Clinical Trials Register

Summary
EudraCT Number:	2017-000764-15
Sponsor's Protocol Code Number:	HOVON145_ETAL-4
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-07-09
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

Netherlands - Competent Authority

A.2

EudraCT number

2017-000764-15

A.3

Full title of the trial

European Intergroup Trial on panobinostat maintenance after HSCT for high-risk AML and MDS - A randomized, multicenter phase III study to assess the efficacy of panobinostat maintenance therapy vs. standard of care following allogeneic stem cell transplantation in patients with high-risk AML or MDS

A.3.1

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

European investigation on the efficacy of panobinostat treatment after donor stem cell transplantation

Europees onderzoek naar de effectiviteit van panobinostat therapie na donor stamcel transplantatie

A.3.2

Name or abbreviated title of the trial where available

HOVON 145 ETAL-4

A.4.1

Sponsor's protocol code number

HOVON145_ETAL-4

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	Universitätsklinikum Frankfurt
B.1.3.4	Country	Germany
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	Novartis Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinikum Frankfurt
B.5.2	Functional name of contact point	Studienzentrale Hämatologie
B.5.3	Address:
B.5.3.1	Street Address	Theodor-Stern-Kai 7
B.5.3.2	Town/ city	Frankfurt
B.5.3.3	Post code	60590
B.5.3.4	Country	Germany
B.5.4	Telephone number	00496963016365
B.5.5	Fax number	00496963017463
B.5.6	E-mail	goekbuget@em.uni-frankfurt.de

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	Farydak
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Farydak
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PANOBINOSTAT
D.3.9.1	CAS number	404950-80-7
D.3.9.4	EV Substance Code	SUB31049
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	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	No
D.IMP: 2
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	Farydak
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Farydak
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PANOBINOSTAT
D.3.9.1	CAS number	404950-80-7
D.3.9.4	EV Substance Code	SUB31049
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	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

High risk acute myeloid leukemia or myelodysplastic syndrome

Hoog risico acute myeloide leukemia of myelodysplastisch syndroom

E.1.1.1

Medical condition in easily understood language

Acute myeloid leukemia (AML). Myelodysplastic syndrome (MDS)

Acute myeloide leukemie (AML). Myelodyplastisch syndroom (MDS)

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 determine the efficacy of panobinostat maintenance therapy versus standard of care administered to patients with high-risk MDS or AML in complete hematologic remission after an allogeneic hematologic stem cell transplantation (HSCT)

Het bepalen van de efficientie van panobinostat onderhoudstherapie ten opzichte van standard therapie voor patienten met hoog risico AML of MDS tijdens complete hematologische remissie na allogene hematologische stamceltransplantatie

E.2.2

Secondary objectives of the trial

- To assess the safety and tolerability of panobinostat maintenance therapy after HSCT compared with standard of care.
- To evaluate HRQoL of patients under panobinostat maintenance therapy after HSCT.
- To study the treatment effect in subgroups of patients defined by treatment approach (i.e. HOVON-approach vs. RIC vs MAC conditioning), donor type (HLA-compatible versus haploidentical) and molecular distinct subgroups of AML/MDS.

- Onderzoek naar de veiligheid en verdraagzaamheid van panobinostat onderhoudstherapie na HSCT, vergeleken met standard zorg.
- Evaluatie van kwaliteit van leven van patienten die worden behandeld met panobinostat na HSCT.
- Het bestuderen van het effect van de behandeling bij sub groepen patienten, gedefinieerd door behandelstrategie (ie. HOVON-strategie vs RIC vs MAC conditionering), donor typen (HLA-compatible vs haplo-identiek) en moleculaire sub groepen van AML/MDS.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Eligibility criteria for registration prior to HSCT:
• Adult patients (18-70 years of age)
• AML (except acute promyelocytic leukemia with PML-RARA and AML with BCR-ABL1) according to WHO 2016 classification with high-risk features defined as one or more of the following criteria:
o refractory to or relapsed after at least one cycle of standard chemotherapy
o > 10% bone marrow blasts at day 14-21 of the first induction cycle
o adverse risk according to ELN 2017 risk stratification by genetics regardless of stage
o secondary to MDS or radio-/chemotherapy
o MRD positive before HSCT based on flow cytometry or PCR
or
• MDS with excess blasts (MDS-EB) according to the WHO 2016 classification, or high-risk or very high-risk according to IPSS-R
and
• First allogeneic HSCT scheduled within the next 4-6 weeks using one of the following donors, conditioning regimens and strategies for GvHD prophylaxis:
o Matched sibling or matched unrelated donor (i.e. 10/10 or 9/10 HLA-matched) or haploidentical family donor
o conditioning regimens:
(1) Reduced-intensity conditioning:
o Fludarabine/Melphalan
o Fludarabine/Busulfan2 (FB2)
(2) Myeloablative conditioning:
a. Fludarabine/Busulfan4 (FB4)
b. Busulfan/Cyclophosphamide (BU/CY)
c. Fludarabine/TBI 8 Gy
d. Cyclophosphamide/TBI 12 Gy
(3) Fludarabine/Cyclophosphamide/TBI 2 Gy in combination with post-Tx cyclophosphamide (PT-CY) only
(4) Thiotepa/Busulfan/Fludarabine (TBF) in the context of an haploidentical HSCT only
(5) In case of active disease at HSCT, salvage chemotherapy prior to conditioning is permitted
o strategies for GvHD prophylaxis:
• HLA-matched donors:
o CSA + MMF +/- ATG
o CSA + MTX +/- ATG
o PT-CY + CSA
• Haploidentical donors:
o PT-CY + CSA + MMF
• No history of significant cardiac disease and absence of active symptoms, otherwise documented left ventricular EF ≥ 40%
• Written informed consent for registration

