Myelofibrosis
Conditions
Keywords
Myelofibrosis, Panobinostat, Ruxolitinib
Brief summary
This is a single-center, single arm, dose finding study to assess safety and tolerability of the oral combination of Panobinostat and Ruxolitinib in patients with myelofibrosis (MF) in chronic and accelerated phase.
Detailed description
Phase I/II open label, single institution, combination therapy trial of induction Ruxolitinib followed by combination with Panobinostat in dose escalation cohorts with a primary endpoint of determining the safety and tolerability of combination therapy in patients with myelofibrosis (MF) in chronic and accelerated phase. A 3+3standard dose escalation scheme will be employed and the occurrence of dose limiting toxicities (DLTs) will be captured and the occurrence of such events will determine dose cohort escalation by predetermined and established rules. In addition to establishing the DLTs, maximally tolerated dose (MTD), and recommended phase II dose (RPTD) in the phase I portion of this trial, exploratory biomarkers will be evaluated within phase I as well. Pharmacodynamics and exploratory genetic and epigenetic biomarkers will be explored as predictors of response to therapy. The RPTD cohort will be expanded to incorporate a total of 22 patients, including 6 from phase I, in order to assess clinical response as assessed by International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) as a primary endpoint for the phase II portion of this trial.
Interventions
DRUGPanobinostat
PO TIW QOW or PO TIW QW
DRUGRuxolitinib
PO BID x 28 days
Sponsors
John Mascarenhas
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients aged ≥ 18 years old * Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed * Intermediate-2 and higher by IWG-MRT Post PV/ET MF and PMF patients either in 1. Chronic Phase (MF-CP) 2. Accelerated Phase (MF-AP) * Patients must meet the following laboratory criteria: 1. ANC ≥ .750 x 109/L 2. Platelets ≥ 75 x 109/L 3. Creatinine ≤ 1.5 x ULN, 4. AST and ALT ≤ 2.5 x ULN 5. Serum bilirubin ≤ 1.5 x ULN (unless Gilbert's syndrome and evidence of hemolysis) 6. Serum potassium ≥ LLN 7. Total serum calcium \[corrected for serum albumin\] or ionized calcium ≥LLN, 8. Serum magnesium ≥ LLN 9. Serum phosphorus ≥ LLN 10. Free T4 within normal limits * ECOG Performance Status of ≤ 3 * Any prior therapy with JAK2-TKI, hypomethylating agents, HDACI, mTORi, or iMiDs is allowed as long as it is greater than 3 weeks since last dose of administration and in the case of a JAK2-TKI or HDACI that discontinuation was not due to non-hematologic drug toxicity. An exception to this criteria are patients currently on at least 10mg BID of ruxolitinib for greater than 3 months and who have not shown an optimal response (i.e. without 50% reduction in palpable splenomegaly or 50% reduction in symptom burden). With a reduction of ruxolitinib to 10mg BID these patients may enter onto the study without stopping ruxolitinib
Exclusion criteria
* Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first PANOBINOSTAT treatment. * Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: 1. With permanent cardiac pacemaker 2. Resting bradycardia defined as \<50 beats per minute 3. QTcF \>450 msec on screening ECG 4. Complete Left bundle branch block, bifascicular block 5. Any clinically significant ST segment and/or T-wave abnormalities 6. Presence of unstable atrial fibrillation (ventricular response rate \>100 bpm). Patients with stable atrial fibrillation can be enrolled provided they do not meet other cardiac
