Post-essential Thrombocythemia Myelofibrosis, Post-polycythemia Vera Myelofibrosis, Primary Myelofibrosis
Conditions
Brief summary
This is a phase II, open label, prospective, single-arm study evaluating the efficacy and safety of selinexor in patients with PMF or secondary MF (PPV-MF or PET-MF) who are refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors.
Interventions
DRUGSelinexor
Selinexor will be administered orally at a dose of 80 mg once weekly until IWG-MR disease progression, intolerable toxicity, or no clinical benefit per treating physician's discretion whichever occurs first. For patients enrolled after Protocol v7, Selinexor will be administered by oral route beginning at 40mg once weekly. Prior to protocol version 7, the starting dose of sSelinexor was 60 mg and 80 mg once weekly.
Sponsors
University of Utah
Karyopharm Therapeutics Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open label, non-randomized, prospective, single-arm study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subject aged ≥ 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Diagnosis of primary myelofibrosis (PMF), post-essential thrombocytosis (PET-MF) or post-polycythemia vera (PPV-MF). * Life expectancy ≥ 6 months. * Prior treatment with ruxolitinib or any experimental JAK1/2 inhibitor with any one or more of the following: a. Inadequate response after being on ≥ 3 months of treatment defined by: i. Palpable spleen ≥ 10 cm below the left subcostal margin on physical examination at the screening visit OR ii. Palpable spleen ≥ 5cm below the left subcostal margin on physical examination at the screening visit AND active symptoms of MF at the screening visit defined presence of 1 symptom score of ≥ 5 or two symptom scores each of ≥ 3 using the Screening Symptoms Form (Appendix 6) b. Intolerant to ruxolitinib and/or other JAK1/2 inhibitors due to any grade ≥ 3 non-hematologic AEs of or any grade ≥ 2 AEs requiring treatment discontinuation AND palpable spleen ≥ 5cm below the left subcostal margin on physical examination at the screening visit. * Adequate organ function as defined as: * Hematologic (≤ 28 days prior to C1D1): * Total white blood cell (WBC) count ≥ 1000/mm3 * Absolute neutrophil count (ANC) ≥ 500/mm3 * Hemoglobin ≥ 7 g/dL * Platelet count ≥ 30,000/mm3 For patients receiving transfusion and growth factor support, the following delays must be observed between the last administration and hematologic laboratory screening assessments: • For hematopoietic growth factor support (including erythropoietin, darbepoetin, granulocyte-colony stimulating factor \[G-CSF\], granulocyte macrophage-colony stimulating factor \[GM-CSF\], and platelet stimulators \[e.g., eltrombopag, romiplostim, or interleukin-11\]): at least 2 weeks. Growth factor support, RBC and/or platelet transfusions are allowed as clinically indicated per institutional guidelines during the study. * Hepatic (≤ 28 days prior to C1D1): * Total bilirubin \< 1.5 × ULN except in patients with indirect hyperbilirubinemia due to hemolysis or with Gilbert's syndrome where total bilirubin should be \< 5 × ULN * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 2.5 × ULN. * Renal (within 28 days prior to C1D1): * Estimated creatinine clearance (CrCl) ≥ 20 mL/min using the Cockcroft and Gault formula \[(140-Age) × Mass (kg)/(72 × creatinine mg/dL), multiply by 0.85 if the patient is female\] OR * Female patients of childbearing potential must have a negative serum pregnancy test (≤ 3 days prior to C1D1). * Female patients of childbearing potential must agree to use 2 methods of contraception throughout the study and for 3 months following the last dose of study treatment (including 1 highly effective and 1 effective method of contraception as defined in section 7.4) * Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential. * Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior treatments including ruxolitinib or other experimental agents unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. * Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
Exclusion criteria
* Prior exposure to a SINE compound, including selinexor. * Patients who are below their ideal body weight and would be unduly impacted by changes in their weight, in the opinion of the investigator, will be excluded * Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals ≤ 1 week prior to C1D1. Patients on prophylactic antibiotics or with a controlled infection ≤ 1 week prior to C1D1 are acceptable. * Radiation, chemotherapy, immunotherapy, or any other anticancer therapy (including investigational therapies) ≤ 2 weeks. * Ruxolitinib or other JAK1/2 inhibitors ≤ at least 3 days or 5 half-lives prior to C1D1. * Major surgery ≤ 4 weeks prior to C1D1. * Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus ribonucleic acid (RNA) or hepatitis B virus surface antigen. * Any active gastrointestinal dysfunction interfering with the patient's ability to swallow tablets, or any active gastrointestinal dysfunction that could interfere with absorption of study treatment. * Any life-threatening illness, organ system dysfunction, or serious psychiatric, medical, or other conditions/situations which, in the investigator's opinion, could compromise a patient's ability to give informed consent, safety, or compliance with the protocol. * Contraindication to any of the required concomitant drugs or supportive treatments. * Subjects taking prohibited medications as described in Section 6.3. Following discontinuation of prohibited medications, a washout period is required prior to initiating study treatment (the duration of the washout must be as clinically indicated, e.g. at least five half-lives). * Subjects who are breastfeeding and unwilling to stop while on study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants With Reduction in Spleen Volume | Up to 5.5 months | To assess the efficacy of selinexor on spleen volume reduction in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. This outcome will report the number of subjects with ≥ 35% reduction in spleen volume as measured by MRI or CT abdomen from baseline to after six cycles of treatment or end of treatment. Patients who did not complete six cycles of treatment received an MRI at discontinuation of therapy. Patients who died prior to completing six cycles of treatment or a follow-up scan were considered non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events That Occur | while receiving study treatment until 30 days after the last dose of protocol treatment (up to 17 months) | To assess the safety/tolerability and further characterize the safety profile of selinexor in PMF, PET-MF, or PPV-MF patients refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. To evaluate the rate of adverse events (AEs) and serious adverse events (SAEs). This outcome measure will report the count of participants who experienced a Grade ≥ 3 AE while receiving study treatment until 30 days after the last dose of protocol treatment. |
