E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
colorectal carcinoma |
colorectal carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
intestinal cancer |
intestinal cancer |
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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 | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 100000004864 |
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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: To determine the recommended phase 2 dose (RP2D) of galunisertib plus capecitabine in patients with chemotherapy resistant activated TGF-β signature-like CRC.
Phase II: To determine the anti-tumor activity, as measured by response rate (RR) of galunisertib in combination with capecitabine in patients with chemotherapy resistant activated TGF-β signature-like CRC. |
Fase I: determinare la dose raccomandata per la fase 2 (RP2D) di galunisertib in combinazione con capecitabina in pazienti affetti da CRC resistente a chemioterapia con una signature genetica TGF-β like
Fase II: determinare l’attività antitumorale, misurata in base al tasso di risposta (RR) di galunisertib in combinazione con capecitabina in pazienti affetti da CRC resistente a chemioterapia con una signature genetica TGF-β like.
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E.2.2 | Secondary objectives of the trial |
- To characterize the safety and tolerability of galunisertib in combination with chemotherapy regimens, as assessed by the incidence and severity of adverse events
- To assess anti-tumor activity of galunisertib in combination with chemotherapy, as measured by duration of response, time to response and, progression free survival (phase II only) and overall survival (phase II only)
- To determine the pharmacokinetic profile of galunisertib in combination with chemotherapy, as measured by plasma concentrations
- To explore genetic determinants of response to galunisertib in combination with chemotherapy, as measured by baseline molecular status of potential predictive markers of tumor response
- To explore the potential mechanism of resistance to galunisertib in combination with chemotherapy, as measured by gene alterations/expression profiles (e.g. baseline, relapse) in tumor tissue upon progression |
- Caratterizzare la sicurezza e la tollerabilità di galunisertib in combinazione con regimi di chemioterapia, valutate in base ad incidenza e gravità degli eventi avversi - Valutare l’attività antitumorale di galunisertib in combinazione con chemioterapia, misurata in base a durata della risposta, tempo alla risposta, sopravvivenza libera da progressione (solo fase II) e sopravvivenza globale (solo fase II) - Determinare il profilo farmacocinetico di galunisertib in combinazione con chemioterapia, valutato in base alle concentrazioni plasmatiche - Analizzare i determinanti genetici della risposta a galunisertib in combinazione con chemioterapia, valutati in base allo stato molecolare basale di potenziali marcatori predittivi di risposta del tumore - Esplorare il potenziale meccanismo di resistenza a galunisertib in combinazione con chemioterapia, valutato in base ai profili di alterazione/espressione genica (ad es., al basale, alla recidiva) nel tessuto tumorale al momento della progr |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histological or cytological proof of CRC;
2. Disease progression or relapse upon first line of treatment (maximum lines of treatment is one for phase I and phase II of this study) for advanced CRC with fluoropyrimidine containing chemotherapy as single agent or in combination (combinations with oxaliplatin, irinotecan, bevacizumab and cetuximab/panitumumab are allowed);
3. Written documentation of activated TGF-β signature-like gene signature, as determined by the validated assay of Agendia;
4. Age ≥ 18 years;