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients That Achieve Stable Disease or Clinical Improvement | at least 6 months | Number of patients that have either stable disease or clinical improvement treatment response as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Stable disease (SD) - response that is not complete remission, partial remission, clinical improvement, anemia response, spleen response, symptoms response, or progressive disease. Clinical improvement (CI) - a response in anemia, splenomegaly, or MF-SB that is not associated with progressive splenomegaly or increase in severity of anemia, thrombocytopenia, or neutropenia. |
| Number of Participants Who Experienced Dose-Limiting (DLTs) | up to cycle 6, day 29 | Panobinostat related adverse events requiring dose reduction or discontinuing prior to Cycle 6, Day 29 (C6D29) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Spleen Volume | Baseline and Cycle 6, Day 29 | Percent change in spleen volume at C6D29 as compared to baseline |
| Percent Change in Spleen Size for Responders and Non-responders | Cycle 6, Day 29 | Percent change in spleen length size by palpation at cycle 6, day 29 (C6D29) from baseline |
| Percent Change in Spleen Length | Cycle 6, Day 29 | Percent change in spleen length at C6D29 |
| Number of Participants With Percent Change on Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | baseline, C1D1 and Cycle 6 Day 29 | Symptom responders defined as having a percent change in MPN-SAF score from Screening/C1D1 to C6D29 of more than 50%.MPN-SAF is an 18-item instrument. Each item score 0-10 averaged, total scale from0-10, with higher score indicating more symptoms. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Panobinostat and Ruxolitinib Cohort 1 Combination of Panobinostat 10mg and Ruxolitinib 10mg | 3 |
| Panobinostat and Ruxolitinib Cohort 2 Combination of Panobinostat 10mg and Ruxolitinib 15mg | 6 |
| Panobinostat and Ruxolitinib Cohort 3 Combination of Panobinostat 10mg and Ruxolitinib 20mg | 3 |
| Panobinostat and Ruxolitinib Cohort 4 Combination of Panobinostat 15mg and Ruxolitinib 15mg | 3 |
| Total | 15 |
Baseline characteristics
| Characteristic | Panobinostat and Ruxolitinib Cohort 1 | Panobinostat and Ruxolitinib Cohort 2 | Panobinostat and Ruxolitinib Cohort 3 | Panobinostat and Ruxolitinib Cohort 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 60 years | 61 years | 69 years | 64 years | 64 years |
| Cytogenetics Not available | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Cytogenetics Not Unfavorable Karyotype | 1 Participants | 4 Participants | 3 Participants | 3 Participants | 11 Participants |
| Cytogenetics Unfavorable Karyotype | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| DIPSS Score intermediate-1 (score 1 or 2) | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 6 Participants |
| DIPSS Score intermediate-2 (score 3 or 4) | 2 Participants | 4 Participants | 0 Participants | 2 Participants | 8 Participants |
| DIPSS Score low (score 0) | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Disease subtype Post essential thrombocythemia PET-MF | 2 Participants | 3 Participants | 1 Participants | 1 Participants | 7 Participants |
| Disease subtype Post polycythemia vera PPV-MF | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Disease subtype Primary myelofibrosis (PMF) | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 6 Participants |
| Hemoglobin (Hb) Baseline, C1D1 | 8.4 g/DL | 10.75 g/DL | 10.1 g/DL | 11.7 g/DL | 10.4 g/DL |
| Hemoglobin (Hb) Screening | 9.1 g/DL | 9.7 g/DL | 10.5 g/DL | 11.2 g/DL | 9.8 g/DL |
| JAK2^V617F positive | 3 Participants | 4 Participants | 2 Participants | 1 Participants | 10 Participants |
| MRI Spleen Volume | 1190 cm^3 | 2154.5 cm^3 | 2425 cm^3 | 1982 cm^3 | 2077 cm^3 |
| Palpable Spleen Baseline, C1D1 | 2 Participants | 5 Participants | 1 Participants | 3 Participants | 11 Participants |
