Phase IIA Study of the HDAC Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases

• Sponsor: Italfarmaco (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00606307
• Collaborator: (none)
• Enrollment: 29
• Locations: 2
• Arm: 1
• Duration (Months): 12
• Patients Per Site: 14.5
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

Primary Objective:

To evaluate efficacy and safety of ITF2357 in the treatment of patients with JAK2V617F positive myeloproliferative diseases [Polycythemia Vera (PV), Essential Thrombocytosis (ET), Myelofibrosis (MF)]. Efficacy was evaluated by ad hoc haematological and clinical criteria for PV and ET, and by internationally established response criteria (EUMNET criteria) for MF. Safety was evaluated by number of subjects experiencing an Adverse Event (AE), type, frequency, severity, timing and relatedness of AEs, including changes in vital signs and clinical laboratory results.

Secondary Objective:

To evaluate the JAK2 mutated allele burden by quantitative Real-Time Polymerase Chain Reaction (qRTPCR).

Condition or Disease	Intervention/Treatment	Phase
Myeloproliferative Diseases	Drug: ITF2357	Phase 2

Detailed Description

This is a non-randomized, open-label, Phase IIA pilot study testing efficacy and safety of ITF2357 in a population of patients with JAK2V617F positive myeloproliferative diseases. All recruited patients received an initial dose of 50 mg b.i.d. of ITF2357 that was subsequently escalated to 50 mg t.i.d. in case of lack of significant toxicity. Treatment lasted up to a maximum of 24 cumulative weeks of drug administration. The study was carried out in Italy. Enrolled patients were subjects of both genders, with an established diagnosis of polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) according to the revised WHO criteria.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IIA Study of the Histone-deacetylase Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ITF2357 Initial dose of 50 mg b.i.d. that was subsequently escalated to 50 mg t.i.d in case of lack of significant toxicity.	Drug: ITF2357; 50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.; Other Names: Givinostat

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response [Every single week from week 1 to week 24 of treatment]

   Patients with Objective Response were defined as those patients achieving a complete, major, moderate or minor (only for Myelofibrosis patients) response during the experimental treatment course. The "best response" is reported hereunder by intensity of response.

Secondary Outcome Measures

1. Change in JAK2 Mutated Allele Burden [At screening, at week 12, at week 24, at the end of treatment (EOT) visit]

   This outcome was assessed by quantitative real time Polymerase Chain Reaction (RT PCR). At each time point, the number of patients is the following: Screening: N=29 Week 12: N=20 Week 24: N=18 EOT: N=24. End of treatment corresponds to the last visit performed before treatment discontinuation.

2. Number of Subject Experiencing an Adverse Event [At weekly visits (Days 8, 15, 22, 36, 43, 50, 64, 71, 78, 99, 127, 155); At monthly visits (Days 29, 57, 85 113, 141,169); at end of treatment visit]

   An adverse event (AE) is any untoward occurrence in a patient or clinical investigation subject administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The adverse events must to be followed to the end of study (28 days after the last study drug intake). A serious AE (SAE) is defined as an untoward (unfavourable) medical occurrence that at any dose results in death, or is life-threatening or requires inpatient hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed Informed Consent Form

• Male or female, age ≥ 18 years

• Confirmed diagnosis of PV/ET/MF according to the revised World Health Organisation criteria

• JAK-2 V617F positivity

• In need of cytoreductive therapy when hydroxyurea is not indicated (e.g. young patients) or when refractoriness to the drug is documented

Exclusion Criteria:

• Active bacterial or fungal infection requiring antimicrobial treatment on Day 1

• Patients of childbearing potential without a negative pregnancy test prior to initiation of the study drug

• Pregnancy or lactation

• A marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval > 450 ms, according to Bazett's correction formula - see appendix G for the formula)

• The use of concomitant medications that prolong the QT/QTc interval (see appendix F for full list)

• Concomitant acute coronary syndromes; uncontrolled hypertension

• New York Heart Association (NYHA) Grade II or greater congestive heart failure

• History of any cardiac arrhythmia requiring medication (irrespective of its severity)

• A history of additional risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)

• Active Epstein Barr Virus (EBV) infection (i.e. positive serology IgM)

• Known HIV infection

• Active hepatitis B and/or C infection

• History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications

• Eastern Cooperative Oncology Group (ECOG) performance status 3 or greater

• Platelets count <100x109/L within 14 days before enrolment

• Absolute neutrophil count <1.2x109/L within 14 days before enrolment

• Percentage of blast cells in peripheral blood >10% within 14 days before enrolment

• Serum creatinine >2xULN (Upper limit of normal)

• Total serum bilirubin >1.5xULN

• Serum AST (aspartate aminotransferase) / ALT (alanine aminotransferase) > 3xULN

