Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET) - Full Text View

Sponsor:	Cytopia Research Pty Ltd
Information provided by:	Cytopia Research Pty Ltd
ClinicalTrials.gov Identifier:	NCT00935987

Purpose

This study seeks to (i) determine a safe and tolerated dose of CYT387 given to patients with PMF, post-PV or post-ET and, (ii) assess the effectiveness of orally-administered CYT387 as a treatment for PMF, post-PV or post-ET.

Condition	Intervention	Phase
Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Post-Essential Thrombocythemia Myelofibrosis	Drug: CYT387	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Single Group Assignment, Safety/Efficacy Study
Official Title:	A Phase I/II, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability Pharmacokinetics and Pharmacodynamics of Orally-Administered CYT387 in Primary Myelofibrosis or Post-Polycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis.

Resource links provided by NLM:

Genetics Home Reference related topics: hemophilia

MedlinePlus related topics: Spleen Diseases

U.S. FDA Resources

Further study details as provided by Cytopia Research Pty Ltd:

Primary Outcome Measures:

To determine the safety and tolerability, dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of orally-administered CYT387 in patients with PMF or post-ET/PV MF. [ Time Frame: Ongoing throughout therapy up until 30 days after last dose of CYT387 ] [ Designated as safety issue: Yes ]
Objective Response Rate (OOR), as measured by complete response (CR) rate, partial response (PR) rate and clinical improvement (CI) rate according to IWG-MRT consensus criteria [ Time Frame: Response is measured at the end of every cycle of therapy ] [ Designated as safety issue: No ]
To determine the pharmacokinetics (PK) of CYT387 in patients with PMF or post-ET/PV MF [ Time Frame: Day 1 and day 28 in cycle 1 of therapy ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To determine the effect of CYT387 on cytogenetic findings in patients with PMF or post-ET/PV MF. [ Time Frame: At the end of every third cycle of therapy ] [ Designated as safety issue: No ]
To determine the effect of CYT387 on granulocyte JAK2V617F allele burden in patients with PMF or post-ET/PV MF. [ Time Frame: At the end of each cycle of therapy (in relevant patients only) ] [ Designated as safety issue: No ]
To determine the effect of CYT387 on endogenous myeloid colony formation in patients with PMF or post-ET/PV MF. [ Time Frame: At the end of each cycle of therapy ] [ Designated as safety issue: No ]
To determine the effect of CYT387 on plasma levels of inflammatory, fibrogenic and angiogenic cytokines in patients with PMF or post-ET/PV MF [ Time Frame: At the end of each cycle of therapy ] [ Designated as safety issue: No ]
To evaluate pharmacodynamic correlates of CYT387 activity in patients with PMF or post-ET/PV MF who are receiving treatment with CYT387. [ Time Frame: On day 1 of cycles 1, 3, 6 and 9. ] [ Designated as safety issue: No ]

Estimated Enrollment:	60
Study Start Date:	November 2009
Estimated Study Completion Date:	May 2011
Estimated Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
CYT387: Experimental	Drug: CYT387 Patients will be assigned to dose levels in successive cohorts starting with a dose in the first cohort of 100 mg/day. CYT387 will be orally self-administered as a single daily dose beginning on Day 1 of the study, and thereafter at approximately the same time each day of the 28-day cycle. It is recommended that all doses be preceded by a 2-hour fast from food and beverages, and be followed by a 1-hour post-dose fast from food and beverages.

Arms

Assigned Interventions

CYT387: Experimental

Drug: CYT387

Patients will be assigned to dose levels in successive cohorts starting with a dose in the first cohort of 100 mg/day. CYT387 will be orally self-administered as a single daily dose beginning on Day 1 of the study, and thereafter at approximately the same time each day of the 28-day cycle. It is recommended that all doses be preceded by a 2-hour fast from food and beverages, and be followed by a 1-hour post-dose fast from food and beverages.

Detailed Description:

The myeloproliferative neoplasms (MPN), most notably polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are a diverse but inter-related suite of clonal disorders of pluripotent hematopoietic stem cells (Tefferi et al., 2008). The MPN share a range of biological, pathological, and clinical features including the relative overproduction of one or more cells of myeloid origin, growth factor independent colony formation in vitro, marrow hypercellularity, extramedullary hematopoiesis, spleno- and hepatomegaly, and thrombotic and/or hemorrhagic diatheses (Tefferi et al., 2005).

This is a single centre, open-label, non-randomized, dose-escalation study, to be conducted in two phases. The primary aims of the Phase I portion of the study will be to assess the dose-limiting toxicities, maximum tolerated dose (MTD) and safety of orally-administered CYT387 when administered as a capsule dose, once daily, on a 28-day treatment cycle. The dose-confirmatory Phase II portion of the study will then be undertaken at or below the MTD.

Patients will be assigned to dose levels in successive cohorts starting with a dose in the first cohort of 100 mg/day, administered orally as a single daily dose (ie QD: at least 20 and no more than 28 hours apart, preferably in a fasted state at least one hour before and two hours after a meal). Dose-escalation will proceed initially with a 1.5-fold increment however, based on toxicity and efficacy information at a specific dose level, the dose escalation increment may be reduced to a 1.25-fold escalation at the discretion of the investigator. At any dose level, if one patient experiences a Grade 2 toxicity or higher, the dose-escalation may only proceed with 1.25-fold increments.

