Clinical Trials Register

Summary
EudraCT Number:	2018-004758-39
Sponsor's Protocol Code Number:	ESR-18-13485
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-06-17
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-004758-39

A.3

Full title of the trial

A PHASE II STUDY OF CAPECITABINE PLUS CONCOMITANT RADIATION THERAPY FOLLOWED BY DURVALUMAB (MEDI4736) AS PREOPERATIVE TREATMENT IN RECTAL CANCER

STUDIO DI FASE II DEL TRATTAMENTO PREOPERATORIO CON CAPECITABINA E RADIOTERAPIA CONCOMITANTE SEGUITE DA DURVALUMAB (MEDI4736) NEL TUMORE DEL RETTO LOCALMENTE AVANZATO

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

STUDY OF CAPECITABINE PLUS CONCOMITANT RADIATION THERAPY FOLLOWED BY DURVALUMAB AS PREOPERATIVE TREATMENT IN PATIENTS WITH RECTAL CANCER

STUDIO CLINICO DEL TRATTAMENTO PREOPERATORIO CON CAPECITABINA E RADIOTERAPIA SEGUITE DA DURVALUMAB IN PAZIENTI CON TUMORE DEL RETTO

A.3.2

Name or abbreviated title of the trial where available

PANDORA

A.4.1

Sponsor's protocol code number

ESR-18-13485

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AZIENDA UNITÀ SANITARIA LOCALE DELLA ROMAGNA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AstraZeneca S.p.A.
B.4.2	Country
B.4.1	Name of organisation providing support	AUSL della Romagna
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRST IRCCS
B.5.2	Functional name of contact point	Centro di Coordinamento Studi Clini
B.5.3	Address:
B.5.3.1	Street Address	Via P. Maroncelli 40
B.5.3.2	Town/ city	Meldola
B.5.3.3	Post code	47014
B.5.3.4	Country	Italy
B.5.4	Telephone number	0544285813
B.5.5	Fax number	0544285330
B.5.6	E-mail	cc.ubsc@irst.emr.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Durvalumab
D.3.2	Product code	[MEDI4736]
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	durvalumab
D.3.9.1	CAS number	1428935-60-7
D.3.9.2	Current sponsor code	MEDI4736
D.3.9.3	Other descriptive name	anti-PD-L1 monoclonal antibody
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Locally advanced (T3-4 N0-1) rectal cancer.

Carcinoma del retto localmente avanzato, T3-4 e N0-1.

E.1.1.1

Medical condition in easily understood language

Rectal cancer

Tumore del retto

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	PT
E.1.2	Classification code	10038019
E.1.2	Term	Rectal adenocarcinoma
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

Determine the pathological complete response rate (pCR) in patients with rectal cancer treated with standard neo-adjuvant chemotherapy with capecitabine and radiation followed by durvalumab and surgery.

Determinare il tasso di risposta patologica completa (pCR) in pazienti con carcinoma rettale trattati con chemioradioterapia neoadiuvante standard con capecitabina e radioterapia seguita da durvalumab e chirurgia.

E.2.2

Secondary objectives of the trial

1. Determine safety of treatment with durvalumab;
2. Determine clinical complete remission rate (cCR) after durvalumab treatment, before surgery;
3. Determine disease-free survival (DFS).

1.Determinare la sicurezza del trattamento con durvalumab;
2.Determinare il tasso di remissione clinica completa (cCR) dopo il trattamento con durvalumab, prima dell'intervento chirurgico;
3.Determinare la sopravvivenza libera da malattia (DFS).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and Data Privacy Directive obtained from the patient/legal representative prior to performing any protocol- related procedures, including screening evaluations.
2. Age > 18 years at time of study entry.
3. Eastern Cooperative Oncology Group (ECOG) 0 or 1.
4. Histological diagnosis of adenocarcinoma of rectum.
5. Clinical stage 2-3 rectal adenocarcinoma, cT3/4N0/M0 or Tx N1-2/M0, assessed by thorax abdomen pelvis with contrast Computed tomography (CT) scan, pelvi Magnetic resonance imaging (MRI) scan, pancolonscopy.
6. Able to swallow oral medication.
7. Body weight >30kg.
8. Adequate normal organ and marrow function as defined below:
• Haemoglobin =9.0 g/dL
• Absolute neutrophil count (ANC) > 1500 per mm3
• Platelet count >100.000 per mm3
• Serum bilirubin =1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
• AST (SGOT)/ALT (SGPT) =2.5 x institutional upper limit of normal
• Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976).

9. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre- menopausal patients. Women of childbaring potential or male patients with a female partner of childbearing potential must agree to use at least 1 highly effective method of contraception from the time of screening throughout the total duration of the drug treatment and the drug washout period (90 days after the last dose of durvalumab monotherapy) as detailed in section 7.1. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:

• Women <50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post- menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women =50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
11. Must have a life expectancy of at least 12 weeks.

. Esser in grado di esprimere il proprio consenso informato firmato che include il rispetto dei requisiti e delle restrizioni elencate nel modulo di consenso informato (ICF) e nel presente protocollo. Consenso informato scritto e direttiva sulla privacy dei dati ottenuti dal paziente/rappresentante legale prima di eseguire qualsiasi procedura relativa al protocollo, comprese le valutazioni di screening.
2. Età = 18 anni al momento dell'ingresso nello studio.
3. Eastern Cooperative Oncology Group (ECOG) 0 o 1.
4. Diagnosi istologica dell'adenocarcinoma del retto.
5. Stadio clinico II-III di adenocarcinoma rettale, cT3/4N0/M0 o Tx N1-2/M0, valutato mediante tomografia computerizzata (CT), risonanza magnetica pelvi (MRI), pancolonscopia.
6. Il paziente riesce ad assumere farmaci per via orale.
7. Peso corporeo >30 kg.
8. Adeguata funzionalità midollare, epatica e renale come di seguito definito:
• emoglobina = 9g/dL
• conta assoluta neutrofili = 1500/mm2
• conta piastrinica =100000/mm2
• bilirubina sierica = 1.5 * valore massimo normale secondo gli standard del laboratorio del centro. Questo criterio non si applica a pazienti con confermata sindrome di Gilbert (iperbilirubinemia persistente o ricorrente, non coniugata, in assenza di emolisi o patologia epatica), che saranno ammessi allo studio esclusivamente previo consulto con il Medico di Medicina Generale
• AST (SGOT)/ALT(SGPT) = 2.5 * valore massimo normale secondo gli standard del laboratorio del centro
• clearance della creatinina (CL) misurata > 40 mL/min o CL calcolata > 40 mL/min secondo la formula Cockcroft-Gault (Cockcroft and Gault 1976).
9. Paziente in post-menopausa o con test di gravidanza (urinario o sierologico) negativo per pazienti di sesso femminile in pre-menopausa.
Donne in età fertile o uomini con partner femminile in età fertile devono acconsentire ad utilizzare almeno un metodo contraccettivo ad alta efficacia dal momento dello screening e durante la durata complessiva del trattamento farmacologico e del periodo di washout del farmaco (90 giorni dopo l’ultima dose di durvalumab in monoterapia), come dettagliato nella sezione 7.1 del protocollo.
Le donne verranno considerate in post-menopausa se in amenorrea da 12 mesi senza alternativa causa medica. Si applicano inoltre i seguenti requisiti specifici per l’età:
• donne in età < 50 anni saranno considerate in post-menopausa se in amenorrea per almeno 12 mesi in seguito alla cessazione di trattamenti ormonali esogeni e se hanno livelli di ormone luteinizzante o follicolo-stimolante all’interno dell’intervallo considerato di post-menopausa secondo gli standard del laboratorio del centro, o se hanno subìto ooforectomia bilaterale o isterectomia.
• donne in età = 50 anni saranno considerate in post-menopausa se in amenorrea per almeno 12 mesi in seguito alla cessazione di trattamenti ormonali esogeni, se sono state indotte in menopausa da radioterapia con l’ultima mestruazione di almeno un anno precedente l’inizio dello studio, o se sono state sterilizzate chirurgicamente (ooforectomia bilaterale, salpingectomia bilaterale o isterectomia).
10. Il paziente è in grado di seguire il protocollo per l’intera durata dello studio, inclusi il trattamento in corso, le visite programmate, gli esami e il follow up.
11. L’aspettativa di vita deve essere di almeno 12 settimane.

