Clinical Trials Register

Summary
EudraCT Number:	2017-003765-10
Sponsor's Protocol Code Number:	I-Tackle
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
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

2017-003765-10

A.3

Full title of the trial

Immunotherapy Followed By EGFR Inhibitor In Locally Advanced Or Metastatic Squamous Cell Cancer Of The Skin: Tackling Primary And Secondary Resistance

Immunoterapia seguita da inibitore delle EGFR nel carcinoma squamocellulare della cute localmente avanzato o metastatico: combattere le resistenze primarie e secondarie

A.3.1

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

Immunotherapy followed by Epidermal Growth Factor Receptor (EGFR) in Locally advanced or metastatic squamous cell cancer of the skin: tackling ineffectiveness of drugs

Immunoterapia seguita da inibitore del fattore di crescita dell'epidermide (EGFR) nel tumore squamocellulare della pelle localmente avanzato o in metastatico: combattere l'inefficacia dei farmaci

A.3.2

Name or abbreviated title of the trial where available

I-TACKLE

A.4.1

Sponsor's protocol code number

I-Tackle

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	FONDAZIONE IRCCS "ISTITUTO NAZIONALE DEI TUMORI"
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	Merck & Co,. INC
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
B.5.2	Functional name of contact point	S.C. Oncologia Medica 3 - Tumori Te
B.5.3	Address:
B.5.3.1	Street Address	Via Venezian, 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	0223902805
B.5.5	Fax number	0223903769
B.5.6	E-mail	lisa.licitra@istitutotumori.mi.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.2.1.2	Country which granted the Marketing Authorisation	Italy
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	IMP1
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	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	Pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.3	Other descriptive name	Anti-PD-1 monoclonal antibody
D.3.9.4	EV Substance Code	SUB167136
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	20
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)	No
	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	No
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

Patient with Locally Advanced Or Metastatic Squamous Cell Cancer Of The Skin

Pazienti affetti da carcinoma squamocellulare della cute localmente avanzato o metastatico

E.1.1.1

Medical condition in easily understood language

Locally Advanced Or Metastatic Squamous Cell Cancer Of The Skin

Tumore squamocellulare della pelle localmente avanzato o che presentano metastasi

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10041834
E.1.2	Term	Squamous cell carcinoma of skin
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

E.2.2

Secondary objectives of the trial

Compliance to the treatment and safety
Disease control (SD + PR + CR) as best response obtained by single agent or by combination
- Progression-Free Survival (PFS) and Overall Survival (OS)
- Percentage of patients initially not considered for surgery due to difficulty to obtain a curative treatment that undergo surgery after the treatment (pembrolizumab alone or pembrolizumab + anti EGFR agent)
- Reversal of acquired resistance to pembrolizumab obtained through the addition of cetuximab (percentage of responding patients after cetuximab adjunct)

Compliance al trattamento e sicurezza
Controllo della malattia (SD + PR + CR) come migliore risposta ottenuta da un singolo agente o dalla combinazione
- Sopravvivenza libera da progressione (PFS) e sopravvivenza generale (OS)
- Percentuale di pazienti inizialmente non considerati candidabili a intervento chirurgico, che dopo il trattamento (solo pembrolizumab o pembrolizumab + agente anti-EGFR) possono essere sottoposti al trattamento chirurgico.
- Reversibilit¿ della resistenza acquisita al pembrolizumab attraverso l'aggiunta di cetuximab (percentuale di pazienti rispondenti dopo l'aggiunta di cetuximab)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Have histological diagnosis of squamous cell carcinoma of the skin not amenable to surgical treatment and to radiation with curative purposes or with clinical contraindication to surgery and radiation. Hereafter the possible clinical situations matching these criteria. A multidisciplinary evaluation with surgeon, radiation oncologist and medical oncologist is required to be performed:
¿ skin SCC that has recurred in the same location after two or more surgical procedures and curative resection is deemed unlikely; the tumor is not amenable to radiation as it has been already performed or it is not considered effective
anticipated substantial morbidity and/or deformity from surgery (e.g., removal of all or part of a facial structure, such as nose, ear, eyelid, eye; or requirement for limb amputation); radiation therapy is similarly not indicated due to anticipated morbidity and/or deformity
¿ anticipated difficulty in obtaining a curative resection or a curative radiation due to the location of the tumor, the size of disease
¿ anticipated difficulty in reconstructing the area that will be surgically removed
¿ significant comorbidities that preclude the feasibility of a radical surgery
¿ contraindication to radiotherapy:
a) previous radiation therapy administered to the area of disease
b) site of previous burns
c) areas of vascular insufficiency
d) skin areas which lead to compromised healing or increased risk of late skin necrosis (e.g.: skin of the back overlying the spine; skin overlying the shin and malleoli of the lower leg)
e) patients with ataxia telangiectasia or with xeroderma pigmentosus
f) other contraindications according to physician’s judgement (to be reported in clinical chart)
OR
Have metastatic disease
2. Have measurable disease based on RECIST 1.1.
3. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.
4. Have a performance status of 0 or 1 on the ECOG Performance Scale.

