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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04676529
Other study ID # PXS5505-MF-101
Secondary ID
Status Recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date February 18, 2021
Est. completion date August 2025

Study information

Verified date November 2023
Source Syntara
Contact Jana Baskar, MBBS MMedSc MBA
Phone +61 487 651 726
Email jana.baskar@syntaratx.com.au
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This study will be an open-label phase 1/2a study to evaluate the safety and tolerability of PXS-5505 in patients with primary, postpolycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis.


Description:

The study consists of three phases: a dose escalation phase, a cohort expansion phase, and an add-on phase. The dose escalation phase will follow a 3+3 design with a starting dose of 100 mg twice daily, and a treatment duration of 4 weeks. Patients will be able to participate in more than one dose level. During the cohort expansion phase, up to 24 patients will be treated at the dose determined appropriate based on safety, pharmacokinetic and pharmacodynamic results from the dose escalation phase, for a period of up to 6 months. Patients from the dose escalation phase will be able to participate in the cohort expansion phase. In the add-on phase PXS-5505 will be given to patients, already receiving a stable dose of ruxolitinib, for a period of 12 months. Up to 15 patients will enrol in the add-on phase in order to obtain 12 patients with at least 1 month's exposure to PXS-5505 on top of ruxolitinib. Note: The decision to include an add-on phase, where PXS-5505 is to be given on top of a stable ruxolitinib dose, was taken following a review of the data (safety, PK and PD) from the cohort expansion phase. There will be no washout period between dose escalation and dose expansion cohorts.


Recruitment information / eligibility

Status Recruiting
Enrollment 39
Est. completion date August 2025
Est. primary completion date August 2025
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Have a pathologically confirmed established diagnosis of primary myelofibrosis or post-essential thrombocythemia/polycythemia vera myelofibrosis as per the World Health Organization 2016 diagnostic criteria (must include at least Grade 2 marrow fibrosis) - Patients who are not eligible for stem cell transplantation - a) Dose escalation / Cohort expansion phase only: Patients not currently on ruxolitinib or fedratinib (where available) treatment due to ineligibility, or previously treated patients who have been discontinued for at least 2 weeks prior to first dose of study drug due to any of the following criteria: - Ineligible: Platelets <50 x 10^9/L - Intolerant: Development of red blood cell transfusion dependence of at least two units/month for 2 months OR =Grade 3 adverse events of thrombocytopenia, anemia, hematoma, and/or hemorrhage while on treatment with ruxolitinib or fedratinib for at least 28 days - Refractory: < 10% spleen volume reduction by MRI or CT, or < 30% decrease from baseline in spleen volume by palpation after at least 3 months treatment with ruxolitinib or fedratinib - Relapsed: Regrowth to < 10% spleen volume reduction by MRI or CT, or < 30% decrease from baseline in spleen volume by palpation, following an initial response to ruxolitinib or fedratinib and after at least 3 months treatment - b) Add-on phase only: Are being treated with ruxolitinib for at least 12 weeks prior to first administration of study treatment. The patient must be on a stable dose (no dose adjustments) of ruxolitinib for = 8 weeks prior to study treatment and have not achieved complete remission (CR) by International Working Group (IWG) criteria. - Have intermediate -2, or high-risk disease according to the International Working Group prognostic scoring system (DIPSS); - a) Dose escalation / Cohort expansion phase only: Have symptomatic disease according to the MFSAF v4.0; Symptomatic disease is defined as a score of at least one in at least two items of the MFSAF v4.0; b) Add-on phase only: have a score of = 10 on the MFSAF v4.0; - Have symptomatic disease according to the MFSAF v4.0; - Life expectancy of six months or greater; - Must have adequate organ function as demonstrated by the following (within last 2 weeks): - Alanine aminotransferase and/or aspartate aminotransferase = 2.5x upper limit of normal (ULN), or = 4 x ULN (if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis [EMH] related to MF); - Direct bilirubin = 1.5 x ULN; or = 2 x ULN (if upon judgment of the treating physician, it is believed to be due to EMH related to MF); - Estimated glomerular filtration rate (eGFR) > 50 mL/min - Eastern Cooperative Oncology Group performance status = 2; - Men must agree to using one medically approved contraceptive measure and have their partners agree to an additional barrier method of contraception for the duration of the study and for 90 days after the last administration of study drug; women of childbearing potential must use effective contraception - Cohort Expansion and Add-on Phase only: A bone marrow biopsy must have been performed within 3 months prior to Day 1 treatment to establish the baseline fibrosis score or within 6 months of the re-initiation of treatment with PXS-5505 if subject participated in dose escalation phase of the trial Exclusion Criteria: - Greater than (>) 10% blasts in peripheral blood (determined within last two weeks); - Prior splenectomy, or planning to undergo splenectomy, or splenic irradiation within 3 months prior to the first dose of study treatment - Any serious medical condition or psychiatric illness that would prevent (as judged by the treating physician) the subject from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study - Known history of human immunodeficiency virus, active hepatitis C, or active hepatitis B - History or presence of any form of cancer within the three years prior to enrolment, with the exception of excised basal cell or squamous cell carcinoma of the skin, or cervical carcinoma in situ or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis - Participation in an investigational drug or device trial within two weeks prior to study Day 1 or within five times the half-life of the investigational agent in the other clinical study, if known - Use of any cytotoxic chemotherapeutic agents, including hydroxyurea, corticosteroids (prednisone = 10 mg/day or corticosteroid equivalent is allowed), or immune modulators (e.g., thalidomide) within two weeks and interferon use within four weeks prior to study Day 1 - Symptomatic congestive heart failure (New York Heart Association Classification Class II), unstable angina, or unstable cardiac arrhythmia requiring medication - Pregnancy - History of surgery within two weeks prior to enrolment or anticipated surgery during the study period or two weeks post-study - History of aneurysm - Any other condition that might reduce the chance of obtaining data required by the protocol or that might compromise the ability to give truly informed consent.