E.4

Principal exclusion criteria

Exclusion Criteria:

1. Previous treatment for local advanced rectum cancer.
2. Concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.
4. History of hypersensitivity to fluorouracil.
5. Known Dihydropyrimidine dehydrogenase (DPD) deficiency.
6. History of another primary malignancy except for:

- Malignancy treated with curative intent and with no known active disease =5 years before the first dose of study drug and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ

7. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at

physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. The following are exceptions to this criterion:

- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

8. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
9. Major surgical procedure within 28 days prior to the first dose of treatment.
10. Uncontrolled intercurrent illness

Precedente trattamento per carcinoma rettale localmente avanzato
2. Arruolamento concomitante in un altro studio clinico a meno che non sia osservazionale (non interventistico) o durante il follow up di uno studio interventistico.
3. Precedente trattamento con inibitori di PD1 o PD-L1, incluso il durvalumab.
4. Ipersensibilità al fluoro uracile.
5. Noto deficit della diidropirimidina deidrogenasi.
6. Altro tumore primario, eccetto:
• Tumore trattato con intento curatico e con nota inattività per = 5 anni prima della prima dose di farmaco in studio e che basso rischio di recidiva
• Tumore cutaneo (non melanoma) adeguatamente trattato, senza evidenza di malattia
• Carcinoma in situ adeguatamente trattato senza evidenza di malattia (es. carcinoma cervicale in situ).
7. Utilizzo concomitante o precedente di farmaci immunosoppressivi nei 14 giorni antecedenti la prima dose di durvalumab, con l’eccezione di trattamento intranasale o inalatorio di corticosteroidi o corticosteroidi per via sistemica a dosi fisiologiche (= 10 mg/die di prednisone o equivalente corticosteroide). Fanno eccezione:
• Steroidi per via intranasale, inalatoria, topica o iniezioni locali (es. iniezioni intra-articolari)
• Corticosteroidi per via sistemica a dosi fisiologiche (= 10 mg/die di prednisone o equivalente corticosteroide)
• Steroidi come prevenzione per reazioni di ipersensibilità
8. Qualunque chemioterapia concomitante, sperimentale, biologica, o trattamento ormonale antitumorale. Il trattamento concomitante di tipo ormonale per patologie non correlate a tumore (es. terapia ormonale sostitutiva) è accettabile.
9. Interventi di chirurgia maggiore entro 28 giorni dall’inizio del trattamento.
10. presenza di patologie concomitanti non controllate

E.5 End points

E.5.1

Primary end point(s)

proportion of patients with complete pathological response and corresponding confidence intervals after durvalumab treatment.

proporzione di pazienti con risposta patologica completa e corrispondenti intervalli di confidenza in seguito a trattamento con durvalumab.

E.5.1.1

Timepoint(s) of evaluation of this end point

18 months after study start

A 18 mesi dall'apertura dello studio

E.5.2

Secondary end point(s)

Determine safety of treatment with durvalumab in terms of number and the percentage of patients with every type of event; proportion of patients with complete clinical response and corresponding confidence intervals after durvalumab treatment.; DFS is defined as time since surgery until disease occurrence or death, whichever occur first, or last follow-up and will be estimated by using Kaplan-Meier approach

Sicurezza del trattamento con durvalumab in termini di numero e percentuale di pazienti per i quali si verificano eventi avversi; proporzione di pazienti con risposta clinica completa e corrispondenti intervalli di confidenza in seguito a trattamento con durvalumab.; La sopravvivenza libera da malattia, definita come il tempo trascorso dall'intrvento a ripresa di malattia, decesso o ultimo follow up; verrà stimata utilizzando il metodo Kaplan-Meier

E.5.2.1

Timepoint(s) of evaluation of this end point

After 21 months from study start; 18 months after study start; 6 years

After 21 mesi dall'apertura dello studio; A 18 mesi dall'apertura dello studio; 6 anni

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

singolo braccio

single arm

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

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

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Follow-up visit every 4 months after surgery (first 2 years), then every 6 months (next 3 years).
Complete physical exam, digital rectal examination; vital signs, weight; Clinical laboratory tests. Thorax abdomen pelvis CT every 4 months after surgery (first 2 years), then every 6 months (next 3 years).
Sigmoidoscopy every 6 months after surgery (first 2 years). Pancolonscopy at 1 year after surgery, then 3 years and finally every 5 years (with no colon lesions).

Visite di follow-up verranno effettuate ogni 4 mesi dopo la chirurgia per due anni e poi ogni 6 mesi per i successivi 3 anni. Durante le visite saranno effettuati:
- esame obiettivo, con esplorazione rettale
- esami di laboratorio
- rivalutazioni strumentali (CT scan).
La sigmoidoscopia verrà effettuata ogni 6 mesi per i primi due anni. L'estensione a pancolonscopia verrà effettuata dopo 1 anno dall'intervento, dopo 3 anni e successivamente ogni 5 anni in assenza di lesioni al colon.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-05-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-12

P. End of Trial
P.	End of Trial Status	Ongoing

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IMP with orphan designation in the indication
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