| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patient with Lung and GEP-NENs progressive after SSAr, everolimus, sunitinib or PRRT. |
| Neoplasie neuroendocrine polmonari (Lung-NENs) e gastro-entero-pancreatiche (GEP-NENs) in progressione dopo SSAs, everolimus, sunitinib, chemioterapia e/o PRRT. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patient with Lung and GEP-NENs progressive after SSAr, everolimus, sunitinib or PRRT. |
| Neoplasie neuroendocrine polmonari (Lung-NENs) e gastro-entero-pancreatiche (GEP-NENs) in progressione dopo SSAs, everolimus, sunitinib, chemioterapia e/o PRRT. |
|
| 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 | 10028196 |
| E.1.2 | Term | Multiple endocrine neoplasias |
| 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 assess the efficacy of the combination of cabozantinib and one-week-on one-week-off temozolomide, based on overall response rate (ORR). |
| Valutare l'efficacia della combinazione di cabozantinib e temozolomide in un regime terapeutico di 7 giorni di somministrazione seguiti da 7 giorni di stop, in base al tasso di risposta globale (ORR). |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess the activity of the combination of cabozantinib and one-week-on one-week-off temozolomide according to Progression Free Survival (PFS), Clinical Benefit Rate (CBR), Overall Survival (OS), duration of response (DOR).
2. To assess the safety and tolerability of the combination of cabozantinib and one-week-on one-week-off temozolomide.
3. To assess the predictive role of MGMT Methylation Status on response to the combination of cabozantinib and one-week-on one-week-off temozolomide.
4. To assess the activity of the combination of cabozantinib and one-week-on one-week-off temozolomide at 1 year from the start of the treatment. |
1. Valutare l'attività della combinazione di cabozantinib e temozolomide, in un regime terapeutico di 7 giorni di somministrazione seguiti da 7 giorni di stop, in relazione a: sopravvivenza libera da progressione (PFS), tasso di beneficio clinico (CBR), sopravvivenza globale (OS), durata della risposta (DOR).
2. Valutare la sicurezza e la tollerabilità della combinazione di cabozantinib e temozolomide in un regime terapeutico di 7 giorni di somministrazione seguiti da 7 giorni di stop.
3. Valutare il ruolo predittivo dello stato di metilazione di MGMT in risposta alla combinazione di cabozantinib e temozolomide in un regime terapeutico di 7 giorni di somministrazione seguiti da 7 giorni di stop.
4. Valutare l'attività dell'associazione di cabozantinib e temozolomide, in un regime terapeutico di 7 giorni di somministrazione seguiti da 7 giorni di stop, a 1 anno dall'inizio del trattamento. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 18 years and older patients
2. Signed informed consent prior to initiation of any study-specific procedures or treatment, as confirmation of the patient’s awareness and willingness to comply with the study requirements.
3. Documented histological or cytological diagnosis of well differentiated Lung and GEP-NENs (NET G1, NET G2, NET G3 in WHO 2017 classification) progressing after a first line of therapy with SSAs, sunitinib, everolimus, chemotherapy and/or PRRT or documented histological or cytological diagnosis of Large cells neuroendocrine carcinoma patients with Ki67< 55% progressed after platinum-based first line chemotherapy.
4. Subjects must have evidence of progressed disease, radiologically documented in the 12 months previous study entry.
5. Subjects must have evidence of measurable disease as determined by the investigator. Target lesions must have shown evidence of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria in the 12 months prior to study entry. Patients must have measurable disease per RECIST 1.1 by computer tomography (CT) scan or magnetic resonance imaging (MRI). Gallium 68 PET Scan can be considered useful before and during the treatment.
6. Subjects with functional (associated with a clinical hormone syndrome) and non functional tumors are eligible for the study.
7. The concurrent use of somatostatin analogues is allowed provided that the patient has been on a stable dose for at least two months.
