of MCLA-128
- Immunogenicity of MCLA-128.
- Evaluation of anti-tumor response and CBR.
- Frequency and nature of AEs/SAEs
- Assessment of PK variables
- Incidence and serum titers of anti-drug antibodies against MCLA-128.
- Anti-tumor activity and clinical benefit assessed by RECIST v1.1 determining ORR, DOR, PFS and survival
Part 1 - exploratory:
- Presence of biomarkers and PD responses
- Assessment of relevant tumor biomarkers and markers of MCLA-128 activity in archival and/or fresh tumor biopsy material and blood.
Part 2:
- PK profile
- Assessment of PK variables, including total exposure, Cmax, V, Vss, t1/2, AUC0-t, AUC0-8, tmax
- Immunogenicity
- Population PK analysis
- Incidence and serum titers of anti-drug antibodies against MCLA-128.
- Evaluation of PFS and overall survival, duration of response
Part 2 – exploratory:
- Assessment of other relevant tumor biomarkers and markers of MCLA-128 activity
|
Parte 1
Sicurezza e tollerabilità di MCLA-128.
Profilo farmacocinetico di MCLA-128.
Immunogenicità di MCLA-128.
Valutaz risp antitumorale e tasso di beneficio clinico (CBR).
Freq. e natura eventi avversi/eventi avversi gravi
Valutaz variabili farmacocinetiche, Incidenza e titoli sierici anticorpi anti
MCLA-128.
Attività antitumorale e beneficio clinico secondo i criteri RECIST v.1.1 con
det del tasso di risposta obiettiva (ORR) generale, durata della risposta (DOR),
soprav libera da progres (PFS) e soprav
Parte 1 esplorativo
Presenza di biomarcatori e risposte farmacodinamiche (PD)
Valutaz di biomarcatori tumorali specifici e di marc attività di MCLA-128 nel sangue o in campioni di tessuto tumorale a fresco o fissati.
Profilo PK
Valutaz delle variabili farmacocinetiche, tra cui esposizione totale, Cmax, V, Vss, t1/2,
AUC0-t, AUC0-_, tmax.
Immunogenicità
Analisi PK popolazione
Incidenza e titoli sierici degli ant anti MCLA-128.
Valutaz di PFS e soprav complessiva, durata della risposta |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General Inclusion Criteria for Part 2
1. Age =18 yrs
2. =1 measurable lesion, RECIST v1.1
3. ECOG 0-1
4. life expectancy =12 wks
5. Toxicities of previous anti-cancer therapy resolved to =Gr 1, except for alopecia, lymphopenia assessed as non-clinically significant, Gr 2 sensory neurotoxicity
6. =4-wks between last radiotherapy and D1 (except =1X8 Gy for pain palliation)
7. Complete recovery from major surgery
8. Screening Labvalues:
a. neutrophil count =1.5 x 109/L without colony stimulating factor support
b. Platelets =100 x 109/L
c. Hemoglobin =9 g/dL or =2.2 mmol/L (not transfusion dependent)
d. Total bilirubin <1.5 ULN (unless due to Gilbert’s syndrome)
e. AST (SGOT) =2.5 x ULN; ALT (SGPT) =2.5 x ULN; =5 x ULN for patients with advanced solid tumors with liver metastases; patients with confirmed bony metastases will be permitted on study with isolated elevations in ALP >5 x ULN
f. Serum creatinine =1.5 x ULN or estimated GFR of >50 mL/min Cockroft-Gault
g. Coagulation function (INR and aPTT =1.5 ULN, unless on therapeutic anticoagulants)
h. Urine protein dipstick = 2+; or =100 mg/24 hrs urine
9. Able to provide at baseline a mandatory tumor sample, from fresh (preferred) or archival tissue. Archival tissue must be collected within 2 years before screening, other than for NSCLC which must be within 1 year.