1. Avere una diagnosi istologica del carcinoma a cellule squamose della pelle non eleggibile a trattamento chirurgico e a radioterapia o con controindicazione clinica alla chirurgia e alle radioterapia. Di seguito le possibili situazioni cliniche corrispondenti a questi criteri. Deve essere effettuata una valutazione multidisciplinare tra chirurgo, oncologo radioterapista e oncologo medico:
-SCC cutaneo che si è ripresentato nella stessa posizione anatomica dopo due o più interventi chirurgici e la resezione chirurgica non è indicata; il tumore non è suscettibile a radioterapia poiché è già stata eseguita o non è considerata efficace
prevedibile morbilità e / o deformità sostanziale a causa della chirurgia (ad es. rimozione di tutta o parte di una struttura facciale, come naso, orecchio, palpebra, occhio o richiesta di amputazione degli arti); Analogamente, la radioterapia non è indicata a causa di morbilità e / o deformità pregressa
¿ difficoltà nell'ottenere una resezione curativa o radioterapia dovuta alla posizione del tumore, la dimensione della massa tumorale
¿ difficoltà nella ricostruzione dell'area che verrà rimossa chirurgicamente
¿ comorbidità significative che precludono la fattibilità di un intervento chirurgico radicale
¿ controindicazione alla radioterapia:
a) precedente radioterapia somministrata all'area della malattia
b) sito di ustioni precedenti
c) aree con insufficienza vascolare
d) aree cutanee che portano a una guarigione compromessa o ad un aumentato rischio di necrosi cutanea tardiva (ad es .: pelle del dorso in corrispondenza con la colonna vertebrale, pelle dello stinco e i malleoli della parte inferiore della gamba)
e) pazienti con atassia telangiectasia o con xeroderma pigmentoso
f) altre controindicazioni secondo il giudizio del medico (da riportare nella cartella clinica)
O
Presenza di una malattia metastatica
2. Hanno una malattia misurabile basata su RECIST 1.1.
3. Essere disposti a fornire tessuto da un core fresco da una biopsia escissionale di una lesione tumorale. Il nuovo tessuto è definito come un campione ottenuto fino a 6 settimane (42 giorni) prima dell'inizio del trattamento. Soggetti per i quali non possono essere forniti campioni freschi (per esempio siti inaccessibili o che creano problemi di sicurezza pe ri pazienti ) possono presentare solo un campione archiviato previo accordo dello Sponsor.
4. Avere uno stato di prestazioni pari a 0 o 1 sulla scala di prestazioni ECOG.

E.4

Principal exclusion criteria

1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
2. Previous treatment with anti-EGFR agent
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (prednisone equivalent dose > 10 mg per day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
4. Has a known history of active TB (Bacillus Tuberculosis)
5. Has previously received an organ transplant
6. Has previously received bone marrow transplantation

1. Sta attualmente partecipando e ricevendo una terapia sperimentale o ha partecipato a uno studio su un agente in fase di sperimentazione e ha ricevuto una terapia di studio o ha utilizzato un dispositivo sperimentale entro 4 settimane dalla prima dose di trattamento.
2. Trattamento precedente con agente anti-EGFR
3. Ha una diagnosi di immunodeficienza o sta ricevendo terapia steroidea sistemica (dose equivalente di prednisone> 10 mg al giorno) o qualsiasi altra forma di terapia immunosoppressiva entro 7 giorni prima della prima dose del trattamento sperimentale.
4. Ha una storia nota di TB attiva (Bacillus Tuberculosis)
5. Ha già ricevuto un trapianto d'organo
6. Ha già ricevuto il trapianto di midollo osseo

E.5 End points

E.5.1

Primary end point(s)

