| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced, metastatic or unresectable soft tissue sarcoma |
| Sarcoma dei tessuti molli in fase avanzata, metastatica o non candidabile a resezione |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced soft tissue sarcoma |
| Sarcoma dei tessuti molli in fase avanzata |
|
| 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 | HLT |
| E.1.2 | Classification code | 10041298 |
| E.1.2 | Term | Soft tissue sarcomas histology unspecified |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the antitumor activity in terms of PFS at 6-month of trabectedin + olaparib versu trabectedin alone as second or further-line treatment for relapsed and unresectable STS progressing after standard treatment. |
| Confrontare l'attività antitumorale in termini di PSF a 6Mesi di trabectedina + olaparib versus trabectedina da sola nel trattamento di seconda o ulteriore linea del sarcoma dei tessuti molli ricaduto e non resecabile in progressione dopo il trattamento standard. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of the study will be to further explore the activity of T+O and T in STS.
*OS
* overall survival rate at 12-month
* progression-free survival
* Tasso di risposta globale secondo RECIST 1.1
* duration of response, non-dimensional pattern of response,
* disease control rate,
*growth modulation index (GMI),
* safety
* quality of life |
Per la combinazione trabectedina+olaparib confrontata con trattamento in monoterapia di sola trabectedina verranno valutati i seguenti obiettivi secondari
* Sopravvivenza Globale
* Sopravvivenza libera da progressione
* Tasso di sopravvivenza globale a 12 Mesi
* Tasso di risposta globale
* Durata della risposta
*Growth Modulation Index (GMI)
* Sicurezza del trattamento
* Qualità della vista |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
*Written informed consent prior to any study specific procedures.
*Histologically documented and not surgically resectable or metastatic STS that progressed after first- or further-line treatments for relapsing disease.
*At least one previous line of anthracycline-containing chemotherapy for advanced disease or relapsed/progressed within 6 months of a previous treatment with an anthracycline-containing chemotherapy in the neo-adjuvant/adjuvant setting.
*Measurable disease according RECIST 1.1
*ECOG Performance Status of 0 or 1. Patients with an ECOG 2 are eligible if it depends solely on orthopedic problems.
*Estimated life expectancy of at least 16 weeks.
*Age >=18 years.
*Left Ventricular Ejection Fraction = 50% and/or above lower institutional limit of normality
*Adequate bone marrow, liver and renal function assessed within 7 days prior to day1Cy1
*Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1 |
*Consenso informato scritto prima di qualsisasi procedura dello studio
* Sarcoma dei tessuti molli istologicamente confermato, non rescabile chirurgicamente o metastatico che è andato in progressione dopo almeno una line di trattamento per la malattia metastatica
* Almeno un precedente regime per la malattia metastatica contenente antracicline o pazienti che sono andati in ricaduta/progressione entro 6 mesi dal precedente trattamento a base di antracicline nel setting neo-adiuvante
* Malattia misurabile secondo i criteri RECIST 1.1
* ECOG Performance Status 0 o 1
*Aspettativa di vita almeno di 16 settimane .
*Età>=18 years.
*LLVEF >= a 50% e/o al di sopra del limite istitutzionale
*Adeguta funzionalità midollare, renale ed epatica entro i 7 giorni precedenti l'inzio della terapia
*Pazienti in post-menopausa o assenza di stato di gravidanza nelle donne potenzialmente fertili, valutato entro i 28 giorni di screening e confermato prima dell'inzio della terapia |
|
| E.4 | Principal exclusion criteria |
*Participation in another study in the last 4 weeks.
* Previous treatment with trabectedin, olaparib or other Poly Adpribose polymerase 1 (PARP-1) inhibitors
*Persistent toxicities G2 with the exception of alopecia
*Significantly mental status that would prevent the understanding of informed consent and compliance
*Patients with any severe and/or uncontrolled medical conditions such as unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction = 6 months, serious uncontrolled cardiac arrhythmia, uncontrolled hyperlipidemia, active or uncontrolled severe infection, cirrhosis, chronic or persistent active hepatitis or severely impaired lung function.
* Immune compromised patients, e.g., patients who are known to be y positive for HIV.
* Active clinically serious infections (> grade 2 CTCAE).
* Active viral hepatitis
*Metastatic brain or meningeal tumors
*Patients with seizure disorders requiring medication
*Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 28 days before the start of treatment.
* Patients with evidence or history of bleeding diathesis.
*Patients undergoing renal dialysis.
* Patients unable to swallow oral medications.
*Uncontrolled diabetes
*Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent
*Other malignancy unless curatively treated with no evidence of disease for =5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ , Stage 1, grade 1 endometrial carcinoma. Patients with a history of localised triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease
*Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. impairment of gastrointestinal (GI) function, or GI disease that may significantly alter the absorption of the study drugs).
*Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of study entry
*Radiotherapy during study or within 3 weeks of start of study drug. (Palliative radiotherapy will be allowed).
*Major surgery within 4 weeks of start of study. Thus, patients must have recovered from wound or directly surgical related complications at time of study randomization.
*Investigational drug therapy outside of this trial during or within 4 weeks of study entry.
*Patients with known hypersensitivity to trabectedin, olaparib or to their excipients.
*Patients can receive a stable dose of bisphosphonates for bone metastases before and during the study as long as these were started at least 4 weeks prior to treatment with the study drugs.
*Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
* A history of noncompliance to medical regimens or inability or unwillingness to return for scheduled visits.
* Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator , or patients with congenital long QT syndrome.
* Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors . The required washout period prior to starting study drugs is 2 weeks.
