Myelofibrosis, Post- Essential Thrombocythemia Myelofibrosis, Post Polycythemia Vera Myelofibrosis, Primary Myelofibrosis (PMF)
Conditions
Keywords
Thrombocythemia myelofibrosis, PXS-5505, Post polycythemia vera myelofibrosis, amsulostat
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.
Detailed 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.
Interventions
DRUGPXS-5505
PXS-5505 is a hard capsule (size 0) with the additional excipients mannitol and magnesium stearate.
Sponsors
Syntara
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Serious and Non-serious Adverse Events | Day 0 to follow-up visit (28 -1/+7days post-Tx end) after up to 4wks Tx [escalation phase]; Day 0 to follow-up visit (28±3days post-Tx end) after up to 24wks Tx [expansion]); Day 0 to follow-up visit (28± 3days post-Tx end) after up to 52wks Tx [add-on]. | Safety and tolerability of PXS-5505 in patients with myelofibrosis will be assessed. More details on the types of AEs can be found in the safety results section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | 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 | Pharmacokinetic parameters of PXS-5505 in patients with myelofibrosis. Cmax was taken to be the concentration at 1 hour post-dose. |
| Minimum Plasma Concentration (Cmin) | 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 | Pharmacokinetic parameters of PXS-5505 in patients with myelofibrosis will be assessed. Cmin was the concentration pre-dose at each visit. |
| Lysyl Oxidase and Lysyl Oxidase-like 2 Inhibition in Plasma | 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 | Pharmacodynamic parameters of PXS-5505 in patients with myelofibrosis. LOX and LOXL2 inhibition expressed as a percentage of the pre-dose activity on Day 0. |
| Change in Bone Marrow (BM) Fibrosis - Reticulin | Day 0, Week 12 and Week 24 (cohort expansion and add-on phase), and week 52 during add-on phase only | Change in bone marrow reticulin fibrosis assessed according to European Consensus on grading of bone marrow fibrosis, centrally assessed. |
| Change in Bone Marrow (BM) Fibrosis - Collagen | Day 0, Week 12 and Week 24 (cohort expansion and add-on phase), and week 52 during add-on phase only | Change in bone marrow collagen fibrosis, assessed according to European Consensus on grading of bone marrow fibrosis via central review |
| IWG-MRT Response Rate, Investigator Assessment | At week 12 and week 24 (cohort expansion and add-on phase), weeks 38 and 52 during add-on phase only | Response rates as assessed by the investigator based on International Working Group (IWG)-Myeloproliferative Neoplasms Research and Treatment criteria in patients with myelofibrosis administered PXS-5505 |
| Changes in Spleen Volume | Day 0, week 12, and week 24 (cohort expansion and add-on phase), weeks 38 and 52 during add-on phase only | Changes in spleen volume, as measured by computed tomography (CT) or magnetic resonance imaging (MRI) scan, in patients with myelofibrosis administered PXS-5505 |
| Changes in Spleen Volume - Achievement of SVR25 | Week 12, and week 24 (cohort expansion and add-on phase), weeks 38 and 52 during add-on phase only | Achievement of a reduction of 25% from baseline in the spleen volume in patients with myelofibrosis and enlarged spleen administered PXS-5505 |
| Changes in Spleen Volume - Achievement of SVR35 | Week 12, and week 24 (cohort expansion and add-on phase), weeks 38 and 52 during add-on phase only | Achievement of a reduction of 35% from baseline in the spleen volume in patients with myelofibrosis and an enlarged spleen administered PXS-5505 |
| Changes in Myelofibrosis Related Symptoms - Achievement of TSS50 | Screening, week 12, and week 24 (cohort expansion and add-on phase), weeks 38 and 52 during add-on phase only | Achievement of a reduction of 50% from baseline in the Total Symptom Score (TSS) as measured by the Myelofibrosis-Symptom Assessment Form (MFSAF) v4.0, 7 day recall version, in patients with myelofibrosis administered PXS-5505. The MFSAF v4.0 assesses 7 core symptoms of myelofibrosis: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Each symptom is rated on an 11-point scale from 0 (absent) to 10 (worst imaginable). The Total Symptom Score is calculated by adding the scores from each of the 7 individual symptoms. Therefore the range of possible scores is from 0 to 70, with a higher score indicating worse symptoms. |
| Changes in Myelofibrosis Related Symptoms, Absolute Change in TSS | Screening, week 12, and week 24 (cohort expansion and add-on phase), weeks 38 and 52 during add-on phase only | Absolute changes from baseline in Total Symptom Score (TSS) as measured by the Myelofibrosis-Symptom Assessment Form (MFSAF) v4.0, 7 day recall version, in patients with myelofibrosis administered PXS-5505. The MFSAF v4.0 assesses 7 core symptoms of myelofibrosis: fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, and bone pain. Each symptom is rated on an 11-point scale from 0 (absent) to 10 (worst imaginable). The Total Symptom Score is calculated by adding the scores from each of the 7 individual symptoms. Therefore the range of possible scores is from 0 to 70, with a higher score indicating worse symptoms. A positive absolute change is indicative of worsened symptoms compared to baseline. A negative absolute change is indicative of improved symptoms compared to baseline. |