| Palpable Spleen Screening | 3 Participants | 5 Participants | 2 Participants | 3 Participants | 13 Participants |
| Palpable Spleen Length Baseline, C1D1 | 6 cm | 11 cm | 0 cm | 11 cm | 10 cm |
| Palpable Spleen Length Screening | 6 cm | 12.5 cm | 10 cm | 15 cm | 13 cm |
| Platelet (PLT) Baseline, C1D1 | 131 10^3 cells/µl | 192.5 10^3 cells/µl | 166 10^3 cells/µl | 253 10^3 cells/µl | 188 10^3 cells/µl |
| Platelet (PLT) Screening | 495 10^3 cells/µl | 276 10^3 cells/µl | 584 10^3 cells/µl | 377 10^3 cells/µl | 347 10^3 cells/µl |
| Prior Myelofibrous (MF) Directed Therapy | 2 Participants | 6 Participants | 2 Participants | 1 Participants | 11 Participants |
| Prior No. Therapies | 1 therapies | 1.5 therapies | 2 therapies | 0 therapies | 1 therapies |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Red Blood Cell (RBC) Transfusion Dependent Baseline - Cycle 1, Day 1 (C1D1) Rux +Pano | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Red Blood Cell (RBC) Transfusion Dependent Screening | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ruxolitinib Naive | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 2 Participants | 2 Participants | 11 Participants |
| White Blood Cell (WBC) Baseline, C1D1 | 5.1 10^3 cells/µl | 7 10^3 cells/µl | 6 10^3 cells/µl | 25.9 10^3 cells/µl | 6.8 10^3 cells/µl |
| White Blood Cell (WBC) Screening | 11.3 10^3 cells/µl | 9.8 10^3 cells/µl | 9.8 10^3 cells/µl | 34.3 10^3 cells/µl | 12.5 10^3 cells/µl |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 | 2 / 6 | 3 / 3 | 0 / 3 |
Outcome results
Primary
Number of Participants Who Experienced Dose-Limiting (DLTs)
Panobinostat related adverse events requiring dose reduction or discontinuing prior to Cycle 6, Day 29 (C6D29)
Time frame: up to cycle 6, day 29
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Panobinostat and Ruxolitinib Cohort 1 | Number of Participants Who Experienced Dose-Limiting (DLTs) | Discontinuing Panobinostat | 0 Participants |
| Panobinostat and Ruxolitinib Cohort 1 | Number of Participants Who Experienced Dose-Limiting (DLTs) | requiring Panaobinostat dose reduction | 1 Participants |
| Panobinostat and Ruxolitinib Cohort 2 | Number of Participants Who Experienced Dose-Limiting (DLTs) | Discontinuing Panobinostat | 2 Participants |
| Panobinostat and Ruxolitinib Cohort 2 | Number of Participants Who Experienced Dose-Limiting (DLTs) | requiring Panaobinostat dose reduction | 0 Participants |
| Panobinostat and Ruxolitinib Cohort 3 | Number of Participants Who Experienced Dose-Limiting (DLTs) | Discontinuing Panobinostat | 0 Participants |
| Panobinostat and Ruxolitinib Cohort 3 | Number of Participants Who Experienced Dose-Limiting (DLTs) | requiring Panaobinostat dose reduction | 3 Participants |
| Panobinostat and Ruxolitinib Cohort 4 | Number of Participants Who Experienced Dose-Limiting (DLTs) | Discontinuing Panobinostat | 0 Participants |
| Panobinostat and Ruxolitinib Cohort 4 | Number of Participants Who Experienced Dose-Limiting (DLTs) | requiring Panaobinostat dose reduction | 1 Participants |
Primary
Number of Patients That Achieve Stable Disease or Clinical Improvement
Number of patients that have either stable disease or clinical improvement treatment response as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Stable disease (SD) - response that is not complete remission, partial remission, clinical improvement, anemia response, spleen response, symptoms response, or progressive disease. Clinical improvement (CI) - a response in anemia, splenomegaly, or MF-SB that is not associated with progressive splenomegaly or increase in severity of anemia, thrombocytopenia, or neutropenia.
