Clinical Trials Register

Summary
EudraCT Number:	2010-020414-28
Sponsor's Protocol Code Number:	AP24534-10-201
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-01-04
Trial results	View 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

2010-020414-28

A.3

Full title of the trial

A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia

A.3.1

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

Not applicable

A.3.2

Name or abbreviated title of the trial where available

Not applicable

A.4.1

Sponsor's protocol code number

AP24534-10-201

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	ARIAD Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Ariad Pharmaceuticals, Ltd.
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ariad Pharmaceuticals, Ltd.
B.5.2	Functional name of contact point	Dan Bollag
B.5.3	Address:
B.5.3.1	Street Address	1 Northumberland Avenue
B.5.3.2	Town/ city	London
B.5.3.3	Post code	WC2N 5BW
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+0044207 872 5869
B.5.5	Fax number	+0044207 872 5611
B.5.6	E-mail	dan.bollag@pharmanet.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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	C (2010) 789
D.3 Description of the IMP
D.3.1	Product name	Ponatinib
D.3.2	Product code	AP24534
D.3.4	Pharmaceutical form	Film-coated tablet
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	ponatinib
D.3.9.1	CAS number	943319-70-8
D.3.9.2	Current sponsor code	AP24534 HCl
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	45
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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	C (2010) 789
D.3 Description of the IMP
D.3.1	Product name	Ponatinib
D.3.2	Product code	AP24534
D.3.4	Pharmaceutical form	Film-coated tablet
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	ponatinib
D.3.9.1	CAS number	943319-70-8
D.3.9.2	Current sponsor code	AP24534 HCl
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	15
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

Patients with Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia

E.1.1.1

Medical condition in easily understood language

Not applicable

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10024329
E.1.2	Term	Leukemia
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

The primary objective of this study is:
1. To determine the efficacy of ponatinib in patients with chronic myeloid leukemia in chronic, accelerated or blast phase or with Ph+ Acute Lymphoblastic Leukemia who are either:
- resistant or intolerant to either dasatinib or nilotinib,
or
- have the T315I mutation.

E.2.2

Secondary objectives of the trial

1. To further characterize the anti-leukemia activity of ponatinib in these patients as evidenced by clinical responses, molecular responses, and clinical outcomes;
2. To characterize the molecular genetic status of patients; and
3. To examine the safety of ponatinib in these patients.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL (defined in Sections 12.3 and 12.4 of the protocol pages 53 and 54 ).
a. All patients must have screening bone marrow (BM) cytogenetics with conventional banding performed within 42 days prior to initiating treatment.
b. Examination of at least 20 metaphases is required. If less than 20 metaphases are examined, the BM aspirate should be repeated. Patients must either meet criterion 2 or 3:
2. Be previously treated with and resistant, or intolerant, to either dasatinib or nilotinib: For resistance or intolerance criteria please refer to protocol pages 50-51.
OR
3. Develop the T315I mutation after any TKI therapy.
3.1 Patients with T315I mutation after any TKI need not have been treated with dasatinib or nilotinib.
3.2 Patients with T315I in CP must have less than a CCyR (>0% Ph+).
3.3 Patients with T315I in AP, BP, or Ph+ ALL must have less than a MaHR.
3.4 Patients with any history of T315I mutation will be eligible for study participation. However, only those patients who carry a T315I mutation that is detected by direct sequencing in a pre-treatment blood sample using the study’s central laboratory will be analyzed in the T315I subset. Details are provided in Section 12.5.
Patients must meet all of the remaining criteria to be eligible for the study:
4. Patients must be ≥18 years old.
5. Provide written informed consent.
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
7. Minimum life expectancy of 3 months or more.
8. Adequate renal function defined as serum creatinine < 1.5× upper limit of normal (ULN) for institution.
9. Adequate hepatic function defined as:
a. Total bilirubin <1.5 × ULN,
b. Alanine aminotransferase (ALT [SGPT]) and aspartate aminotransferase (AST [SGOT]) < 2.5 × ULN for institution (< 5 x ULN if liver involvement with leukemia),
c. Prothrombin time (PT) < 1.5 × ULN.
10. Normal pancreatic status defined as:
a. Lipase ≤ 1.5 × ULN,
d. Amylase ≤ 1.5 × ULN.
11. Normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
12. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
13. Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout participation in this study.
14. Ability to comply with study procedures, in the Investigator’s opinion.

E.4

Principal exclusion criteria

Patients are not eligible for participation in the study if they meet any of the following exclusion criteria:
1. Received TKI therapy within 7 days prior to receiving the first dose of ponatinib, or have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs (except alopecia) due to agents previously administered.
Received other therapies as follows:
a. For CP and AP patients, received hydroxyurea or anagrelide within 24 hours prior to receiving the first dose of ponatinib, interferon, cytarabine, or immunotherapy within 14 days, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib.
b. For BP patients, received chemotherapy within 14 days prior to the first dose of ponatinib. Otherwise 2a applies.
c. For Ph+ ALL patients, received corticosteroids within 24 hours before the first dose of ponatinib, or vincristine within 7 days prior to the first dose of ponatinib, or received other chemotherapy within 14 days prior to the first dose of ponatinib. Otherwise, 2a applies.
d. All patients are excluded if they have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs (except alopecia) due to agents previously administered.

3. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of ponatinib; any evidence of on-going graft-versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy.
4. Take medications that are known to be associated with Torsades de Pointes. These medications are listed in Attachment B.
5. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
6. Have previously been treated with ponatinib.
7. Patient with CML CP are excluded if they are in CCyR.
8. Patients with CML AP, BP, or Ph+ ALL are excluded if they are in MaHR.
9. Have active central nervous system (CNS) disease as evidenced by cytology or pathology. In the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.
10. Have significant or active cardiovascular disease, specifically including, but not restricted to:
a. Myocardial infarction within 3 months prior to first dose of ponatinib,
b. History of clinically significant atrial arrhythmia or any ventricular arrhythmia,
c. Unstable angina within 3 months prior to first dose of ponatinib,
d. Congestive heart failure within 3 months prior to first dose of ponatinib.
11. Have a significant bleeding disorder unrelated to CML or Ph+ ALL.
12. Have a history of pancreatitis or alcohol abuse.
13. Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
14. Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of orally administered ponatinib.
15. Have been diagnosed with another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ, or controlled prostate cancer, which are allowed within 3 years).
16. Are pregnant or lactating. Women of childbearing potential must agree to effective contraception from the time of signing informed consent through the Follow-up Visit, approximately 30 days after last dose of ponatinib.
17. Underwent major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.
18. Have ongoing or active infection (including known history of human immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV]). Testing for these viruses is not required in the absence of history.
19. Suffer from any condition or illness that, in the opinion of the Investigator or the medical monitor, would compromise patient safety or interfere with the evaluation of the safety of the study drug.

E.5 End points

E.5.1

Primary end point(s)

-For CML patients in Chronic Phase (CP), for Major Cytogenetic response (MCyR): C3D28, end of cycles 6, 9, 12, 15, 18, 21, 24, 26 and at the End of treatment visit
-For CML patients in Acute Phase (AP) or Blast Phase (BP) or Ph+ ALL for Major Hematologic response (MaHR): C1D1, C1D8, C1D15, C1D22, C2D1, C2D15, C3D1, C3D15, and on D1 and D15 from cycles 4 to 26 and at the end of treatment visit

E.5.1.1

Timepoint(s) of evaluation of this end point

1. For CML patients in CP at study entry: major cytogenetic response (MCyR), defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR).
2. For CML patients in AP at study entry: major hematologic response (MaHR), defined as complete hematologic response (CHR) or no evidence of leukemia (NEL).
3. For CML patients in BP at study entry or Ph+ ALL patients: MaHR, consisting of CHR or NEL.

E.5.2

Secondary end point(s)

-For CML patients in CP:
-for Complete hematologic response (CHR) : C1D1, C1D8, C1D15, C1D22, C2D1, C2D15, C3D1, C3D15, D1 from cycle 4 to 13 and D28 from cycles 15, 18, 21, 24, 26 and at the end of treatment visit.
-for confirmed Major Cytogenetic Response (MCyR): C3D28, end of cycles 6, 9, 12, 15, 18, 21, 24, 26 and at the end of treatment visit
-for Molecular response: C3D28, end of cycles 6, 9, 12, 15, 18, 21, 24, 26 and at the End of treatment visit
-For CML patients in AP or BP or Ph+ ALL
-For Cytogenetic response: C1D28, C2D28, and at the end of even cycles 4 to 26 and at the end of treatment visit.
-For Molecular response: C2D28, and at the end of even cycles 4 to 26 and at the end of treatment visit.
-For all patients: time to response, duration of response, progression-free-survival, and overall survival
-For all patients: safety and tolerabitlity

E.5.2.1

Timepoint(s) of evaluation of this end point

1. For CML patients in CP:
a. Hematologic responses: CHR;
b. Cytogenetic responses: confirmed MCyR; and
c. Molecular responses: major molecular response (MMR).
2. For CML patients in AP or BP or Ph+ ALL patients:
a. Cytogenetic responses: CCyR, PCyR, confirmed MCyR; and
b. Molecular responses: MMR.
3. For all patients: time to response, duration of response, progression free survival, and overall survival.
4. For all patients: safety and tolerability.

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

Yes

E.6.11

Pharmacogenomic

Yes

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

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

Yes

E.8.1.7.1

Other trial design description

Open enrollment

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

Australia

Belgium

France

Germany

Italy

Korea, Democratic People's Republic of

Netherlands

Singapore

Spain

Sweden

United Kingdom

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

Last patient, last visit

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