| Hematological Changes - % of Patients With Anemia Response, Minor Anemia Response, 50% Reduction in Transfusion Burden | Any time from week 12 to week 24 (expansion phase) or to week 52 (add-on phase) | Patients with hemoglobin \<100g/L at baseline who achieve an anemia response based on IWG-MRT criteria and who achieve a minor anemia response consistent with 2024 IWG-ELN criteria. Also, patients receiving transfusions at baseline who have a reduction of \>=50% in transfusion units in any rolling 12 week period from week 12 onwards, compared to the 12 weeks prior to treatment. Derived from data on hemoglobin level and transfusions. |
Countries
Australia, South Korea, Taiwan, United States
Contacts
STUDY_DIRECTORJana Baskar, MBBS MMedSc MBA
Syntara
Participant flow
Recruitment details
Some patients participated in multiple cohorts/phases. * 3 patients entered Cohort A. 2 participated in Cohort A only & 1 continued into cohorts B and C and into the expansion phase. * 2 new patients were entered into Cohort B. Both completed B and C and 1 entered into the expansion phase. * 22 new patients were enrolled into the expansion phase. * 16 new patients were enrolled in the add-on phase. Overall, a total of 43 patients were treated.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous Add-on Phase | 69.3 years STANDARD_DEVIATION 9.89 |
| Age, Continuous Escalation 100mg | 73.0 years STANDARD_DEVIATION 3.46 |
| Age, Continuous Escalation 150mg | 67.3 years STANDARD_DEVIATION 6.35 |
| Age, Continuous Escalation 200mg | 67.3 years STANDARD_DEVIATION 6.35 |
| Age, Continuous Expansion Phase | 71.5 years STANDARD_DEVIATION 6.27 |
| Daily dose of ruxolitinib at entry 10mg | 3 Participants |
| Daily dose of ruxolitinib at entry 20mg | 3 Participants |
| Daily dose of ruxolitinib at entry 30mg | 2 Participants |
| Daily dose of ruxolitinib at entry 40mg | 6 Participants |
| Daily dose of ruxolitinib at entry 5mg | 1 Participants |
| Daily dose of ruxolitinib at entry 7.5mg | 1 Participants |
| DIPPS risk category Add-on Phase High risk | 4 Participants |
| DIPPS risk category Add-on Phase Intermediate-1 risk | 0 Participants |
| DIPPS risk category Add-on Phase Intermediate-2 risk | 12 Participants |
| DIPPS risk category Add-on Phase Low risk | 0 Participants |
| DIPPS risk category Escalation 100mg High risk | 2 Participants |
| DIPPS risk category Escalation 100mg Intermediate-1 risk | 0 Participants |
| DIPPS risk category Escalation 100mg Intermediate-2 risk | 0 Participants |
| DIPPS risk category Escalation 100mg Low risk | 0 Participants |
| DIPPS risk category Escalation 150mg High risk | 0 Participants |
| DIPPS risk category Escalation 150mg Intermediate-1 risk | 0 Participants |
| DIPPS risk category Escalation 150mg Intermediate-2 risk | 0 Participants |
| DIPPS risk category Escalation 150mg Low risk | 0 Participants |
| DIPPS risk category Escalation 200mg High risk | 0 Participants |
| DIPPS risk category Escalation 200mg Intermediate-1 risk | 0 Participants |
| DIPPS risk category Escalation 200mg Intermediate-2 risk | 0 Participants |
| DIPPS risk category Escalation 200mg Low risk | 0 Participants |
| DIPPS risk category Expansion Phase High risk | 4 Participants |
| DIPPS risk category Expansion Phase Intermediate-1 risk | 0 Participants |
| DIPPS risk category Expansion Phase Intermediate-2 risk | 0 Participants |
| DIPPS risk category Expansion Phase Low risk | 0 Participants |
| Duration of Prior JAK inhibitor therapy (weeks) Add-on Phase | 140.79 Weeks |
| Duration of Prior JAK inhibitor therapy (weeks) Escalation 100mg | 27.43 Weeks |
| Duration of Prior JAK inhibitor therapy (weeks) Escalation 150mg | 238.29 Weeks |
| Duration of Prior JAK inhibitor therapy (weeks) Escalation 200mg | 238.29 Weeks |
| Duration of Prior JAK inhibitor therapy (weeks) Expansion Phase | 110.36 Weeks |
| Ethnicity (NIH/OMB) Add-on Phase Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Add-on Phase Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Add-on Phase Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Escalation 100mg Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Escalation 100mg Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Escalation 100mg Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Escalation 150mg Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Escalation 150mg Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Escalation 150mg Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Escalation 200mg Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Escalation 200mg Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Escalation 200mg Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Expansion Phase Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Expansion Phase Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Expansion Phase Unknown or Not Reported | 2 Participants |
