Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis

Sponsor

Pharmaxis (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04676529

Collaborator

Parexel (Industry)

Enrollment

Locations

Arms

28.3

Anticipated Duration (Months)

1.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Myelofibrosis	Drug: PXS-5505	Phase 1/Phase 2

Detailed Description

The study consists of two phases: a dose escalation phase and a cohort expansion 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, 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.

There will be no washout period between dose escalation and dose expansion cohorts.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2a Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Postpolycythemia Vera or Post-essential Thrombocythemia Myelofibrosis

Actual Study Start Date :

Feb 18, 2021

Anticipated Primary Completion Date :

Mar 30, 2023

Anticipated Study Completion Date :

Jun 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PXS-5505, Dose Level 1, Escalation Phase (Cohort A) Patients will receive PXS-5505 dose level 1, twice daily for a period of 4 weeks.	Drug: PXS-5505 PXS-5505 is a hard gelatin capsule (size 0) with the additional excipients mannitol and magnesium stearate.
Experimental: PXS-5505, Dose Level 2, Escalation Phase (Cohort B) Patients will receive PXS-5505 dose level 2, twice daily for a period of 4 weeks.	Drug: PXS-5505 PXS-5505 is a hard gelatin capsule (size 0) with the additional excipients mannitol and magnesium stearate.
Experimental: PXS-5505, Dose Level 3, Escalation Phase (Cohort C) Patients will receive PXS-5505 dose level 3, twice daily for a period of 4 weeks.	Drug: PXS-5505 PXS-5505 is a hard gelatin capsule (size 0) with the additional excipients mannitol and magnesium stearate.
Experimental: PXS-5505, Expansion Phase All patients will receive PXS-5505 at the selected twice daily dose for a period of 24 weeks, or until progressive disease, unacceptable toxicity, dose-limiting toxicity or withdrawal of consent.	Drug: PXS-5505 PXS-5505 is a hard gelatin capsule (size 0) with the additional excipients mannitol and magnesium stearate.

Outcome Measures

Primary Outcome Measures

Number of subjects with serious and non-serious adverse events [Day 0 to follow-up visit (28 days ± 1 day post-Tx discontinuation [dose escalation phase]; Day 0 to 28 days ± 1 day post-Tx discontinuation [cohort expansion phase])]
Safety and tolerability of PXS-5505 in patients with myelofibrosis will be assessed

Secondary Outcome Measures

Maximum plasma concentration (C1hr=Cmax) [Day 0, week 1 and week 4 (dose escalation), and Day 0, week 4, 12 and 24 weeks (cohort expansion phase only)]
Pharmacokinetic parameters of PXS-5505 in patients with myelofibrosis will be assessed.
Minimum plasma concentration (Cmin) [Day 0, week 1 and week 4 (dose escalation), and Day 0, week 4, 12 and 24 weeks (cohort expansion phase only)]
Pharmacokinetic parameters of PXS-5505 in patients with myelofibrosis will be assessed.
Lysyl oxidase and lysyl oxidase-like 2 inhibition in plasma [Day 0, week 1 and week 4 dose escalation, and at weeks 0, 4, 12 and 24 weeks (cohort expansion phase only)]
Pharmacodynamic parameters of PXS-5505 in patients with myelofibrosis will be assessed.
Change in bone marrow (BM) fibrosis (cohort expansion phase) [Day 0, Week 12 and Week 24]
Change in bone marrow fibrosis will be assessed according to European Consensus on grading of bone marrow fibrosis
Response rate (cohort expansion phase) [At Week 12 and Week 24]
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.
Changes in spleen volume (cohort expansion phase) [Day 0, Week 12, and Week 24]
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.
Changes in myelofibrosis related symptoms (cohort expansion phase) [Day 0, Week 12, and Week 24]
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.
Percentage of patients with hematological changes [Day 0, Week 12, and 24]
Hematological changes will be determined

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 135 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
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
Have intermediate -2, or high-risk disease according to the International Working Group prognostic scoring system (DIPSS);
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 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 5 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Comprehensive Cancer Center (UAB CCC)	Birmingham	Alabama	United States	98374
2	Harvard U Med School IRB #1	Boston	Massachusetts	United States	02115
3	Novant Health Cancer Institute	Winston-Salem	North Carolina	United States	27103
4	Cleveland Clinic - Medical Oncology/Hematology	Cleveland	Ohio	United States	44195
5	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
6	Liverpool Hospital	Liverpool	New South Wales	Australia	2170
7	Ashford Cancer Centre Research	Adelaide	South Australia	Australia	5037
8	One Clinical Research	Perth	Western Australia	Australia	6009
9	The Perth Blood Institute	West Perth	Western Australia	Australia	6005
10	Inje University Busan Paik Hospital - Internal Medicine	Busan	Busan Gwang'yeogsi [Pusan-Kwan	Korea, Republic of	47392
11	Keimyung University Dongsan Medical Center	Daegu	Daegu Gwang'yeogsi [Taegu-Kwan	Korea, Republic of	42601
12	Gachon University Gil Hospital	Incheon	Incheon Gwang'yeogsi [Inch'n-K	Korea, Republic of	21565
13	Seoul National University Hospital	Seoul		Korea, Republic of	03080
14	Severance Hospital, Yonsei University Health System- Haemat	Seoul		Korea, Republic of	03711
15	Samsung Medical Center	Seoul		Korea, Republic of	06351
16	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul		Korea, Republic of	06591
17	Chang Gung Medical Foundation - ChiaYi Chang Gung Memorial Hospital - Hematology and Oncology	Chiayi City	Chiayi	Taiwan	613
18	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan	807
19	China Medical University Hospital - Internal Medicine - Taichung	Taichung		Taiwan	40447
20	National Cheng Kung University Hospital - Internal Medicine	Tainan		Taiwan	70403
21	National Taiwan University Hospital - Hematology And Oncology	Taipei		Taiwan	100