*Concomitant use of known strong or moderate CYP3A inducers . The required washout period prior to starting study drugs is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
*Previous allogenic bone marrow transplant or double umbilical cord blood transplantation
*Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of them |
• Partecipazione ad un trial con altri IMP nelle 4 settimane precedenti
• Precedente terapia con trabectedina, olaparib o altri inibitori di PARP-1
• Tossicità persistente G2 con l’eccezione dell’alopecia
• Alterazione dello stato mentale che possono precludere la comprensione del consenso informato e l’adesione al protocollo.
• Condizioni mediche severe e/o non controllate come angina pectoris, scompenso cardiaco sintomatico, infarto miocardico meno di 6 mesi prima, aritmia cardiaca severa non controllata, iperlipidemia non controllata, infezione severa attiva o non controllata, cirrosi epatica, epatite cronica o persistente attiva, funzionalità polmonare compromessa. In particolare in caso di storia di cardiopatia: insufficienza cardiaca congestizia> NYHA classe 2; malattia coronarica attiva (sono includibili pazienti con infarto miocardico oltre 6 mesi prima dell'ingresso nello studio); aritmie cardiache che richiedono una terapia antiaritmica (sono consentiti beta bloccanti o digossina) o ipertensione non controllata, compressione instabile del midollo spinale (non trattata e instabile per almeno 28 giorni prima dell'ingresso nello studio), sindrome della vena cava superiore, estesa malattia polmonare bilaterale alla scansione HRCT
• Pazienti immunocompromessi con nota siero positività ad HIV
• Infezione clinicamente severa > G2 in fase attiva.
• Presenza di metastasi cerebrali o menigee
• Epilessia che richiede trattamento farmacologico
• Gravidanza o allattamento.
• Storia di diatesi emorragica.
• Pazienti in dialisi
• Pazienti con impossibilità alla deglutizione di medicinali per via orale
• Diabete non controllato (glicemia a digiuno > 2 LSN)
• Pazienti in terapia cronica con corticosteroidi o altro agente immunosoppressore
• Storia di altra patologia tumorale nei 5 anni precedenti con l’eccezione di tumori cutanei non melanotici o tumore della cervice in situ trattati radicalmente, carcinoma duttale in situ (DCIS), carcinoma endometriale stadio 1, grado 1.
• Pazienti con patologie concomitanti severe o non controllate che, a giudizio dello sperimentatore, possono porre a rischio la sicurezza del paziente o compromettere l’adesione
• Chemioterapia, immunoterapia o altri agenti sperimentali antitumorali nelle 4 settimane precedenti l'avvio dello studio.
• lo studio o nelle 3 settimane precedenti l'avvio dello studio.
• Interventi di chirurgia maggiore nelle 4 settimane precedenti l'avvio dello studio. Trattamento all’interno di trial clinici con prodotti sperimentali nelle 4 settimane precedenti l’avvio dello studio
• Nota ipersensibilità a trabectedina, olaparib o ai loro eccipienti
• ECG a riposo che indichi problematica cardiaca potenziale reversibile (quali ischemia instabile, aritmia sintomatica instabile, insufficienza cardiaca congestizia, prolungamento dell’intervallo QTcF < 500 msec.).
• Pazienti con sindrome mielodisplastica o leucemia acuta. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival (PFS) a 6 Months
PFS data will be censored on the day following the date of last tumor assessment documenting absence of progressive disease for patients who do not have objective tumor progression and are still on trial at the time of an analysis, are given antitumor treatment other than the trial treatment, or removed from trial follow-up prior to documentation of objective tumor progression. |
Sopravvivenza libera di progressione a 6 Mesi
Ogni 6 settimane verrà valutata la risposta RECIST 1.1
I dati PFS saranno censored al giorno successivo la data dell'ultima valutazione documentata di assenza di progressione di malattia per quei pazienti che non avranno avuto una PD o saranno ancora in studio al moment dell'analisi Ptive tumor progression. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Progression-free survival (PFS) is defined as the time from the date of enrollment to the date of first documentation of disease progression, or to the death from any cause.
PFS data will be censored on the day following the date of last tumor assessment documenting absence of progressive disease for patients who do not have objective tumor progression and are still on trial at the time of an analysis, are given antitumor treatment other than the trial treatment, or removed from trial follow-up prior to documentation of objective tumor progression. |
| Ogni 6 mesi |
|
| E.5.2 | Secondary end point(s) |
*OS
* overall survival rate at 12-month
* progression-free survival
* ORR according RECIST 1.1
* duration of response, non-dimensional pattern of response,
* disease control rate,
*growth modulation index (GMI),
* safety
* quality of life; * Sopravvivenza Globale
* Sopravvivenza libera da progressione
* Tasso di sopravvivenza globale a 12 Mesi
* Tasso di risposta globale misurata in accordo ai criteri RECIST 1.1
* Durata della risposta
*Growth Modulation Index (GMI)
* Sicurezza del trattamento
* Qualità della vista |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
*OS: at 3 and 5 years
* overall survival rate at 12-month
* progression-free survival : at 3 and 5 years
* ORR according RECIST 1.1
* duration of response: form treatment start to the date of progression.
*growth modulation index (GMI): form the date of treatment start and the date of progression.
* safety : from treatment start every 3 weeks |
* Sopravvivenza Globale: a 3 e a 5 anni
* Sopravvivenza libera da progressione: a 3 e a 5 anni
* Tasso di sopravvivenza globale a 12 Mesi
* Tasso di risposta globale misurata in accordo ai criteri RECIST 1.1
* Durata della risposta: dall'inzio della terapia fino alla data di progressione
*Growth Modulation Index (GMI): dall'inzio della terapia fino alla data di progressione
* Sicurezza del trattamento: dall''inzio della terapia ogni 3 settimane fino a fine del trattamento
* Qualità della vista : dall''inzio della terapia ogni 3 settimane, fino a fine del trattamento |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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