Subjects will be evaluated weekly for the first cycle, every 2 weeks for Cycles 2 and 3, and at the end of each subsequent cycle, for up to 9 cycles of CYT387 treatment. Subjects will return for a follow-up visit 30 days after completion of the last dose of study drug. Subjects who achieve at least clinical improvement (per IWG-MRT criteria) and tolerate the drug well may be allowed to continue to receive CYT387 beyond the planned 9 cycles at the discretion of the Investigator and with approval from the Sponsor.

The MTD is defined as the highest dose level at which > 2 of 6 subjects develop first cycle DLT. New dose levels may begin accrual only if all subjects at the current dose level have been observed for a minimum of 28 days from the first day of treatment. The recommended Phase II dose will be the MTD unless significant clinical activity (efficacy) is seen below the MTD. With the exception of the first cohort, dose levels may be decreased from the intended dose levels for the next cohort, if Grade 2 or greater toxicities are observed.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Diagnosis of PMF or post-ETIPV MF as per revised World Health Organization (WHO) criteria.
High-risk or Intermediate-2 risk MF (as defined by the International Prognostic Scoring System [IPSS]; or intermediate-I risk MF (IPSS) associated with symptomatic splenomegaly and/or unresponsive to available therapy.
Must be at least 18 years of age with life expectancy of greater/equal to 12 weeks.
Must be able to provide informed consent and be willing to sign an informed consent form.
Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
Must have evidence of acceptable organ function within 4 days of initiating study drug as evidenced by the following:
- SGOT (AST) or SGPT (ALT) less/equal to 2.5 x ULN (or less/equal 5 x ULN if in the investigator's opinion the elevation is due to extramedullary hematopoiesis)
- Bilirubin less/equal to 1.5 x ULN
- Serum creatinine less/equal to 1.5 x ULN
- Absolute neutrophil count greater/equal to 1,000/uL
- Platelet count greater/equal to 50,000/uL
Females of childbearing potential must have a negative pregnancy test within 4 days of initiating study drug.

Exclusion Criteria:

Any chemotherapy (e.g., hydroxyurea), immunomodulatory drug therapy (e.g., thalidomide), immunosuppressive therapy, corticosteroids >10 mg/day prednisone or equivalent, or growth factor treatment (e.g., erythropoietin) within 14 days prior to initiation of study drug.
Incomplete recovery from major surgery within four weeks of study entry.
Radiation therapy within four weeks of study entry.
Women of childbearing potential, unless surgically sterile for at least 3 months (i.e., hysterectomy), OR postmenopausal for at least 12 months (FSH > 30 U/mL), OR unless they agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through end of study. Permitted methods for preventing pregnancy must be communicated to study subjects and their understanding confirmed.
Men who partner with a woman of childbearing potential, unless they agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through to the end of study. Permitted methods for preventing pregnancy must be communicated to study subjects and their understanding confirmed.
Females who are pregnant or are currently breastfeeding.
Known positive status for HIV.
Clinically active hepatitis B or C.
Diagnosis of another malignancy unless free of disease for at least three years following therapy with curative intent. Patients with early-stage basal cell or squamous cell skin cancer, cervical intraepithelial neoplasia, cervical carcinoma in situ or superficial bladder cancer may be eligible participate at the Investigator's discretion.
Any acute active infection.
Cardiac dysrhythmias requiring treatment, bundle branch block on ECG or QRS duration > 120 msec, or prolongation of the QTc (Fridericia) interval to > 450 msec for males or > 470 msec for females at pre-study screening.
Presence of ≥ Grade 2 peripheral neuropathy.
Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), uncontrolled or unstable angina, myocardial infarction, cerebrovascular accident, or pulmonary embolism within 3 months prior to initiation of study drug.
Uncontrolled inter current illness or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00935987

Contacts

Contact: Ayalew Tefferi, MD

+1 507-284-3159

tefferi.ayalew@mayo.edu

Locations

United States, Minnesota
Mayo Clinic	Recruiting
Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Cytopia Research Pty Ltd

Investigators

Principal Investigator:

Ayalew Tefferi, MD

Mayo Clinic

More Information

No publications provided

Responsible Party:	Cytopia Research Pty Ltd ( Dr Gregg Smith, Director: Drug Development & Operations )
Study ID Numbers:	CCL09101
Study First Received:	July 7, 2009
Last Updated:	November 4, 2009
ClinicalTrials.gov Identifier:	NCT00935987 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Cytopia Research Pty Ltd:

Primary Myelofibrosis
Post-Polycythemia Vera
Post-Essential Thrombocythemia
CYT387

Additional relevant MeSH terms:

Polycythemia
Polycythemia Vera
Myelofibrosis
Hematologic Diseases
Blood Coagulation Disorders
Blood Platelet Disorders
Myeloproliferative Disorders

Myeloid Metaplasia
Lymphatic Diseases
Hemorrhagic Disorders
Thrombocytosis
Thrombocythemia, Hemorrhagic
Bone Marrow Diseases
Splenic Diseases

ClinicalTrials.gov processed this record on February 04, 2010