Eligibility criteria for enrollment after HSCT:
• Adult patients with high-risk AML or MDS as defined above
and
• First allogeneic HSCT performed within 30 - 65 days prior to enrollment
• Eastern Cooperative Group (ECOG) performance status ≤ 2
• Complete hematologic remission or complete hematologic remission with incomplete recovery documented by bone marrow aspiration within 14 days prior to enrollment
• Laboratory test results maximum 14 days prior to enrollment within the following ranges:
o Absolute neutrophil count ≥ 1.0 x 109/L
o Platelet count ≥ 75 x 109/L
o Potassium, magnesium and phosphate within normal limits
o Serum creatinine clearance ≥ 30 mL/min
o Total bilirubin ≤ 1.5 x ULN
o AST (SGOT) and ALT (SGOT) ≤ 2.5 x ULN
• Negative serum pregnancy test (within 14 days prior to enrollment) in women of child-bearing potential (WOCBP)
• Willingness of WOCBP to use a highly effective method of contraception during study treatment and for three months following the last dose of study drug. Highly effective methods of contraception include:
o oral, intravaginal or transdermal combined (estrogen and progestogen containing) hormonal contraceptive associated with inhibition of ovulation
plus barrier contraceptive
o oral, injectable or implantable progestogen-only hormone contraception associated with inhibition of ovulation plus barrier contraceptive
o intrauterine hormone-releasing system (IUS) plus barrier contraceptive
o intrauterine device (IUD)
o bilateral tube occlusion
o vasectomised partner
o sexual abstinence
Women using hormonal contraceptives should additionally use a barrier method of contraception (preferably male condom).
• Willingness of male subjects whose sexual partners are WOCBP to use a highly effective method of contraception as defined above during the man’s treatment and for six months following the last dose of study drug.
• Written informed consent for enrollment, willingness and ability to comply with all study procedures

E.4

Principal exclusion criteria

Eligibility criteria for registration prior to HSCT:
• Prior treatment with a DAC inhibitor
• Hypersensitivity to the active substance or to any of the excipients of panobinostat
• HIV or HCV antibody positivity
• Psychiatric disorder that interferes with ability to understand the study and give informed consent, and/or impacts study participation or follow-up.
• Female patients who are pregnant or breast feeding
• History of another primary malignancy that is currently clinically significant or currently requires active intervention

Eligibility criteria for enrollment after HSCT:
• Active acute GvHD grade III-IV according to modified Glucksberg criteria
• Active acute GvHD grade II or chronic GvHD moderate/severe according to NIH criteria requiring systemic corticosteroids > 0.5 mg/kg body weight of methylprednisolone equivalent or combination immunosuppressive treatment
• Uncontrolled or significant heart disease, including recent myocardiac infarction, cardiac failure (NYHA II-IV), unstable angina pectoris, or clinically significant bradycardia
• Long QT syndrome
• QTcF ≥ 480 msec on screening ECG to be performed within 14 days prior to enrollment
• Concurrent use of medications that have a relative risk of prolonging QT interval or of inducing Torsade de Pointes, if such treatment cannot be discontinued or switched to a different medication prior to the first dose of study drug
• Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes mellitus, chronic obstructive or chronic restrictive pulmonary disease including dyspnoea at rest from any cause) or history of serious organ dysfunction or disease involving the heart, kidney, or liver and/or seropositive HIV or HCV (screening HIV or HCV testing is not required).
• Serious active infection
• CMV reactivation, which is not responsive to first-line valganciclovir or ganciclovir
• Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, obstruction, or stomach and/or small bowel resection).

E.5 End points

E.5.1

Primary end point(s)

Overall survival (OS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Minimum of 24 months after HSCT or until death

E.5.2

Secondary end point(s)

• Event-free survival (EFS)
• Disease-free survival (DFS)
• Cumulative incidence of hematologic relapse
• Cumulative incidence, time and cause of non-relapse mortality
• Cumulative incidence of new onset or aggravation of acute GvHD grade III-IV
• Cumulative incidence and maximal grade of severity of chronic GvHD requiring systemic treatment within one year after HSCT
• Percentage of patients who are free of systemic immunosuppressive therapy at one and two years after HSCT
• Percentage of patients completing the one year study treatment and duration of panobinostat administration in patients who discontinue study treatment prematurely
• Patient-reported HRQoL during panobinostat maintenance therapy

E.5.2.1

Timepoint(s) of evaluation of this end point

Minimum of 24 months after HSCT or until death

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Yes

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)

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Switzerland

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

Prerequisite for termination of the trial is LVLS (i.e. end of follow up on June 2022 for the last patient) and completed data collection

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

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)

According to standard of care

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

2018-07-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-12-24

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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