Clinical Trials Register

Summary
EudraCT Number:	2012-000087-15
Sponsor's Protocol Code Number:	CRd
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:	2012-04-02
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

2012-000087-15

A.3

Full title of the trial

A PHASE II, MULTI-CENTER, OPEN LABEL STUDY OF CYCLOPHOSPHAMIDE IN MULTIPLE MYELOMA PATIENTS WITH BIOCHEMICAL PROGRESSION DURING LENALIDOMIDE-DEXAMETHASONE TREATMENT FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA

STUDIO DI FASE II IN APERTO, MULTICENTRICO, IN PAZIENTI CON MIELOMA MULTIPLO RECIDIVI/REFRATTARI IN TERAPIA CON LENALIDOMIDE-DESAMETASONE: AGGIUNTA DI CICLOFOSFAMIDE IN CASO DI PROGRESSIONE SIERICA SENZA SEGNI (CRAB) DI MALATTIA ATTIVA

A.3.1

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

A PHASE II STUDY OF CYCLOPHOSPHAMIDE IN MULTIPLE MYELOMA PATIENTS WITH BIOCHEMICAL PROGRESSION DURING LENALIDOMIDE-DEXAMETHASONE TREATMENT FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA

STUDIO DI FASE II IN PAZIENTI CON MIELOMA MULTIPLO RECIDIVI/REFRATTARI IN TERAPIA CON LENALIDOMIDE-DESAMETASONE CON AGGIUNTA DI CICLOFAOSFAMIDE IN CASO DI PROGRESSIONE SENZA SEGNI DI MALATTIA ATTIVA

A.4.1

Sponsor's protocol code number

CRd

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 NEOPLASIE SANGUE ONLUS
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	FONDAZIONE NEOPLASIE SANGUE ONLUS
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	FO.NE.SA Onlus
B.5.2	Functional name of contact point	Ufficio Sperimentazioni Cliniche
B.5.3	Address:
B.5.3.1	Street Address	Via Genova 3
B.5.3.2	Town/ city	TORINO
B.5.3.3	Post code	10126
B.5.3.4	Country	Italy
B.5.4	Telephone number	011 633 6107
B.5.5	Fax number	011 696 3737
B.5.6	E-mail	gismm2001@yahoo.com

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	Yes
D.2.1.1.1	Trade name	REVLIMID*21CPS 25MG
D.2.1.1.2	Name of the Marketing Authorisation holder	CELGENE Srl
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.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oromucosal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.1	CAS number	191732-72-6
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	Yes
D.3.11.13.1	Other medicinal product type	IMMUNOMODULATORE

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

RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS

PAZIENTI AFFETTI DA MIELOMA MULTIPLO RECIDIVI/REFRATTARI

E.1.1.1

Medical condition in easily understood language

MULTIPLE MYELOMA PATIENTS

PAZIENTI AFFETTI DA MIELOMA MULTIPLO

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 addiction of Cyclophosphamide to Revlimid-low dose dexamethasone (Rd) in relapsed/refractory Multiple Myeloma patients, who experienced a biochemical progression, without CRAB, during Rd treatment

• Valutare l’efficacia (risposta) dell’aggiunta della Ciclofosfamide alla Lenalidomide-Desametasone (Rd) nei Pazienti con Mieloma Multiplo in recidiva/refrattari, che dimostrano una progressione bioumorale durante il trattamento con Rd

E.2.2

Secondary objectives of the trial

•To assess the safety •To assess progression free survival (PFS) •To assess overall survival (OS) •Duration of time to progression (TTP). •Time to next therapy (TNT) •To assess prognostic factors (ISS, FISH, age, sex, renal function)