• Interferon alpha within 14 days before enrolment

• Hydroxyurea within 14 days before enrolment

• Anagrelide within 7 days before enrolment

• Any other investigational drug within 28 days before enrolment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ospedali riuniti	Bergamo		Italy	24158
2	IRCCS - Pol. San Matteo	Pavia		Italy	27100

Sponsors and Collaborators

• Italfarmaco

Investigators

• Study Director: tiziano oldoni, MD, Italfarmaco
• Principal Investigator: Alessandro Rambaldi, MD, A.O. Ospedale Papa Giovanni XXIII

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Italfarmaco
• ClinicalTrials.gov Identifier: NCT00606307
• Other Study ID Numbers: DSC/07/2357/28
• First Posted: Feb 1, 2008
• Last Update Posted: Dec 3, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by Italfarmaco: polycythemia vera (PV); essential thrombocythemia (ET); myelofibrosis (MF)
• Additional relevant MeSH terms: Myeloproliferative Disorders; Givinostat hydrochloride

Study Results

Participant Flow

Arm/Group Title	ITF2357
Arm/Group Description	Initial dose of 50 mg b.i.d. that was subsequently escalated to 50 mg t.i.d in case of lack of significant toxicity. ITF2357: 50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.
Period Title: Overall Study
STARTED	29
COMPLETED	18
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	ITF2357
Arm/Group Description	Initial dose of 50 mg b.i.d. that was subsequently escalated to 50 mg t.i.d in case of lack of significant toxicity. ITF2357: 50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.
Overall Participants	29
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.6 (10.7)
Sex: Female, Male (Count of Participants)
Female	14.0 48.3%
Male	15.0 51.7%
Region of Enrollment (participants) [Number]
Italy	29 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response
Description	Patients with Objective Response were defined as those patients achieving a complete, major, moderate or minor (only for Myelofibrosis patients) response during the experimental treatment course. The "best response" is reported hereunder by intensity of response.
Time Frame	Every single week from week 1 to week 24 of treatment

Outcome Measure Data

Analysis Population Description

ITT population: all recruited patients who received study medication and for whom at least one on-study tumour evaluation is available.

Arm/Group Title	ITF2357
Arm/Group Description	Initial dose of 50 mg b.i.d. that was subsequently escalated to 50 mg t.i.d in case of lack of significant toxicity. ITF2357: 50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.
Measure Participants	29
complete responders	2 6.9%
major responders	12 41.4%
moderate responders	2 6.9%
minor responders	1 3.4%
non responders	12 41.4%

2. Secondary Outcome

Title	Change in JAK2 Mutated Allele Burden
Description	This outcome was assessed by quantitative real time Polymerase Chain Reaction (RT PCR). At each time point, the number of patients is the following: Screening: N=29 Week 12: N=20 Week 24: N=18 EOT: N=24. End of treatment corresponds to the last visit performed before treatment discontinuation.
Time Frame	At screening, at week 12, at week 24, at the end of treatment (EOT) visit

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: all recruited patients who received study medication and for whom at least one on-study tumour evaluation is available.

Arm/Group Title	ITF2357
Arm/Group Description	Initial dose of 50 mg b.i.d. that was subsequently escalated to 50 mg t.i.d in case of lack of significant toxicity. ITF2357: 50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.
Measure Participants	29
screening	54.0 (19.7)
week 12	49.4 (20.1)
week 24	47.1 (20.0)
EOT	49.0 (21.5)

3. Secondary Outcome

Title	Number of Subject Experiencing an Adverse Event
Description	An adverse event (AE) is any untoward occurrence in a patient or clinical investigation subject administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The adverse events must to be followed to the end of study (28 days after the last study drug intake). A serious AE (SAE) is defined as an untoward (unfavourable) medical occurrence that at any dose results in death, or is life-threatening or requires inpatient hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect.
Time Frame	At weekly visits (Days 8, 15, 22, 36, 43, 50, 64, 71, 78, 99, 127, 155); At monthly visits (Days 29, 57, 85 113, 141,169); at end of treatment visit

Outcome Measure Data

Analysis Population Description

safety population: all recruited patients who received at least one dose of the study medication.

