Myelofibrosis Transformation in Essential Thrombocythemia, Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase, Primary Myelofibrosis
Conditions
Brief summary
This phase II trial studies how well PAT-1251 works in treating patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytosis myelofibrosis. PAT-1251 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To determine the efficacy of LOXL2 inhibitor PAT-1251 (PAT-1251) as therapy for primary myelofibrosis (PMF), post-polycythemia vera (PV) myelofibrosis (MF), and post-essential thrombocytosis (ET) MF. II. To determine the objective response of PAT-1251 treatment which is defined as CR (complete remission) + PR (partial remission) + CI (clinical improvement) after three and six cycles of treatment. SECONDARY OBJECTIVES: I. To determine the safety of PAT-1251 as therapy for PMF, post-PV MF and post-ET MF. II. To determine time to response and response duration. III. To assess changes in symptom burden as assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). EXPLORATORY OBJECTIVES: I. To explore changes in bone marrow reticulin fibrosis, collagen, osteosclerosis (grading). II. To determine the percent target engagement based on a plasma target engagement assay after treatment with PAT-1251. OUTLINE: Patients receive LOXL2 inhibitor PAT-1251 orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days.
Interventions
DRUGLOXL2 Inhibitor PAT-1251
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must provide written informed consent * Willing and able to comply with scheduled visits, treatment plan and laboratory tests * Patient is able to swallow and retain oral medication * Must be diagnosed with treatment requiring PMF or post ET/PV MF with intermediate -1, intermediate -2 or high risk disease according to the International Working Group (IWG) prognostic scoring system, or if with low risk disease then with symptomatic splenomegaly that is greater than or equal to 5 cm below left costal margin by physical exam * Patients who are not candidates for, intolerant of, or relapsed/refractory to ruxolitinib * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L (1500/mm\^3) * Serum direct bilirubin =\< 2.0 x ULN (upper limit of normal) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) (if both measured, then this applies to both measurements) =\< 2.5 x ULN, except for patients with MF involvement of the liver who must have levels =\< 5 x ULN * Treatment-related toxicities from prior therapies must have resolved to grade =\< 1 * At least 2 weeks from prior MF-directed treatment (till the start of study drug)
Exclusion criteria
* Any concurrent severe and/or uncontrolled medical conditions that could increase the patient's risk for toxicity while in the study or that could confound discrimination between disease- and study treatment-related toxicities * Impaired cardiac function or clinically significant cardiac diseases, including any of the following: * History or presence of ventricular tachyarrhythmia * Presence of unstable atrial fibrillation (ventricular response \> 100 beats per minute \[bpm\]); patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) | Up to 6 cycles, each cycle is 28 days. | Will be defined as complete remission (CR) + partial remission (PR) + clinical improvement (CI). Responses will be categorized according to the revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) consensus criteria for myelofibrosis. Will be estimated along with the exact 95% confidence interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events (AEs) | Up to 2 years | Toxicity is defined as grade 3-4 clinically relevant non-hematologic toxicity or a serious adverse event that is at least possibly drug related (Common Terminology Criteria for Adverse Events version 4.03) and occurs anytime during the treatment. The method of Thall, Simon and Estey will be used for toxicity monitoring. Safety data will be summarized by category, severity and frequency. The proportion of patients with AEs will be estimated, along with the Bayesian 95% credible intervals. |
| Time to response | From date of first treatment to the first date at which the subject's objective status was classified as a response (CR, PR, or CI), assessed up to 2 years | The distribution will be estimated by Kaplan-Meier curves. |
| Duration of response | From the date at which the patient's objective status is first noted to be a CR, PR, or CI to the date of progression (no longer meeting criteria for either CR, PR, or CI) is documented (if one has occurred), assessed up to 2 years | The distribution will be estimated by Kaplan-Meier curves. |
| Changes in symptom burden | Baseline up to 2 years | Will be assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score. |
| The Descriptive statistics in the improvement of anemia | Baseline up to 2 years | Will be used to explore improvements in anemia and the following outcomes will be summarized: mean changes in hemoglobin at monthly intervals. |
| Proportion of transfusion dependent patients who become transfusion independent and have a 1 g/dL increase in hemoglobin | Baseline up to 2 years | Will be summarized. |
| Proportion of transfusion independent patients requiring a transfusion | Baseline up to 2 years | Will be summarized. |
| The Descriptive statistics in Improvements of transfusion dependence. | Baseline up to 2 years | Will be used to explore improvements in the transfusion dependence. The following outcomes will be summarized: mean changes in hemoglobin at monthly intervals. |
| The Transfusion of independent patients | Baseline up to 2 years | Will be summarized if the patient is not requiring transfusions on the study who experience an increase of 2 g/dL in their hemoglobin. |
| Proportion of transfusion dependent patients who become transfusion independent | Baseline up to 2 years | The proportion of transfusion dependent patients (defined as requiring a transfusion of 2 units packed red blood cells (PRBCs) monthly for 3 months (12 weeks) prior to starting the trial) who become transfusion independent (not requiring a transfusion of PRBCs over a period of 3 months (12 weeks) while on study) will be summarized. |
Other
| Measure | Time frame | Description |
|---|---|---|
| The Correlative Studies | Baseline up to 2 years | Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. For continuous outcomes, t-test and analysis of variance (ANOVA) will be used to compare outcome measures across patient characteristics. Dunnett's and Tukey's test that properly adjust for multiplicity in multiple tests will be implemented. Pair-wise comparisons will be performed using pre- and post-therapy samples from each patient. The chi-square test or Fisher's exact test will be used to test the association between two categorical variables such as disease state and performance status. |
| Percent target engagement after treatment | Baseline up to 2 years | The percent target engagement based on a plasma target engagement assay after treatment with LOXL2 inhibitor PAT-1251 will be determined. Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. For continuous outcomes, t-test and ANOVA will be used to compare outcome measures across patient characteristics. Dunnett's and Tukey's test that properly adjust for multiplicity in multiple tests will be implemented. Pair-wise comparisons will be performed using pre- and post-therapy samples from each patient. The chi-square test or Fisher's exact test will be used to test the association between two categorical variables such as disease state and performance status. |
Countries
United States
Outcome results
None listed