10. Negative pregnancy test at Screening and =7 days of D1
11. Sexually active male and female patients of childbearing potential must agree to use an effective method of birth control during the entire study and for 6 months after final administration of MCLA-128
12. give written informed consent
13. Capable of understanding protocol requirements, is willing and able to comply with study procedures and has signed the main informed consent document. For any optional biopsy sampling (tissue and/or blood) and long-term sample storage, additional consent is required
14. Patient with metastatic cancer who has disease progression after having received treatment with all available therapies known to convey clinical benefit
Specific Inclusion Criterion Part 2
Group A (BC) -**
15.Histologically-confirmed and documented advanced/metastatic breast cancer (BC), relapsed/refractory to =2 prior HER2 directed
regimen for breast cancer
16.Confirmed HER2 amplification (HER2 2+ by IHC confirmed by FISH, or HER2 3+ by IHC) based on historical pathology report or analysis of baseline fresh/archival tumor sample
Group B (CRC) -**
17.Histologically-confirmed and documented advanced/metastatic colorectal cancer (CRC), relapsed/refractory to at least 2 prior regimens
of standard treatments for metastatic CRC, including 1anti-EGFR treatment (if RASWT)
18.Confirmed HER2 amplification based on historical pathology report prior to commencing screening assessments
Group C (OC) -**
19.Histologically-confirmed and documented advanced/metastatic epithelial ovarian cancer (OC) for which no curative therapy is available
20.Prior therapy including all available standard therapies and =1 platinium based chemotherapy
Group D (GC or GEC)
21.Histologically-confirmed and documented advanced/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEC)
22.Prior chemotherapy including platinium and fluoropyrimidine based treatment and trastuzumab
23.Confirmed HER2 amplification (HER2+ by IHC confirmed by FISH, or HER3+ by IHC) based on historical pathology report or analysis of fresh/archival tumor sample
Groupe E (EC)-**
24.Histologically-confirmed and documented advanced/metastatic endometrial cancer (mEC) with no curative therapy available
25.Prior theray with all available standard and =1 prior chemotherapy
Group F (NSCLC) - Select countries only*
26.Unresectable or metastatic NSCLC meeting one of the following conditions:
-Biopsy-proven invasive mucinous adenocarcinoma (IMA). Note: IMA patients who have not performed the pre-screening test for NRG1 fusion can enter the trial.
OR
-NSCLC with documented NRG1 fusion determined at in a qualified local laboratory by molecular profiling using methods such as PCR, next generation sequencing [DNA or RNA] or FISH in patients with no known driver mutations or fusions in EGFR/ALK genes.
27.Documented disease progression by investigator assessment on at least one line of standard therapy in the locally advanced or metastatic setting.
*Previously open in EU with different inclusion criteria
For group F patients outside of Asia, prescreening not needed as only patients with currently documented NRG1 fusion or confirmed diagnosis of IMA and documented absence of EGFR/ALK alterations may be included
**Group currently closed
|
Crit gen Parte 2
1.Età =18 anni
2.=1 lesion misur/valut, RECIST v1.1
3.ECOG 0-1
4.Aspettativa vita =12 sett.
5.Tossicità sperimentate a seguito di precedenti terapie antitumorali risoltesi con =Gr 1, ad eccezione di alopecia, di linfocitopenia giudicata non clinicamente significativa e della neurotossicità sensorGr 2 6.=4 sett. tra l’ultima radioterapia eseguita e il D1 (con l’eccezione =1X8 Gy come palliativo per il dolore)
7.Recupero completo da interventi chirurgici importanti
8.Valori di lab allo Screening:
a.Conta dei neutrofili =1.5 x 10^9/L senza supporto del fattore stimolante crescita di colonie
b.Piastrine =100 x 10^9/L
c.Emoglobina =9 g/dL o =2.2 mmol/L (non dipend da trasfusione)
d.Bilirubina tot <1.5 ULN (a meno di sindrome di Gilbert)
e.AST (SGOT) =2.5 x ULN; ALT (SGPT) =2.5 x ULN; =5 x ULN nei pz con tum solido avanzato con metast epatiche; i pz con metastasi ossee confermate saranno ammessi nello studio con innalzamenti isolati di ALP >5 x ULN
f. Creatinina sierica =1,5 x ULN o GFR stimata >50 mL/min Cockroft-Gault
g.Funzione di coagulazione (INR e aPTT =1,5 ULN, a meno che non si stanno assumendo anticoagulanti terapeutici)
h.Proteine nelle urine = 2+ (misur mediante uno stick) o urine =100 mg/24 ore
9.Disporre al basale di un camp tumor. obbligat., da tessuto fresco (preferito) o fissato. Il tessuto fissato deve essere stato raccolto entro 2 anni prima dello screening, ad eccezione di NSCLC che deve essere stato raccolto entro 1 anno.