| Myelofibrosis Type Add-on Phase Post-essential thrombocythemia myelofibrosis | 0 Participants |
| Myelofibrosis Type Add-on Phase Post-polycythemia vera myelofibrosis | 7 Participants |
| Myelofibrosis Type Add-on Phase Primary myelofibrosis | 0 Participants |
| Myelofibrosis Type Escalation 100mg Post-essential thrombocythemia myelofibrosis | 2 Participants |
| Myelofibrosis Type Escalation 100mg Post-polycythemia vera myelofibrosis | 0 Participants |
| Myelofibrosis Type Escalation 100mg Primary myelofibrosis | 0 Participants |
| Myelofibrosis Type Escalation 150mg Post-essential thrombocythemia myelofibrosis | 2 Participants |
| Myelofibrosis Type Escalation 150mg Post-polycythemia vera myelofibrosis | 0 Participants |
| Myelofibrosis Type Escalation 150mg Primary myelofibrosis | 0 Participants |
| Myelofibrosis Type Escalation 200mg Post-essential thrombocythemia myelofibrosis | 2 Participants |
| Myelofibrosis Type Escalation 200mg Post-polycythemia vera myelofibrosis | 0 Participants |
| Myelofibrosis Type Escalation 200mg Primary myelofibrosis | 0 Participants |
| Myelofibrosis Type Expansion Phase Post-essential thrombocythemia myelofibrosis | 0 Participants |
| Myelofibrosis Type Expansion Phase Post-polycythemia vera myelofibrosis | 0 Participants |
| Myelofibrosis Type Expansion Phase Primary myelofibrosis | 10 Participants |
| Race/Ethnicity, Customized Add-on Phase American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Add-on Phase Asian | 0 Participants |
| Race/Ethnicity, Customized Add-on Phase Black or African American | 0 Participants |
| Race/Ethnicity, Customized Add-on Phase Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Add-on Phase Other | 0 Participants |
| Race/Ethnicity, Customized Add-on Phase Unknown | 0 Participants |
| Race/Ethnicity, Customized Add-on Phase White | 0 Participants |
| Race/Ethnicity, Customized Escalation 100mg American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Escalation 100mg Asian | 1 Participants |
| Race/Ethnicity, Customized Escalation 100mg Black or African American | 0 Participants |
| Race/Ethnicity, Customized Escalation 100mg Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Escalation 100mg Other | 0 Participants |
| Race/Ethnicity, Customized Escalation 100mg Unknown | 0 Participants |
| Race/Ethnicity, Customized Escalation 100mg White | 2 Participants |
| Race/Ethnicity, Customized Escalation 150mg American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Escalation 150mg Asian | 0 Participants |
| Race/Ethnicity, Customized Escalation 150mg Black or African American | 0 Participants |
| Race/Ethnicity, Customized Escalation 150mg Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Escalation 150mg Other | 0 Participants |
| Race/Ethnicity, Customized Escalation 150mg Unknown | 0 Participants |
| Race/Ethnicity, Customized Escalation 150mg White | 0 Participants |
| Race/Ethnicity, Customized Escalation 200mg American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Escalation 200mg Asian | 0 Participants |
| Race/Ethnicity, Customized Escalation 200mg Black or African American | 0 Participants |
| Race/Ethnicity, Customized Escalation 200mg Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Escalation 200mg Other | 0 Participants |
| Race/Ethnicity, Customized Escalation 200mg Unknown | 0 Participants |
| Race/Ethnicity, Customized Escalation 200mg White | 0 Participants |
| Race/Ethnicity, Customized Expansion Phase American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Expansion Phase Asian | 11 Participants |
| Race/Ethnicity, Customized Expansion Phase Black or African American | 0 Participants |
| Race/Ethnicity, Customized Expansion Phase Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Expansion Phase Other | 0 Participants |
| Race/Ethnicity, Customized Expansion Phase Unknown | 0 Participants |
| Race/Ethnicity, Customized Expansion Phase White | 12 Participants |
| Sex: Female, Male Add-on Phase Female | 0 Participants |
| Sex: Female, Male Add-on Phase Male | 0 Participants |
| Sex: Female, Male Escalation 100mg Female | 3 Participants |
| Sex: Female, Male Escalation 100mg Male | 0 Participants |
| Sex: Female, Male Escalation 150mg Female | 0 Participants |
| Sex: Female, Male Escalation 150mg Male | 0 Participants |
| Sex: Female, Male Escalation 200mg Female | 0 Participants |
| Sex: Female, Male Escalation 200mg Male | 0 Participants |
| Sex: Female, Male Expansion Phase Female | 0 Participants |
| Sex: Female, Male Expansion Phase Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 3 | 0 / 3 | 3 / 24 | 1 / 16 |
| other Total, other adverse events | 2 / 3 | 3 / 3 | 2 / 3 | 19 / 24 | 14 / 16 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 0 / 3 | 8 / 24 | 8 / 16 |
Outcome results
None listed