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Trial registered on ANZCTR


Registration number
ACTRN12611000159954
Ethics application status
Approved
Date submitted
8/11/2010
Date registered
9/02/2011
Date last updated
5/11/2020
Date data sharing statement initially provided
5/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET)
Scientific 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.
Secondary ID [1] 253049 0
NCT00935987
Secondary ID [2] 253070 0
CCL09101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Primary Myelofibrosis 258611 0
Post-Polycythemia Vera Myelofibrosis 258612 0
Post-Essential Thrombocythemia Myelofibrosis 258613 0
Condition category
Condition code
Blood 258756 258756 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 257573 0
Treatment: Drugs
Comparator / control treatment
All cohorts will receive varying doses ranging from 100mg up to 400mg
Control group
Dose comparison

Outcomes
Primary outcome [1] 259617 0
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.

Measures include physical examination, vital signs and body weight, neurological examination, laboratory testing, bloods - coagulation, peripheral blood smear, 12-lead ECG, bone marrow cellularity, reticulin fibrosis, cytogenetics, IWG-MRT response assessment, JAK2V617F assay, CD34+ assay, pharmacodynamic sampling (STAT5 phosphorylation & cytokines).
Timepoint [1] 259617 0
Ongoing throughout therapy up until 30 days after last dose of CYT387
Primary outcome [2] 259618 0
Objective Response Rate (ORR), as measured by complete response (CR) rate, partial response (PR) rate and clinical improvement (CI) rate according to IWG-MRT consensus criteria
Timepoint [2] 259618 0
Response is measured at the end of every cycle of therapy
Primary outcome [3] 259619 0
To determine the pharmacokinetics (PK) of CYT387 in patients with PMF or post-ET/PV MF
Timepoint [3] 259619 0
Day 1 and day 28 in cycle 1 of therapy
Secondary outcome [1] 266261 0
To determine the effect of CYT387 on bone marrow or peripheral blood cytogenetic findings in patients with PMF or post-ET/PV MF.
Timepoint [1] 266261 0
At the end of every third cycle of therapy
Secondary outcome [2] 266262 0
To determine the effect of CYT387 on peripheral blood granulocyte JAK2V617F allele burden in patients with PMF or post-ET/PV MF.
Timepoint [2] 266262 0
At the end of each cycle of therapy (in relevant patients only)
Secondary outcome [3] 266263 0
To determine the effect of CYT387 on peripheral blood endogenous myeloid colony formation in patients with PMF or post-ET/PV MF.
Timepoint [3] 266263 0
At the end of each cycle of therapy
Secondary outcome [4] 266264 0
To determine the effect of CYT387 on plasma levels of inflammatory, fibrogenic and angiogenic cytokines in patients with PMF or post-ET/PV MF
Timepoint [4] 266264 0
At the end of each cycle of therapy
Secondary outcome [5] 266265 0
To evaluate pharmacodynamic correlates of CYT387 activity in patients with PMF or post-ET/PV MF who are receiving treatment with CYT387.
Timepoint [5] 266265 0
On day 1 of cycles 1, 3, 6 and 9.

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
23/11/2009
Actual
31/08/2011
Date of last participant enrolment
Anticipated
Actual
31/08/2011
Date of last data collection
Anticipated
Actual
1/04/2012
Sample size
Target
140
Accrual to date
Final
165
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 17960 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 3432 0
3050
Recruitment postcode(s) [2] 31834 0
3050 - Parkville
Recruitment outside Australia
Country [1] 3023 0
Canada
State/province [1] 3023 0
Ontario
Country [2] 3024 0
Canada
State/province [2] 3024 0
Quebec
Country [3] 3025 0
United States of America
State/province [3] 3025 0
California
Country [4] 3026 0
United States of America
State/province [4] 3026 0
Minnesota
Country [5] 23094 0
United States of America
State/province [5] 23094 0
Masschusetts

Funding & Sponsors
Funding source category [1] 258028 0
Commercial sector/Industry
Name [1] 258028 0
Gilead Sciences Inc.
Country [1] 258028 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences Inc.
Address
333 Lakeside Dr.
Foster City
CA 94404
Country
United States of America
Secondary sponsor category [1] 257220 0
None
Name [1] 257220 0
Address [1] 257220 0
Country [1] 257220 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 260446 0
Mayo Clinic Insitutional Review Boards
Ethics committee address [1] 260446 0
Mayo Clinic
Rochester, Minnesota, US
Ethics committee country [1] 260446 0
United States of America
Date submitted for ethics approval [1] 260446 0
Approval date [1] 260446 0
29/10/2009
Ethics approval number [1] 260446 0
IRB#: 09-004964

Summary
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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31889 0
Dr Ayalew Tefferi
Address 31889 0
Mayo Clinic
200 First St. SW
Rochester
MN 55905
Country 31889 0
United States of America
Phone 31889 0
+1 507 284 3159
Fax 31889 0
Email 31889 0
[email protected]
Contact person for public queries
Name 15136 0
Kate Sterling
Address 15136 0
Gilead Pharmaceuticals
333 Lakeside Dr.
Foster City CA
94404
Country 15136 0
United States of America
Phone 15136 0
+1 650 577 6677
Fax 15136 0
+1 650 524 9476
Email 15136 0
[email protected]
Contact person for scientific queries
Name 6064 0
Kate Sterling
Address 6064 0
Gilead Pharmaceuticals
333 Lakeside Dr.
Foster City CA
94404
Country 6064 0
United States of America
Phone 6064 0
+1 650 577 6677
Fax 6064 0
+1 650 524 9476
Email 6064 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.