•Valutare la sicurezza •Valutare la PFS •Valutare la OS •Valutare la TTP •Valutare la TNT •Valutare fattori prognostici (ISS, FISH, età, sesso, funzionalità renale)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patient with relapse/refractory multiple myeloma who experienced biochemical progression, without CRAB, during treatment with Rd. CRAB means the presence of organ damage, multiple myeloma related (renal impairment and/or anemia and/or new bone lesions and/or hypercalcemia). It is sufficient one of the previous signs for defining the presence of CRAB. Biochemical progression means: positivization of serum/urine immunofixation for patients who reached a complete remission with Rd treatment or at least 25% increment of monoclonal component in serum/urine for patients who reached at least a stable disease (SD). • Patient exposed to previous therapy included Lenalidomide, Thalidomide, Bortezomib and/or ASCT and in treatment with Rd. • Patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements. • Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care. • Female patient is either post-menopausal or surgically sterilized or, if at child-bearing potential, must: understand that the study medication could have an expected teratogenic risk. • Agree to use, and be able to comply with, effective contraception without interruption, 4 weeks before starting study drug, throughout study drug therapy (including dose interruptions) and for 4 weeks after the end of study drug therapy, even if she has amenorrhea. This applies unless the subject commits to absolute and continued abstinence confirmed on a monthly basis. The following are effective methods of contraception*: o Implant** o Levonorgestrel-releasing intrauterine system (IUS)** o Medroxyprogesterone acetate depot o Tubal sterilisation o Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses o Ovulation inhibitory progesterone-only pills (i.e., desogestrel) • Combined oral contraceptive pills are not recommended. If a subject was using combined oral contraception, she must switch to one of the methods above. The increased risk of VTE continues for 4 to 6 weeks after stopping combined oral contraception. • **prophylactic antibiotics should be considered at the time of insertion particularly in patients with neutropenia due to risk of infection. • Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml not more than 3 days before the start of study medication once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practice complete and continued abstinence. • Agree to have a medically supervised pregnancy test every 4 weeks including 4 weeks after the end of study treatment, except in the case of confirmed tubal sterilization. These tests should be performed not more than 3 days before the start of next treatment. This requirement also applies to women of childbearing potential who practice complete and continued abstinence. • † A female subject or a female partner of a male subject is considered to have childbearing potential unless she meets at least one of the following criteria: Age ≥50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea following cancer therapy does not rule out childbearing potential), premature ovarian failure confirmed by a specialist gynaecologist, previous bilateral salpingo-oophorectomy or hysterectomy, XY genotype, Turner’s syndrome or uterine agenesis. • •Male subjects must: o Agree to use condoms throughout study drug therapy, during any dose interruption and for one week after cessation of study therapy if their partner is of childbearing potential and has no contraception.