Arm/Group Title	ITF2357
Arm/Group Description	Initial dose of 50 mg b.i.d. that was subsequently escalated to 50 mg t.i.d in case of lack of significant toxicity. ITF2357: 50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.
Measure Participants	29
number of patients with AE	29 100%
number of patients with serious AE	3 10.3%

Adverse Events

Time Frame	At weekly visits (Days 8, 15, 22, 36, 43, 50, 64, 71, 78, 99, 127, 155); At monthly visits (Days 29, 57, 85 113, 141,169); at three-monthly visit (Day 85)
Arm/Group Title	ITF2357
Arm/Group Description	Initial dose of 50 mg b.i.d. that was subsequently escalated to 50 mg t.i.d in case of lack of significant toxicity. ITF2357: 50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.
All Cause Mortality
	ITF2357
	Affected / at Risk (%)	# Events
Total	0/29 (0%)
Serious Adverse Events
	ITF2357
	Affected / at Risk (%)	# Events
Total	3/29 (10.3%)
Gastrointestinal disorders
Melena	1/29 (3.4%)	1
General disorders
Disease progression	1/29 (3.4%)	1
Infections and infestations
Cellulitis	1/29 (3.4%)	1
Localised infection	1/29 (3.4%)	1
Other (Not Including Serious) Adverse Events
	ITF2357
	Affected / at Risk (%)	# Events
Total	29/29 (100%)
Blood and lymphatic system disorders
Anaemia	6/29 (20.7%)	6
Leukopenia	1/29 (3.4%)	1
Neutropenia	1/29 (3.4%)	1
Cardiac disorders
Thrombocytopenia	3/29 (10.3%)	3
Palpitation	1/29 (3.4%)	1
Tachycardia	1/29 (3.4%)	1
Gastrointestinal disorders
Abdominal pain	6/29 (20.7%)	6
Abdominal pain upper	3/29 (10.3%)	3
Constipation	1/29 (3.4%)	1
Diarrhoea	18/29 (62.1%)	18
Dyspepsia	1/29 (3.4%)	1
Flatulence	1/29 (3.4%)	1
Gingival bleeding	1/29 (3.4%)	1
Intestinal polyp	1/29 (3.4%)	1
Nausea	3/29 (10.3%)	3
Rectal Haemorrhage	2/29 (6.9%)	2
General disorders
Vomiting	1/29 (3.4%)	1
Asthenia	9/29 (31%)	9
Chest pain	1/29 (3.4%)	1
Chills	1/29 (3.4%)	1
Fatigue	3/29 (10.3%)	3
Hepatobiliary disorders
Oedema peripheral	2/29 (6.9%)	2
Pyrexia	8/29 (27.6%)	8
Hypertransaminasaemia	2/29 (6.9%)	2
Portal vein thrombosis	1/29 (3.4%)	1
Infections and infestations
Bronchitis	1/29 (3.4%)	1
Cystitis	2/29 (6.9%)	2
Cystitis escherichia	1/29 (3.4%)	1
Ear infection	1/29 (3.4%)	1
Fungal infection	1/29 (3.4%)	1
Gastritis bacterial	1/29 (3.4%)	1
Gastroenteritis	1/29 (3.4%)	1
Influenza	5/29 (17.2%)	5
Oral candidiasis	1/29 (3.4%)	1
Pneumonia	1/29 (3.4%)	1
Tooth infection	1/29 (3.4%)	1
Injury, poisoning and procedural complications
Injury	1/29 (3.4%)	1
Investigations
Alanine aminotransferase	1/29 (3.4%)	1
Aspertate aminotransferase	1/29 (3.4%)	1
Blood uric acid increased	1/29 (3.4%)	1
Electrocardiogram QT prolonged	5/29 (17.2%)	5
Weight decreased	12/29 (41.4%)	12
Metabolism and nutrition disorders
Anorexia	2/29 (6.9%)	2
Hyperkalaemia	1/29 (3.4%)	1
Hypertriglyceridaemia	1/29 (3.4%)	1
Hyperuricaemia	2/29 (6.9%)	2
Hypocalcaemia	1/29 (3.4%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	3/29 (10.3%)	3
Muscoloskeletal pain	2/29 (6.9%)	2
Pain in extremity	1/29 (3.4%)	1
Nervous system disorders
Dizziness	1/29 (3.4%)	1
Headache	1/29 (3.4%)	1
Neurological symptom	1/29 (3.4%)	1
Paraesthesia	3/29 (10.3%)	3
Renal and urinary disorders
Peripheral sensory neuropathy	1/29 (3.4%)	1
sciatica	1/29 (3.4%)	1
Renal failure	1/29 (3.4%)	1
Reproductive system and breast disorders
Breast discomfort	1/29 (3.4%)	1
Respiratory, thoracic and mediastinal disorders
Gynaecomastia	1/29 (3.4%)	1
Epistaxis	1/29 (3.4%)	1
Skin and subcutaneous tissue disorders
Erythema	2/29 (6.9%)	2
Surgical and medical procedures
Pruritus	3/29 (10.3%)	3
Rush	2/29 (6.9%)	2
Astringent therapy	1/29 (3.4%)	1
Vascular disorders
Angiopathy	1/29 (3.4%)	1
Erythromelalgia	1/29 (3.4%)	1
Hypertension	1/29 (3.4%)	1

Limitations/Caveats

Non reported

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.