Time frame: at least 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Panobinostat and Ruxolitinib Cohort 1 | Number of Patients That Achieve Stable Disease or Clinical Improvement | Stable disease | 3 Participants |
| Panobinostat and Ruxolitinib Cohort 1 | Number of Patients That Achieve Stable Disease or Clinical Improvement | No response evaluated | 0 Participants |
| Panobinostat and Ruxolitinib Cohort 1 | Number of Patients That Achieve Stable Disease or Clinical Improvement | Clinical Improvement | 0 Participants |
| Panobinostat and Ruxolitinib Cohort 2 | Number of Patients That Achieve Stable Disease or Clinical Improvement | Stable disease | 4 Participants |
| Panobinostat and Ruxolitinib Cohort 2 | Number of Patients That Achieve Stable Disease or Clinical Improvement | No response evaluated | 1 Participants |
| Panobinostat and Ruxolitinib Cohort 2 | Number of Patients That Achieve Stable Disease or Clinical Improvement | Clinical Improvement | 1 Participants |
| Panobinostat and Ruxolitinib Cohort 3 | Number of Patients That Achieve Stable Disease or Clinical Improvement | Clinical Improvement | 2 Participants |
| Panobinostat and Ruxolitinib Cohort 3 | Number of Patients That Achieve Stable Disease or Clinical Improvement | Stable disease | 1 Participants |
| Panobinostat and Ruxolitinib Cohort 3 | Number of Patients That Achieve Stable Disease or Clinical Improvement | No response evaluated | 0 Participants |
| Panobinostat and Ruxolitinib Cohort 4 | Number of Patients That Achieve Stable Disease or Clinical Improvement | Stable disease | 3 Participants |
| Panobinostat and Ruxolitinib Cohort 4 | Number of Patients That Achieve Stable Disease or Clinical Improvement | No response evaluated | 0 Participants |
| Panobinostat and Ruxolitinib Cohort 4 | Number of Patients That Achieve Stable Disease or Clinical Improvement | Clinical Improvement | 0 Participants |
Secondary
Number of Participants With Percent Change on Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)
Symptom responders defined as having a percent change in MPN-SAF score from Screening/C1D1 to C6D29 of more than 50%.MPN-SAF is an 18-item instrument. Each item score 0-10 averaged, total scale from0-10, with higher score indicating more symptoms.
Time frame: baseline, C1D1 and Cycle 6 Day 29
Population: C6D29 not available for one participant in cohort 2 and 2 participants in cohort 4
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Panobinostat and Ruxolitinib Cohort 1 | Number of Participants With Percent Change on Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | 1 Participants |
| Panobinostat and Ruxolitinib Cohort 2 | Number of Participants With Percent Change on Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | 2 Participants |
| Panobinostat and Ruxolitinib Cohort 3 | Number of Participants With Percent Change on Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | 0 Participants |
| Panobinostat and Ruxolitinib Cohort 4 | Number of Participants With Percent Change on Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) | 0 Participants |
Secondary
Percent Change in Spleen Length
Percent change in spleen length at C6D29
Time frame: Cycle 6, Day 29
Population: One participant did not return for C6,D29 visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panobinostat and Ruxolitinib Cohort 1 | Percent Change in Spleen Length | -83 percent change |
| Panobinostat and Ruxolitinib Cohort 2 | Percent Change in Spleen Length | -17 percent change |
| Panobinostat and Ruxolitinib Cohort 3 | Percent Change in Spleen Length | -14 percent change |
| Panobinostat and Ruxolitinib Cohort 4 | Percent Change in Spleen Length | -31 percent change |
Secondary
Percent Change in Spleen Size for Responders and Non-responders
Percent change in spleen length size by palpation at cycle 6, day 29 (C6D29) from baseline
Time frame: Cycle 6, Day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panobinostat and Ruxolitinib Cohort 1 | Percent Change in Spleen Size for Responders and Non-responders | -100 percent change |
| Panobinostat and Ruxolitinib Cohort 2 | Percent Change in Spleen Size for Responders and Non-responders | -29 percent change |
Secondary
Percent Change in Spleen Volume
Percent change in spleen volume at C6D29 as compared to baseline
Time frame: Baseline and Cycle 6, Day 29
Population: One participant did not return for C6,D29 visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panobinostat and Ruxolitinib Cohort 1 | Percent Change in Spleen Volume | -41 percent change |
| Panobinostat and Ruxolitinib Cohort 2 | Percent Change in Spleen Volume | -8 percent change |
| Panobinostat and Ruxolitinib Cohort 3 | Percent Change in Spleen Volume | -40 percent change |
| Panobinostat and Ruxolitinib Cohort 4 | Percent Change in Spleen Volume | -17 percent change |