• Pazienti con MM in recidiva/refrattari che dimostrano una progressione di malattia umorale, senza segni attivi di malattia (CRAB), durante il trattamento con Rd. Il CRAB indica un danno d’organo dovuto al MM (insufficienza renale, e/o anemia, e/o nuove lesioni osteolitiche e/o ipercalcemia); si parla di CRAB anche in presenza di uno solo di questi segni. Per progressione umorale si intende: positivizzazione della immunofissazione del siero/urine per i pazienti che avevano ottenuto una remissione completa o un aumento della componente monoclonale > del 25% per i pazienti che avevano raggiunto una remissione parziale o una malattia stabile durante il trattamento con Rd. • Pazienti già trattati con Lenalidomide, Talidomide, Bortezomib e/o ASCT e in terapia con Rd. • Pazienti che rispondono ai requisiti del protocollo e che sono capaci di completare le procedure. • Pazienti che firmano volontariamente il consenso informato prima di eseguire qualunque procedura, consapevoli che il consenso potrà essere ritirato da loro senza pregiudicare nessuna terapia. • Pazienti di sesso femminile sia in menopausa o potenzialmente fertili devono essere a conoscenza del fatto che il farmaco in studio ha un potenziale rischio teratogeno. • Pazienti che sono d’accordo e capaci di utilizzare, senza interrompere, metodi contraccettivi per 4 settimane prima dell’inizio del trattamento, durante tutta la terapia anche in caso di interruzione e per 4 settimane dopo la fine del trattamento, anche se sono in amenorrea. Tutto questo dovrà essere applicato a tutti i pazienti a rischio, fatta eccezione per i soggetti che si astengono dai rapporti sessuali in modo continuativo. I metodi contraccettivi considerati validi* sono sottoelencati: o Impianti** o Sistemi intrauterine che rilasciano Levonorgestrel (IUS)** o Chiusura delle tube o Vasectomia che dovrà essere confermata con 2 test negativi dello spermatogramma • La pillola anticoncezionale non viene raccomandata, per cui se la paziente la sta utilizzando si consiglia di sostituirla con uno dei metodi su indicati tenendo presente che l’aumentato rischio trombotico dovuto alla contraccezione orale continua anche dopo 4 o 6 settimane dalla sua interruzione. • **la profilassi antibiotica dovrebbe essere considerata nel momento dell’inserzione dell’impianto, in modo particolare nei pazienti neutropenici. • Tutte le pazienti dovranno essere d’accordo ad eseguire un test di gravidanza, con un minimo di sensibilità di 25 mIU/ml, non più di 3 giorni prima di iniziare la terapia e dopo aver iniziato ad utilizzare i metodi contraccettivi da almeno 4 settimane. Il test è richiesto anche per le donne potenzialmente fertili che praticano una completa e continua astinenza. • Tutte le pazienti dovranno essere d’accordo ad eseguire un test di gravidanza ogni 4 settimane fino a 4 settimane dopo la fine del trattamento, il test è richiesto anche per le donne potenzialmente fertili che praticano una completa e continua astinenza. • † Una paziente di sesso femminile o la partner di un paziente di sesso maschile è considerate fertile fatta eccezione per uno dei seguenti criteri: Età ≥50 anni e con amenorrea naturale per ≥ 1 anno (l’amenorrea conseguente alla terapia antitumorale non è considerata tale), prematura insufficienza ovarica confermata dal ginecologo, precedente salpingo-ovariectomia bilaterale e isterectomia, genotipo XY, sindrome di Turner o agenesia uterina. • Soggetti di sesso maschile devono: o Essere d’accordo ad utilizzare il profilattico durante tutto il periodo di studio, anche durante l’interruzione della terapia e per una settimana dopo la fine della terapia se le loro partner sono in età fertile e non utilizzano contraccettivi. o Essere d’accordo a non donare lo sperma durante tutto il periodo di studio e per una settimana dopo la fine della terapia.

E.4

Principal exclusion criteria

• Patients with newly diagnosed multiple myeloma. • Patients who relapsed from multiple myeloma with signs of organ damage related to disease (CRAB). • Any serious medical condition, including the presence of laboratory abnormalities, which places the subject at an unacceptable risk if he or she participates in this study or confounds the experimental ability to interpret data from the study. • Pregnant or lactating females. • Prior history of malignancies, other than multiple myeloma, unless the subject has been free of the disease for ≥ 3 years. Exceptions include the following: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological finding of prostate cancer (TNM stage of T1a or T1b).

• Pazienti con MM alla diagnosi. • Pazienti che recidivano con segni di danno d’organo (CRAB). • Qualunque condizione medica seria, comprese le alterazioni di laboratorio, che possono causare rischi per i pazienti o che rendono difficili l’interpretazione dei dati dello studio. • Donne incinte o che allattano. • Storia antecedente di altra neoplasia, oltre al MM, ad eccezione di quelli diagnosticati da ≥ 3 anni. Fatta eccezione per: carcinoma basale della cute, carcinoma squamoso della cute, carcinoma in situ della cervice, carcinoma in situ della mammella, cancro della prostata (TNM stadio T1a o T1b).

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

9 months

9 mesi

E.5.2

Secondary end point(s)

9 months

9 mesi

E.5.2.1

Timepoint(s) of evaluation of this end point

9 months

9 mesi

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

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

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

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)

Yes

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

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.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)

During the LTFU period, after development of confirmed PD, all patients are to be followed for survival every 1-3 months via telephone or office visit.

Durante il periodo di LTFU, dopo una confermata PD, tutti i pazienti tramite telefono o visita presso il centro dovranno essere valutati per la sopravvivenza ogni 1-3 mesi.

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

2012-03-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-03-15

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

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