5. Able and willing to give written informed consent;
6. WHO performance status of ≤ 1;
7. LVEF ≥ 55%;
8. Able and willing to undergo blood sampling for PK and PD analysis;
9. Able and willing to undergo tumor biopsies before start, during treatment and at the end of treatment
10. Life expectancy ≥ 3 months allowing adequate follow up of toxicity evaluation and anti-tumor activity;
11. Evaluable disease according to RECIST 1.1 criteria (measurable disease for the phase II part; evaluable disease is sufficient for the phase I part);
12. Minimal acceptable safety laboratory values
a. ANC of ≥ 1.5 x 109 /L
b. Platelet count of ≥ 100 x 109 /L
c. Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 3.0 x ULN, or ALAT and ASAT ≤ 5 x ULN in patients with liver metastases
d. Renal function as defined by serum creatinine ≤1.5 x ULN
e. Creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula or MDRD);
13. Negative pregnancy test (urine or serum) for female patients with childbearing potential. |
1. Conferma istologica o citologica di CRC 2. Progressione di malattia o recidiva dopo una prima linea di trattamento per CRC avanzato con chemioterapia contenente una fluoropirimidina come agente singolo o in combinazione (sono ammesse combinazioni con oxaliplatino, irinotecan, bevacizumab e cetuximab/panitumumab) 3. Documentazione scritta di signature genetica TGF-βlike, determinata mediante test validato di Agendia 4. Età 18 anni 5. Soggetto in grado di, e disponibile, a fornire consenso informato scritto, con firma del modulo di consenso informato prima dell’inizio della sperimentazione 6. Stato di validità OMS ≤1 7. FEVS ≥55% 8. Soggetto in grado di, e disponibile a sottoporsi a prelievi di sangue per l’analisi farmacocinetica (PK) e farmacodinamica (PD) 9. Soggetto in grado di, e disponibile a sottoporsi a biopsia tumorale prima dell’avvio, durante e alla fine del trattamento 10. Aspettativa di vita 3 mesi, che consenta un follow-up adeguato della valutazione della tossicità e dell’attività antitumorale 11. Malattia valutabile secondo i Criteri di valutazione della risposta nei tumori solidi (RECIST) 1.1 (malattia misurabile per la parte di fase II; per la parte di fase I è sufficiente che la malattia sia valutabile) 12. Valori minimi accettabili degli esami di laboratorio per la sicurezza a. Conta assoluta dei neutrofili (ANC) 1,5 x 109/l b. Conta piastrinica 100 x 109 /L c. Funzione epatica definita da livelli sierici di bilirubina 1,5 x il limite superiore della norma (ULN), ALAT e ASAT 3,0 x ULN o ALAT e ASAT <5 x ULN nei pazienti con metastasi epatiche d. Funzione renale definita da livelli sierici di creatinina 1,5 x ULN e. Clearance della creatinina 50 ml/min (secondo la formula di Cockroft-Gault o la formula “Modifica della dieta nella patologia renale” [MDRD]) 13. Test di gravidanza (urinario o sierico) negativo per le pazienti in età fertile
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E.4 | Principal exclusion criteria |
1. Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment;
2. Known or suspected dihydropirimidine dehydrogenase deficit (Mutant for DPD*2A genotype, 1236 GA genotype, 1679TG genotype and 2846A>T genotype);
3. Symptomatic or untreated leptomeningeal disease;
4. Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enrol. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT (<21 days before start of treatment) completed at screening demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs or corticosteroids;
5. History of cardiac disease, including myocardial infarction within 6 months before study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension, major cardiac abnormalities, a predisposition for developing aneurysms including family history of aneurysms, Marfan syndrome, bicuspid aortic valve, or evidence of damage to the large vessels of the heart.
6. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral galunisertib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection);
7. Woman who are pregnant or breast feeding;
8. Unreliable contraceptive methods. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms);
9. Radio- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed;
10. Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery;
11. Active infection requiring systemic antibiotics or uncontrolled infectious disease;
12. Patients with a known history of hepatitis B or C or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;
13. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study;
14. Known hypersensitivity to one of the study drugs or excipients. |
1. Qualsiasi trattamento con farmaci sperimentali nei 30 giorni precedenti la somministrazione della prima dose di trattamento sperimentale 2. Deficit noto o sospetto di diidropirimidina deidrogenasi (genotipo mutato per DPD*2A, genotipo 1236 GA, genotipo 1679TG e genotipo 2846A>T) 3. Malattia leptomeningea sintomatica o non trattata 4. Metastasi cerebrali sintomatiche. È consentito l’arruolamento di pazienti, trattati o meno in precedenza per queste condizioni, che appaiano asintomatici in assenza di terapia corticosteroidea. Le metastasi cerebrali devono essere stabili, con verifica mediante esami di imaging (ad es., RM o TC cerebrale eseguita allo screening che non dimostri alcuna attuale evidenza di metastasi cerebrali in progressione). I pazienti non possono ricevere farmaci antiepilettici induttori enzimatici o corticosteroidi 5. Anamnesi di patologia cardiaca, tra cui infarto miocardico nei 6 mesi precedenti l’ingresso nello studio, angina pectoris instabile, insufficienza cardiaca congestizia di classe III/IV secondo la classificazione della New York Heart Association (Associazione dei cardiologi di New York) o ipertensione non controllata, anomalie cardiache maggiori, predisposizione allo sviluppo di aneurismi, inclusa anamnesi familiare di aneurismi, sindrome di Marfan, valvola aortica bicuspide o evidenza di lesione a carico dei grossi vasi del cuore 6. Compromissione della funzione gastrointestinale (GI) o patologia GI che possa alterare in modo significativo l’assorbimento di galunisertib per via orale (ad es., patologie ulcerative, nausea non controllata, vomito, diarrea, sindrome da malassorbimento, resezione dell’intestino tenue) 7. Donne in gravidanza o che allattano al seno 8. Metodi contraccettivi non affidabili. Sia gli uomini che le donne arruolati in questa sperimentazione devono acconsentire ad utilizzare un metodo contraccettivo affidabile per tutta la durata dello studio (sono metodi contraccettivi adeguati il preservativo, la sterilizzazione, altre misure contraccettive di barriera preferibilmente in combinazione con preservativi) 9. Radioterapia o chemioterapia nelle ultime 2 settimane (30 giorni per i farmaci sperimentali) prima della somministrazione della prima dose di trattamento sperimentale. È consentita la radioterapia palliativa (1 x 8 Gy) 10. Pazienti sottoposti a qualsiasi intervento chirurgico maggiore nelle ultime 2 settimane prima dell’avvio del farmaco dello studio o che non si siano ripresi completamente da un precedente intervento chirurgico 11. Infezione in fase attiva con necessità di terapia antibiotica per via sistemica o patologia infettiva non controllata 12. Pazienti con anamnesi nota di epatite B o C o con infezione nota da virus dell’immunodeficienza umana di tipo 1 (HIV-1) o 2 (HIV-2) 13. Altra condizione medica o psichiatrica o anomalia di laboratorio grave, acuta o cronica, che possa aumentare il rischio associato alla partecipazione allo studio o alla somministrazione del farmaco dello studio o che possa interferire con l’interpretazione dei risultati dello studio e che, a giudizio dello sperimentatore, renderebbe il paziente un candidato non idoneo per lo studio 14. Ipersensibilità nota a uno dei farmaci dello studio o degli eccipienti
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I: To determine the recommended phase 2 dose (RP2D) of galunisertib plus capecitabine in patients with chemotherapy resistant activated TGF-β signature-like CRC.
Phase II: To determine the anti-tumor activity, as measured by response rate (RR) of galunisertib in combination with capecitabine in patients with chemotherapy resistant activated TGF-β signature-like CRC. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- To characterize the safety and tolerability of galunisertib in combination with chemotherapy regimens, as assessed by the incidence and severity of adverse events
- To assess anti-tumor activity of galunisertib in combination with chemotherapy, as measured by duration of response, time to response and, progression free survival (phase II only) and overall survival (phase II only)
- To determine the pharmacokinetic profile of galunisertib in combination with chemotherapy, as measured by plasma concentrations
- To explore genetic determinants of response to galunisertib in combination with chemotherapy, as measured by baseline molecular status of potential predictive markers of tumor response
- To explore the potential mechanism of resistance to galunisertib in combination with chemotherapy, as measured by gene alterations/expression profiles (e.g. baseline, relapse) in tumor tissue upon progression |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.10 | Pharmacogenetic | Yes |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
pharmacokinetic study |
pharmacokinetic study |
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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 | 0 |
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 | 2 |
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 | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 17 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 18 |
E.8.9.2 | In all countries concerned by the trial days | 0 |