10.Esito neg del Test di gravidanza condotto allo Screening e =7 giorni dal Giorno 1
11.Gli uomini sex attivi e le donne età fertile dovranno accettare di usare metodo efficace per controllo nascite per tutta la durata dello studio e per 6 mesi dopo ultima somministr MCLA-128
12.Essere in grado di fornire il consenso informato scritto
13.Essere in grado di comprendere i requisiti del protocollo, volere ed essere in grado di aderire al protocollo di studio e firmare il documento principale del consenso informato. Per prelevare campioni bioptici opzionali (tessuto e/o sangue) e per conservare campioni a lungo termine è necessario un consenso aggiuntivo
14.Il pz con tumor metastat che ha progressione della malattia dopo aver ricevuto il trattamento con tutte le terapie disponibili che è risaputo che danno benefici clinici
Crit inclus spec per Parte 2
Gruppo A (BC)-**
15.Tumor al seno (BC) avanzato/metastat istologic confermato e documentato che è recidivante/refrattario a = 2 precedenti trattamenti posologici diretti contro HER2 per il tumor al seno
16.Amplificaz confermata di HER2 (HER2 2+ da IHC confermata da FISH, o HER2 3+ da IHC) basata su relazione patologica storica o analisi di camp bioptico basale fresco/fissato
Gruppo B (CRC)-**
17.Tumor del colon-retto avanzato/metastat (CRC) recidivante/refrattario ad almeno 2 precedenti terapie standard disponibili per il CRC metastat, compreso 1 trattamento anti-EGFR (se RASWT)
18.Amplificaz di HER2 confermata da referti istologici anamnestici prima delle valutaz dello Screening
Gruppo C (OC)-**
19.Tumor ovarico epiteliale (OC) avanzato/metastat istologicam confermato e documentato per cui non è disponibile alcuna terapia curativa.
20.La terapia precedente avrebbe dovuto includere tutte le terapie stand disponibili e = 1 precedente chemioter a base di platino.
Gruppo D (GC o GEC)
21.Tumor gastrico (GC) o adenocarcin della giunz gastro-esofagea (GEC) avanzato/metastat istologicam confermato e documentato
22.Precedente chemioterapia includendo il trattamento a base di platino e un trattamento a base di fluoropiridina e trastuzumab
23.Amplificaz confemata di HER2 (HER2 2+ in IHC confermata da FISH, o HER2 3+ in IHC) basata su relazione patologica storica o analisi camp bioptico basale fresco/fissato
Gruppo E (EC)-**
24.Tumor endometrio (EC) avanzato/metastat confermato istologicam e documentato per il quale non sia disponibile una terapia curativa
25.Precedente terapia avrebbe dovuto includere tutte le terapie stand disponibili e = 1 precedente trattamento di chemiot
Gruppo F (NSCLC)-solo nazioni selez*
26.NSCLC non resecabile o metastat che soddisfa una delle seguenti condizioni:
-Adenocarcinoma mucinoso invasivo (IMA) testato dalla biopsia. Nota: i pazienti IMA che non hanno eseguito il test di pre-screening per la fusione NRG1 posso entrare nella sperimentazione.
