CompletedPhase 2ACTRN12611000159954

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

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.

Sponsor

Gilead Sciences Inc.

Enrollment

140 participants

Start Date

Aug 31, 2011

Study Type

Interventional

Conditions

Primary Myelofibrosis

Summary

This is an open-label, non-randomized, dose-escalation study, to be conducted in two phases: a single-centre dose-escalation phase with supernumerary patient addition (Part 1), to determine the safety and tolerability of CYT387, and to identify a therapeutic dose for the confirmation portion of the study; and a multiple-centre dose-confirmation phase (Part 2), which will be a cohort expansion at or below the maximum tolerated dose (MTD) of CYT387.

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria12

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/hepatomegaly and/or unresponsive to available therapy.
Must be at least 18 years of age with life expectancy of >= 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 7 days of initiating study drug as evidenced by the following:
>SGOT (AST) or SGPT (ALT) <= 2.5 x upper limit of normal (ULN) (or <= 5 x ULN if in the investigator's opinion the elevation is due to extramedullary hematopoiesis)
>Bilirubin <= 2.0 x ULN or direct bilirubin < 1.0
>Serum creatinine <= 2.5 x ULN
>Absolute neutrophil count >= 500/microlitre
>Platelet count >= 50,000/microlitre
Females of childbearing potential must have a negative pregnancy test within 4 days of initiating study drug.

Exclusion Criteria14

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 to participate at the Investigator's discretion.
Any acute active infection.
Cardiac dysrhythmias requiring treatment, or prolongation of the QTc (Fridericia) interval to >450 msec for males or >470 msec for females at pre-study screening, unless attributable to pre-existing bundle branch block.
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.

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Interventions

In the Phase I dose-escalation phase of the study, patients were assigned to dose levels in successive cohorts starting with a dose in the first cohort of 100 mg/day. Dose-escalation proceeded initia

In the Phase I dose-escalation phase of the study, patients were assigned to dose levels in successive cohorts starting with a dose in the first cohort of 100 mg/day. Dose-escalation proceeded initially with a 1.5-fold increment, however, based on toxicity and efficacy information at a specific dose level, the dose escalation increment may have been reduced to a 1.25-fold escalation at the discretion of the investigator. At any dose level, if one patient experienced a Grade 2 toxicity or higher, the dose-escalation could only proceed with 1.25-fold increments. The dose escalation proceeded as follows: Cohort 1 = 100 mg Cohort 2 = 150 mg Cohort 3 = 200 mg Cohort 4 = 300 mg Cohort 5 = 400 mg 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. Patients will receive up to 9 cycles of therapy unless one of the following occurs: - disease progression (Progressive disease; PD) by IWG-MRI consensus criteria - Intercurrent illness that prevents further administration of treatment - Unacceptable adverse event(s) - Patient decides to withdraw from the study - General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator Twenty additional patients will be assigned to a 150 mg BID (twice daily) dosing schedule. CYT387 will be orally self-administered twice-daily with doses approximately 10-12 hours apart beginning on Day 1 of the study, and thereafter at approximately the same times each day of the 28-day cycle. Patients will continue for up to 9 cycles as above. For the Part 2 dose confirmation portion of the study, 60 additional patients will be assigned to either 150 mg or 300 mg QD (once daily) dose groups. As with Part 1 of the study, patients will receive up to 9 cycles of CYT387, at 28 days per cycle as above.