8. At least 4 weeks of wash-out from previous targeted therapies.
9. At least 6 months of wash-out from previous PRRT treatment.
10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2
11. Subjects must have adequate organ function, including the following:
- Bone marrow reserve consistent with: absolute neutrophil count (ANC) =1.5 x109/L; platelet count = 100 x 109/L; haemoglobin = 9 g/dL;
- Hepatic: total bilirubin = 1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase [AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase [ALT/SGPT]) = 2.5 x ULN (< 5 x ULN if liver metastases are present);
- Renal: normal serum creatinine or calculated creatinine clearance = 60 mL/min (Cockroft-Gault formula);
12. Recovery from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
13. Estimated life expectancy of =12 weeks.
14. Sexually active fertile subjects (male and female) must agree to use medically accepted methods of contraception during the course of the study and for 4 months after the last dose of study treatment.
15. For women of child-bearing potential, negative serum pregnancy test within 14 days prior to the first study drug administration;
16. Ability to understand and willingness to sign informed consent form prior to initiation of any study procedures and willingness to comply with the study requirements. |
1. Pazienti di età = 18 anni
2. Diagnosi istologica o citologica documentata di polmone e GEP-NENs ben differenziati (NET G1, NET G2, NET G3 nella classificazione WHO 2017) metastatici in progressione dopo una prima linea di terapia con SSA, sunitinib, everolimus, chemioterapia e / o PRRT.
3. Documentata diagnosi istologica o citologica di pazienti con
carcinoma neuroendocrino a grandi cellule con Ki67 < 55%
progredito dopo chemioterapia di prima linea a base di platino.
4. Progressione di malattia documentata radiologicamente nei 12 mesi precedenti l'ingresso nello studio.
5. Sono ammessi tumori funzionali (associati a una sindrome ormonale clinica) o non funzionali.
6. Pertanto è consentito l'uso concomitante di analoghi della somatostatina a condizione che il paziente abbia assunto una dose stabile per almeno due mesi .
7. Devono essere trascorse almeno 4 settimane di wash-out da
precedenti terapie target .
8. Devono essere trascorse almeno 6 mesi di wash-out dal precedente trattamento con PRRT.
9. Malattia misurabile come determinato dallo sperimentatore. Le lesioni target devono aver mostrato l'evidenza di progressione di malattia in base ai criteri di valutazione della risposta nei tumori solidi (RECIST) versione (v) 1.1 nei 12 mesi precedenti l'ingresso
nello studio. I pazienti devono avere malattia misurabile secondo RECIST 1.1 mediante tomografia computerizzata (TAC) o risonanza magnetica (MRI). La diagnostica per immagini con tomografia a emissione di positroni (PET)/TAC [68Ga] può essere considerata utile prima e durante il trattamento.
10. ECOG performance status (PS) deve essere compreso tra 0-2.
11. I pazienti devono firmare un modulo di consenso informato prima di iniziare qualsiasi procedura o trattamento specifico per lo studio, come conferma della consapevolezza e della volontà del paziente di rispettare i requisiti dello studio.
12. Recupero da tossicità correlata a qualsiasi trattamento precedente, a meno che gli AE non siano clinicamente non significativi e / o stabili con terapie di supporto.
13. Adeguata funzione di organo e midollo.
14. Aspettativa di vita stimata =12 settimane.
15. I soggetti fertili, sessualmente attivi ,(maschi e femmine) devono accettare di utilizzare metodi contraccettivi validi nel corso dello studio e per i 4 mesi successivi all'ultima dose del trattamento in studio.
16. I soggetti femminili in età fertile non devono essere in stato di gravidanza allo screening. |
|
| E.4 | Principal exclusion criteria |
1. Receipt of any type of anticancer therapy within 4 weeks before study entry.
2. Previous treatment with Temozolomide or cabozantinib
3. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before recruitment.
4. Previous PRRT treatment: Systemic treatment with radionuclides within 6 months before study entry.
5. Subjects with clinically relevant ongoing complications from prior radiation therapy and/or surgery are not eligible.
6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before study entry
7. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors.
8. Chronic treatment with corticosteroids or other immuno-suppressive agents.
9. Serious illness other than cancer:
a. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before recruitment. Note: Complete healing of an intra-abdominal abscess must be confirmed prior to recruitment.
b. Cavitating pulmonary lesion(s) or endobronchial disease
c. Lesion invading a major blood vessel including, but not limited to: inferior vena cava, pulmonary artery, or aorta. Subjects with lesions invading the portal vasculature are eligible.
d. Clinically significant bleeding risk including the following within 3 months of recruitment: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors
e. Other clinically significant disorders such as:
i. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome (AIDS)-related illness.
ii. Serious non-healing wound/ulcer/bone fracture
iii. Malabsorption syndrome iv. Uncompensated/symptomatic hypothyroidism v. Requirement for hemodialysis or peritoneal dialysis vi. History of solid organ transplantation
4. Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to recruitment, preferably via gated equilibrium radionuclide ventriculography. The results from an earlier assessment (not exceeding 30 days prior to recruitment) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient’s measured cardiac ejection fraction in these patients must be >40% before recruitment.
5. QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome.
6. Patients with rare hereditary problems of galattose intolerance, congenital lactase deficiency or glucose-galattose malabsorption.
7. Major surgery within 3 months before study entry. Complete wound healing from major surgery must have occurred 1 month before study entry and from minor surgery at least 10 days before study entry.
8. Pregnant or lactating females.
9. History of another malignancy within 2 years before study entry, except for superficial skin cancers.
10. Serious and/or unstable pre-existing medical or psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures |
1. Aver ricevuto qualsiasi tipo di terapia antitumorale entro 4 settimane precedenti l'ingresso nello studio.
2. Aver ricevuto trattamento precedente con Temozolomide o cabozantinib
3. Aver fatto radioterapia per metastasi ossee entro 2 settimane,o qualsiasi altra radioterapia esterna entro 4 settimane precedenti della randomizzazione.
4. Aver ricevuto precedente trattamento PRRT: trattamento sistemico con radionuclidi entro 6 mesi prima dell'ingresso nello studio.
5. Soggetti con in corso complicazioni clinicamente rilevanti, derivanti da precedente radioterapia e / o interventi chirurgici non sono eleggibili.
6. Metastasi cerebrali note o malattia epidurale cranica, se non adeguatamente trattate con radioterapia e / o chirurgia e stabili per almeno 3 mesi prima dell'ingresso nello studio.
7. Terapie concomitanti con anticoagulanti ,a dosi terapeutiche, con anticoagulanti orali o inibitori piastrinici.
8. Trattamento cronico con corticosteroidi o altri agenti immunosoppressori.
9. Malattia gravi diversi dal cancro.
10. Chirurgia maggiore entro 3 mesi prima dell'ingresso nello studio. La guarigione completa della ferita dall' intervento di chirurgico maggiore deve essere avvenuta 1 mese prima dell'ingresso nello studio e da un intervento chirurgico minore almeno 10 giorni prima dell'ingresso nello studio.
11. Donne in gravidanza o in allattamento.
12. Diagnosi di un'altra neoplasia entro 2 anni prima dell'ingresso nello studio, ad eccezione dei tumori superficiali della pelle. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR (as assessed by RECIST v1.1) defined by complete response (CR) or partial response (PR). |
Overall response rate (ORR)
Il primo endpoint è l’ORR (Overall response rate) secondo i criteri RECIST |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
PFS (as assessed by RECIST v1.1) defined as time from study entry to first evidence of disease progression or death due to any cause.
CBR (as assessed by RECIST v1.1) defined by complete response (CR) or partial response (PR) or stable disease (SD).
OS defined as time from study entry to death due to any cause or to study termination.
DOR defined as time from study entry to change in response from CR or PR to Stable Disease (SD) or Progressive Disease (SD) (as assessed by RECIST v1.1).
Safety and tolerability as assessed by adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
MGMT Methylation Status will be assessed and any correlation with the efficacy endpoints will be evaluated.
1 year overall survival (OS) |
Sopravvivenza libera da progression (PFS)
Clinical Benefit Rate (CBR)
Overall survival (OS)
1 anno di OS
MGMT stato di metilazione
Sicurezza e tollerabilità
Durata della risposta |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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
| 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 | 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
|
| The purpose of this study is highlighted and the safety of the combination of Cabozantinib and Temozolomide in lung neuroendocrine and GEP-NEN neoplasms, progressing after first-line therapy, including target therapies (everolimus, sunitinib) chemotherapy and / or PRRT. |
| Lo scopo di questo studio è dimostrare l'attività e la safety della combinazione di Cabozantinib e Temozolomide nelle neoplasie neuroendocrine polmonari e GEP-NENs, in progressione dopo una terapia di prima linea, comprese le terapie target (everolimus, sunitinib) chemioterapia e /o PRRT. |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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