-NSCLC con fusione NRG1 documentata in un lab locale qualificato mediante profiling molec utilizz metodi come PCR, next gen seq [DNA o RNA] o FISH in pz senza alcuna driver mut nota o fusioni nei geni EGFR/ALK.
27.Progressione malattia documentata da valutaz sperimentatore con almeno una linea di terapia stand nel setting avanzato o metastat
*Precedentem aperto in UE con diversi crit di inclus; Per i paz del gruppo F fuori dall'Asia, il prescreening non è necessario poichè solo i paz con fusione NRG1 attualm documentata o diagnosi confermata di IMA e l'assenza documentata di alterazioni di EGFR/ALK possono essere inclusi
** Gruppo attualmente chiuso |
|
| E.4 | Principal exclusion criteria |
General Exclusion Criteria for Part 2
1. Pregnant or lactating;
2. Presence of an active infection or an unexplained fever greater than 38.5°C during Screening up to the first scheduled day of dosing. At the discretion of the Investigator, patients with tumor fever may be enrolled;
3. Known hypersensitivity to any of the components of MCLA-128 or history of severe hypersensitivity reactions to human or humanized monoclonal antibodies, including therapeutic antibodies;
4. Known HIV, Hepatitis B or Hepatitis C; patients who have previously been treated for Hepatitis C and have undetectable viral loads are eligible;
5. Any untreated central nervous system (CNS) lesion. However, patients are eligible if: a) all known CNS lesions have been treated with radiotherapy and/or surgery and b) patient remained without evidence of CNS disease progression = 4 weeks after treatment and c) patients must be off corticosteroid therapy for = 3 weeks;
6. Patients with leptomeningeal metastases;
7. Previous or concurrent malignancy (excluding non-basal cell carcinoma of skin or carcinoma in situ of the uterine cervix) unless the tumor was treated with curative intent more than 2 years prior to study entry;
8. Prior anti-tumor therapy including:
a. Approved anti-HER2 therapies and/or anti-EGFR approved therapies within 28 days prior to the first scheduled day of dosing with MCLA-128;
b. Investigational therapy administered within 28 days prior to the first scheduled day of dosing with MCLA-128. Dosing with MCLA-128 within 28 days of receiving investigational therapy is acceptable once a time interval equal to at least five halflives of the investigational agent has passed or in case of prior checkpoint
inhibitory treatment;
c. Treatment with chemotherapy agents within 28 days prior to the first scheduled day of dosing with MCLA-128;
9. Presence of NYHA Class III or IV congestive heart failure or LVEF <50% or history of significant cardiac disease, unstable angina, congestive heart failure, myocardial infarction, or ventricular arrhythmia requiring medication;
10. Presence of any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate or participate in the study, or interfere with the interpretation of the results. |
Criteri generali di esclusione per la Parte 2
1.Gravidanza o allattamento;
2.Presenza di un’infezione attiva o di una febbre inspiegabile superiore a 38.5°C durante lo Screening fino al primo giorno di somministrazione programmato. I pazienti con febbre tumorale possono essere arruolati a discrezione dello Sperimentatore;
3.Ipersensibilità nota a uno dei componenti di MCLA-128 o storia di reazioni di ipersensibilità grave agli anticorpi monoclonali umani o umanizzati, inclusi gli anticorpi terapeutici;
4.HIV, epatite B o epatite C note; i pazienti che sono stati precedentemente trattati per epatite C e hanno cariche virali non rilevabili sono idonei;
5.Qualsiasi lesione del sistema nervoso centrale (SNC) non trattata. I pazienti sono tuttavia idonei se: a) tutte le lesioni note del SNC sono state trattate con radioterapia e/o intervento chirurgico e b) il paziente è rimasto senza evidenze di progressione della malattia del SNC = 4 settimane dopo il trattamento e c) pazienti non assumono corticosteroidi da = 3 settimane.
6.Pazienti con metastasi leptomeningee.
