None listed
Conditions
Brief 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.
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 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
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.
Sponsors
Gilead Sciences Inc.
Study design
Allocation
Non-randomised trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
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/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 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 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.
Outcome results
None listed