Increase in cumulative response rate (PR + CR) obtained by single agent or by combination strategy (pembrolizumab alone or with pembrolizumab + EGFR inhibiting agent) in respect to monotherapy with anti-EGFR agent. We will consider this approach as effective if the cumulative response rate is at least 45%, with an increase of 17% with respect to previous study with cetuximab in the same setting of disease, in which a response rate of 28% was shown.

aumento del tasso di risposta cumulativa (PR + CR) ottenuto dall'agente singolo o dalla strategia di combinazione (pembrolizumab da solo o con pembrolizumab + agente inibitore dell'EGFR) rispetto ai dati pubblicati in letteratura con monoterapia con agente anti-EGFR.
Considereremo questo approccio efficace se il tasso di risposta cumulativa è almeno del 45%, con un aumento del 17% rispetto allo studio precedente con cetuximab nello stesso quadro di malattia, in cui è stato mostrato un tasso di risposta del 28%

E.5.1.1

Timepoint(s) of evaluation of this end point

15 patients will be first enrolled and the first evaluation will take place as soon as the last patient has completed 3 cycles of treatment with Pembrolizumab +/- anti EGFR agent. Then, if we do not observe at least 5 responses (partial or complete), no additional patient will be enrolled into the study and we will reject the hypothesis. These patients will be nevertheless followed until progression.
If at least 5 patients have responded, then we will enroll 28 additional patients. When the last patient will have completed 4 months of treatment, a second analysis of the response rate will be performed. If the total number of responders is at least 16, then the drug will be considered as effective and worth for further investigation. All patients will be followed until progression.

15 pazienti verranno inizialmente arruolati e la prima valutazione avrà luogo non appena l'ultimo paziente avrà completato 3 cicli di trattamento con Pembrolizumab +/- anti EGFR. Quindi, se non osserviamo almeno 5 risposte (parziali o complete), nessun altro paziente verrà arruolato nello studio e rifiuteremo l'ipotesi. Questi pazienti saranno comunque seguiti fino alla progressione.
Se almeno 5 pazienti hanno risposto, allora registreremo 28 ulteriori pazienti. Quando l'ultimo paziente avrà completato 4 mesi di trattamento, verrà eseguita una seconda analisi del tasso di risposta. Se il numero totale di responder è di almeno 16, il farmaco sarà considerato efficace e meritevole di ulteriori indagini. Tutti i pazienti saranno seguiti fino alla progressione.

E.5.2

Secondary end point(s)

- Compliance to the treatment and safety
- Disease control as best response obtained by single agent or by combination
- Progression-Free Survival (PFS) and Overall Survival (OS)
- Percentage of patients initially not considered for surgery due to difficulty to obtain a curative treatment that undergo surgery after the treatment (pembrolizumab alone or pembrolizumab + anti EGFR agent)
- Reversal of acquired resistance to pembrolizumab obtained through the addition of cetuximab (percentage of responding patients)

- Compliance al trattamento e sicurezza
- Controllo della malattia come migliore risposta ottenuta da un singolo agente o dalla combinazione
- Sopravvivenza libera da progressione (PFS) e sopravvivenza generale (OS)
- Percentuale di pazienti inizialmente non considerati candidabili a intervento chirurgico, che dopo il trattamento (solo pembrolizumab o pembrolizumab + agente anti-EGFR) possono essere sottoposti al trattamento chirurgico.
- Reversibilit¿ della resistenza acquisita al pembrolizumab attraverso l'aggiunta di cetuximab (percentuale di pazienti rispondenti dopo l'aggiunta di cetuximab)

E.5.2.1

Timepoint(s) of evaluation of this end point

In case of SD or PD revaluation of the disease at 4 weeks. Revaluation after 6 weeks of combined treatment, revaluation at 4 weeks.
Secondary endpoints will be evaluated during the treatment period.

In caso di SD o PD rivalutazione della malattia a 4 settimane. Rivalutazione dopo 6 settimane di trattamento combinato , rivalutazione a 4 settimane.
Gli endpoint secondari saranno valutati durante il periodo di trattamento.

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

Yes

E.6.4

Safety

Yes

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

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

Yes

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 visits will be performed after 30 days to the end of treatment. Subsequently every 2 months during the first year and later after 12 weeks.

Le visite di follow-up saranno effettuate 30 giorni dopo la fine del trattamento e, successivamente, ogni 2 mesi per il primo anno ed in seguito ogni 12 settimane.

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

2018-07-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2025-01-24

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