7.Neoplasia maligna pregressa o concomitante (esclusi il carcinoma non delle cellule basali e il carcinoma in situ della cervice uterina), a meno che il tumore non sia stato trattato con intento curativo più di 2 anni prima dell’ingresso nello studio;
8.Terapia antitumorale pregressa comprendente:
a.Terapie anti-HER2 approvate e/o terapie anti-EGFR approvate nei 28 giorni precedenti il primo giorno di somministrazione di MCLA-128;
b.Trattamento sperimentale somministrato nei 28 giorni precedenti il primo giorno di somministrazione di MCLA-128. La somministrazione di MCLA-128 nei 28 giorni precedenti il trattamento sperimentale è accettabile una volta trascorso un lasso di tempo pari ad almeno cinque emivite dell’agente sperimentale o in caso di precedente trattamento inibitorio dei checkpoint;
c.Trattamento con agenti chemioterapici nei 28 giorni precedenti il primo giorno di somministrazione di MCLA-128;
9.Presenza di insufficienza cardiaca congestizia di Classe NYHA III o IV o LVEF <50% o storia di malattia cardiaca importante, angina instabile, insufficienza cardiaca congestizia, infarto miocardico o aritmia ventricolare che richiede il trattamento farmacologico;
10.Presenza di altre condizioni mediche o fisiologiche che, a giudizio dello Sperimentatore, possono interferire con la capacità del paziente di firmare il consenso informato, di cooperare o di partecipare allo studio, o interferire con l’interpretazione dei risultati. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1:
- Determination of MTD/MRD and tolerability
- Evaluation of adverse events (AEs) and dose limiting toxicities (DLT)
Part 2:
Primary Safety End Point:
- To characterize the safety and tolerability of MCLA-128
- Frequency and nature of AEs
Primary Efficacy End Point:
- To explore the relationships between the anti-tumor activity of MCLA-128 and disease-related biomarkers
- Overall response rate (ORR), DOR, CBR (defined as the proportion of patients in whom a CR or PR is observed, or SD of a minimum duration of12 weeks) per RECIST 1.1 as per local investigator's assessment.The relationship between anti-tumor activity and biomarkers including
expression of HER2, HER3, and heregulin will be explored and serum biomarkers as CA-125 (ovarian) and CA-15-3 (breast). |
Part 1:
- Determination of MTD/MRD and tolerability
- Evaluation of adverse events (AEs) and dose limiting toxicities (DLT)
Part 2:
Primary Safety End Point:
- To characterize the safety and tolerability of MCLA-128
- Frequency and nature of AEs
Primary Efficacy End Point:
- To explore the relationships between the anti-tumor activity of MCLA-128 and disease-related biomarkers
- Overall response rate (ORR), DOR, CBR (defined as the proportion of patients in whom a CR or PR is observed, or SD of a minimum duration of 12 weeks) per RECIST 1.1 as per local investigator's assessment.The relationship between anti-tumor activity and biomarkers including expression of HER2, HER3, and heregulin will be explored and serum biomarkers as CA-125 (ovarian) and CA-15-3 (breast). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumor assessment
• 3week: Radiological: Scr., every 2 Cyc, FSV, LTFU. Serum marker: Scr., end of every Cyc if elevated at baseline (except Cyc1), EOT, FSV, LTFU
• 4week: Radiological: Scr., every 6 weeks until EOT, FSV, LTFU. Serum marker: Screening, end of every cycle (pre-dose day 1), EOT, FSV, LTFU
AEs recorded all through the study, from Cyc 1 D1 until FSV |
Tumor assessment
• 3week: Radiological: Scr., every 2 Cyc, FSV, LTFU. Serum marker: Scr., end of every Cyc if elevated at baseline (except Cyc1), EOT, FSV, LTFU
• 4week: Radiological: Scr., every 6 weeks until EOT, FSV, LTFU. Serum marker: Screening, end of every cycle (pre-dose day 1), EOT, FSV, LTFU
AEs recorded all through the study, from Cyc 1 D1 until FSV |
|
| E.5.2 | Secondary end point(s) |
Part 1:
- To characterize the safety and tolerability of MCLA-128
- PK profile of MCLA-128
- Immunogenicity of MCLA-128.