Study Design


Intervention

Drug:
PXS-5505
PXS-5505 is a hard capsule (size 0) with the additional excipients mannitol and magnesium stearate.

Locations

Country Name City State
Australia Ashford Cancer Centre Research Adelaide South Australia
Australia St Vincent's Hospital Melbourne Fitzroy Victoria
Australia Liverpool Hospital Liverpool New South Wales
Australia One Clinical Research Perth Western Australia
Australia The Perth Blood Institute West Perth Western Australia
Korea, Republic of Inje University Busan Paik Hospital - Internal Medicine Busan Busan Gwang'yeogsi [Pusan-Kwan
Korea, Republic of Keimyung University Dongsan Hospital Daegu Daegu Gwang'yeogsi [Taegu-Kwangyokshi]
Korea, Republic of National Cancer Center (Seoul Metro; northern) Gyeonggi-do
Korea, Republic of Seoul National University Hospital - Bundang Gyeonggi-do
Korea, Republic of Gachon University Gil Hospital Incheon Incheon Gwang'yeogsi [Inch'n-K
Korea, Republic of Asan Medical Centre Seoul
Korea, Republic of Samsung Medical Center Seoul
Korea, Republic of Seoul National University Hospital Seoul
Korea, Republic of Severance Hospital, Yonsei University Health System- Haemat Seoul
Korea, Republic of The Catholic University of Korea, Seoul St. Mary's Hospital Seoul
Taiwan Chang Gung Medical Foundation - ChiaYi Chang Gung Memorial Hospital - Hematology and Oncology Chiayi City Chiayi
Taiwan Kaohsiung Medical University Chung-Ho Memorial Hospital Kaohsiung
Taiwan China Medical University Hospital - Internal Medicine - Taichung Taichung
Taiwan National Cheng Kung University Hospital Tainan
Taiwan National Taiwan University Hospital - Hematology And Oncology Taipei
United States Comprehensive Cancer Center (UAB CCC) Birmingham Alabama
United States The University of Texas MD Anderson Cancer Center Houston Texas
United States Novant Health Cancer Institute Winston-Salem North Carolina

Sponsors (1)

Lead Sponsor Collaborator
Syntara

Countries where clinical trial is conducted

United States,  Australia,  Korea, Republic of,  Taiwan, 

Outcome

Type Measure Description Time frame Safety issue
Primary Number of subjects with serious and non-serious adverse events Safety and tolerability of PXS-5505 in patients with myelofibrosis will be assessed Day 0 to follow-up visit (28 days -1 to +7days post-Tx discontinuation [dose escalation phase]; Day 0 to 28 days ± 3 days post-Tx discontinuation [cohort expansion phase]); Day 0 to follow-up visit (28 days ± 3 days post-Tx discontinuation [add-on phase]
Secondary Maximum plasma concentration (C1hr=Cmax) Pharmacokinetic parameters of PXS-5505 in patients with myelofibrosis will be assessed. Day 0, week 1 and week 4 (dose escalation), and Day 0, week 4, 12 and 24 (cohort expansion and add-on phase), and week 52 during add-on phase only
Secondary Minimum plasma concentration (Cmin) Pharmacokinetic parameters of PXS-5505 in patients with myelofibrosis will be assessed. Day 0, week 1 and week 4 (dose escalation), and Day 0, week 4, 12 and 24 (cohort expansion and add-on phase), and week 52 during add-on phase only
Secondary Lysyl oxidase and lysyl oxidase-like 2 inhibition in plasma Pharmacodynamic parameters of PXS-5505 in patients with myelofibrosis will be assessed. Day 0, week 1 and week 4 dose escalation, and at week 0, 4, 12, 24 (cohort expansion and add-on phase), and week 52 during add-on phase only
Secondary Change in bone marrow (BM) fibrosis Change in bone marrow fibrosis will be assessed according to European Consensus on grading of bone marrow fibrosis Day 0, Week 12 and Week 24 (cohort expansion and add-on phase), and week 52 during add-on phase only
Secondary Response rate Response rates as defined by International Working Group (IWG)-Myeloproliferative Neoplasms Research and Treatment criteria in patients with myelofibrosis administered PXS-5505 will be determined. At week 12 and week 24 (cohort expansion and add-on phase), weeks 38 and 52 during add-on phase only
Secondary Changes in spleen volume Changes in spleen volume, as measured by computed tomography (CT) or magnetic resonance imaging (MRI) scan, in patients with myelofibrosis administered PXS-5505 will be determined. Day 0, week 12, and week 24 (cohort expansion and add-on phase), weeks 38 and 52 during add-on phase only
Secondary Changes in myelofibrosis related symptoms Changes in myelofibrosis related symptoms based on Myelofibrosis-Symptom Assessment Form (MFSAF) v4.0 scores, in patients with myelofibrosis administered PXS-5505 will be determined. A higher score indicates worse symptoms. Screening, week 12, and week 24 (cohort expansion and add-on phase), weeks 38 and 52 during add-on phase only
Secondary Percentage of patients with hematological changes Hematological changes will be determined Day 0, week 12, and 24 (cohort expansion and add-on phase), weeks 38 and 52 during add-on phase only
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