- Evaluation of anti-tumor response and CBR.
- Frequency and nature of AEs/serious adverse events (SAEs).
- Assessment of PK variables, including total exposure, maximum concentration (Cmax) clearance, volume of distribution (V), volume of
distribution at steady state (Vss), half-life (t1/2), AUC0-t (area under the concentration versus time curve from time zero to time t), AUC0-8 (area under the concentration versus time curve), tmax (time to reach maximum concentration).
- Incidence and serum titers of anti-drug antibodies against MCLA-128.
- Anti-tumor activity and clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR), duration of response
(DOR), progression-free survival (PFS) and survival; CBR is defined as the proportion of patients in whom a complete response (CR) or partial response (PR) or stable disease (SD) is observed (where SD duration is a minimum of 12 weeks).
Part 1 - exploratory:
- Presence of biomarkers and pharmacodynamic (PD) responses to MCLA-128.
- Assessment of relevant tumor biomarkers and markers of MCLA-128 activity in archival and/or fresh tumor biopsy material and blood. The
following candidate biomarkers will be assessed:
o HER2, HER3, pHER2, pHER3 and heregulin;
o KRAS, NRAS, PIK3CA, BRAF mutation status (metastatic colorectal cancer (mCRC) patients only);
o circulating tumor deoxyribonucleic acid (DNA) and mutations in genes associated with HER2/HER3 signaling;
o phosphorylated molecules in the MAPK and AKT signaling pathway.
Part 2:
- PK profile of MCLA-128
- Assessment of PK variables, including total exposure, Cmax, V, Vss, t1/2, AUC0-t, AUC0-8, tmax.
- Immunogenicity of MCLA-128
- Incidence and serum titers of anti-drug antibodies against MCLA-128.
- Evaluation of PFS and overall survival, duration of response
Part 2 - exploratory:
- Assessment of other relevant tumor biomarkers and markers of MCLA-128 activity in archival and/or fresh tumor sample/biopsy material and blood.
- The following candidate biomarkers will be assessed if sufficient sample is available:
Tumor sample:
o pHER2, pHER3, HER2:HER3 dimerization;
o Heregulin and (depending on availability) mutations in genes associated with HER2 and HER3
o Phosphorylated molecules in the MAPK and AKT signaling pathway.
o Heregulin-gene fusions (in case of a validated assay
Blood:
o CD16 (Fcgamma receptor polymorphism)
o Circulating tumor DNA and mutation analysis in genes associated with HER2/HER3 signaling;
o Circulating Tumor Cells for HER2 |
Part 1:
- To characterize the safety and tolerability of MCLA-128
- PK profile of MCLA-128
- Immunogenicity of MCLA-128.
- Evaluation of anti-tumor response and CBR.
- Frequency and nature of AEs/serious adverse events (SAEs).
- Assessment of PK variables, including total exposure, maximum concentration (Cmax) clearance, volume of distribution (V), volume of
distribution at steady state (Vss), half-life (t1/2), AUC0-t (area under the concentration versus time curve from time zero to time t), AUC0-8 (area under the concentration versus time curve), tmax (time to reach maximum concentration).
- Incidence and serum titers of anti-drug antibodies against MCLA-128.
- Anti-tumor activity and clinical benefit assessed by RECIST v1.1 determining objective overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and survival; CBR is defined as the proportion of patients in whom a complete response (CR) or partial response (PR) or stable disease (SD) is observed (where SD duration is a minimum of 12 weeks).
Part 1 - exploratory:
- Presence of biomarkers and pharmacodynamic (PD) responses to MCLA-128.
- Assessment of relevant tumor biomarkers and markers of MCLA-128 activity in archival and/or fresh tumor biopsy material and blood. The following candidate biomarkers will be assessed:
o HER2, HER3, pHER2, pHER3 and heregulin;
o KRAS, NRAS, PIK3CA, BRAF mutation status (metastatic colorectal cancer (mCRC) patients only);
o circulating tumor deoxyribonucleic acid (DNA) and mutations in genes associated with HER2/HER3 signaling; o phosphorylated molecules in the MAPK and AKT signaling pathway.
Part 2:
- PK profile of MCLA-128
- Assessment of PK variables, including total exposure, Cmax, V, Vss, t1/2, AUC0-t, AUC0-8, tmax.
- Immunogenicity of MCLA-128
- Incidence and serum titers of anti-drug antibodies against MCLA-128.
- Evaluation of PFS and overall survival, duration of response
Part 2 - exploratory:
- Assessment of other relevant tumor biomarkers and markers of MCLA-128 activity in archival and/or fresh tumor sample/biopsy material and blood.
- The following candidate biomarkers will be assessed if sufficient sample is available:
Tumor sample:
o pHER2, pHER3, HER2:HER3 dimerization;
o Heregulin and (depending on availability) mutations in genes associated with HER2 and HER3
o Phosphorylated molecules in the MAPK and AKT signaling pathway.
o Heregulin-gene fusions (in case of a validated assay
Blood:
o CD16 (Fcgamma receptor polymorphism)
o Circulating tumor DNA and mutation analysis in genes associated with HER2/HER3 signaling;
o Circulating Tumor Cells for HER2 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK
• 3week: Cyc1 D1, 4 (or 3), 8, 15, Cyc 2-4 D1
• 4week: Cyc1 D1, 8, 15, 22, Cyc2-3 D15, Cyc4 D1, 15, Cyc>5 (every 2 Cyc) D15
Immunogenicity: Cyc1-4 D1, then D1 of every 4 Cyc, EOT, FSV
Biomarker/PD
• 3week: Biopsy: Scr., optionally Cyc4 D21 & EOT. Blood sample: predose at Cyc1 D1 and every 4 cycles, EOT
• 4week: Biopsy: Scr., tumor sample optionally Cyc 5 D1, EoT. Blood sample: pre-dose at Cyc1 D1 and every 4 cycles, EOT
Tumor assessment
• 3week: Radiological: Scr., every 2 Cyc, FSV, LTFU. Serum marker:
Screening, end of every Cyc if elevated at baseline (except Cyc1), EOT, FSV, LTFU
• 4week: Radiological: Scr., every 6 weeks until EOT, FSV, LTFU. Serum marker: Scr., end of every cycle (predose day 1), EOT, FSV, LTFU
AEs recorded all through the study, from Cyc 1 D1 until FSV |
PK
• 3week: Cyc1 D1, 4 (or 3), 8, 15, Cyc 2-4 D1
• 4week: Cyc1 D1, 8, 15, 22, Cyc2-3 D15, Cyc4 D1, 15, Cyc>5 (every 2 Cyc) D15
Immunogenicity: Cyc1-4 D1, then D1 of every 4 Cyc, EOT, FSV
Biomarker/PD
• 3week: Biopsy: Scr., optionally Cyc4 D21 & EOT. Blood sample: predose at Cyc1 D1 and every 4 cycles, EOT
• 4week: Biopsy: Scr., tumor sample optionally Cyc 5 D1, EoT. Blood sample: pre-dose at Cyc1 D1 and every 4 cycles, EOT
Tumor assessment
• 3week: Radiological: Scr., every 2 Cyc, FSV, LTFU. Serum marker:
Screening, end of every Cyc if elevated at baseline (except Cyc1), EOT, FSV, LTFU
• 4week: Radiological: Scr., every 6 weeks until EOT, FSV, LTFU. Serum marker: Scr., end of every cycle (predose day 1), EOT, FSV, LTFU
AEs recorded all through the study, from Cyc 1 D1 until FSV |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Part 2 is parallel design, Part 1 is not |
| Part 2 is parallel design, Part 1 is not |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Korea, Republic of |
| Singapore |
| Taiwan |
| United States |
| France |
| Italy |
| Netherlands |
| Portugal |
| 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
|
|
| 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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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