| Percent Change of Spleen Volume | Up to 5.5 months | To further assess the efficacy and clinical activity of selinexor (by means of overall response) in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. This outcome will report the mean percent change of spleen volume as measured by MRI or CT abdomen from baseline to after six cycles of treatment or end of treatment. Patients who did not complete six cycles of treatment received an MRI at discontinuation of therapy. Patients who died prior to completing six cycles of treatment or a follow-up scan were not included in this endpoint. The mean and standard will be reported for the change in spleen volume. |
| Change in Symptoms Score | Up to 5.5 months | To further assess the efficacy and clinical activity of selinexor (by means of reduction in symptoms) in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. This outcome reports the count of patients with ≥ 50% reduction of total symptoms scores as measured by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) from baseline after 6 cycles of treatment. Patients who did not complete 6 cycles of treatment will receive the MPN-SAF assessment at discontinuation of therapy. The MPN-SAF is a symptom assessment completed by the patients including fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the sum of all the individual scores (0-100 scale). |
| Overall Response | Up to 24 months after initiation of study therapy. | To further assess the efficacy and clinical activity of selinexor (by means of overall response) in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. Overall response according to the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) consensus criteria for treatment response in primary and secondary MF (post-PV and post-ET). The IWG-MRT response categories are CR (Complete Response), PR (Partial Response), CI (Clinical Improvement), Anemia Response, Spleen Response, Symptoms Response, Progressive Disease, Stable Disease, and Relapse. This outcome measure will report the number of participants who have progressed or died at 24 months after initiation of study therapy. |
| Overall Survival | Up to 24 months from the initiation of study therapy | Overall survival at 24 months from the initiation of study therapy. This outcome measure will report the count of participants who were not deceased at 24 months after the initiation of study treatment. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSrinivas Tantravahi, MD
University of Utah
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Selinexor, All Patients Single Arm Study, all patients received selinexor.
Selinexor: Selinexor was administered weekly until IWG-MR disease progression, intolerable toxicity, or no clinical benefit per treating physician's discretion whichever occurs first.
For patients enrolled after Protocol v7, Selinexor was administered by oral route beginning at 40mg once weekly. Prior to protocol version 7, the starting dose of Selinexor was 60 mg and 80 mg once weekly. | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | Selinexor, All Patients |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 64.82 years STANDARD_DEVIATION 11.05 |
| BMI | 28.36 kg/m^2 STANDARD_DEVIATION 5.79 |
| Constitutional symptoms No | 10 Participants |
| Constitutional symptoms Yes | 7 Participants |
| Diagnosis Post-Essential Thrombocytosis (PET-MF) | 4 Participants |
| Diagnosis Post-Polycythemia Vera (PPV-MF) | 5 Participants |
| Diagnosis Primary Myelofibrosis (PMF) | 8 Participants |
| DIPSS Risk Group High | 0 Participants |
| DIPSS Risk Group Intermediate-1 (INT-1) | 7 Participants |
| DIPSS Risk Group Intermediate-2 (INT-2) | 9 Participants |
| DIPSS Risk Group Low | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Height | 173.19 cm STANDARD_DEVIATION 11.17 |
| Hemoglobin < 10 g/dL | 9 Participants |
| Hemoglobin >= 10 g/dL | 8 Participants |
| Peripheral blood blast < 1 % | 8 Participants |
| Peripheral blood blast >= 1 % | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 9 Participants |
| WBC <= 25 cells x 10^9/L ( <= 25 k/uL) | 17 Participants |
| WBC > 25 cells x 10^9/L) ( > 25 k/uL) | 0 Participants |
| Weight | 85.17 kg STANDARD_DEVIATION 19.13 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 17 |
| other Total, other adverse events | 17 / 17 |
| serious Total, serious adverse events | 4 / 17 |
Outcome results
Primary
Count of Participants With Reduction in Spleen Volume
To assess the efficacy of selinexor on spleen volume reduction in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. This outcome will report the number of subjects with ≥ 35% reduction in spleen volume as measured by MRI or CT abdomen from baseline to after six cycles of treatment or end of treatment. Patients who did not complete six cycles of treatment received an MRI at discontinuation of therapy. Patients who died prior to completing six cycles of treatment or a follow-up scan were considered non-responders.
Time frame: Up to 5.5 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selinexor, All Patients | Count of Participants With Reduction in Spleen Volume | 3 Participants |
Secondary
Adverse Events That Occur
To assess the safety/tolerability and further characterize the safety profile of selinexor in PMF, PET-MF, or PPV-MF patients refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. Secondary Endpoints: rate of adverse events (AEs) and serious adverse events (SAEs).
Time frame: Up to 24 months
Secondary
Change in Symptoms Score
To further assess the efficacy and clinical activity of selinexor (by means of reduction in symptoms) in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. This outcome reports the count of patients with ≥ 50% reduction of total symptoms scores as measured by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) from baseline after 6 cycles of treatment. Patients who did not complete 6 cycles of treatment will receive the MPN-SAF assessment at discontinuation of therapy. The MPN-SAF is a symptom assessment completed by the patients including fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the sum of all the individual scores (0-100 scale).
Time frame: Up to 5.5 months
Population: One participant was not evaluable for this endpoint; this participant did not complete a baseline assessment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Selinexor, All Patients | Change in Symptoms Score | ≥ 50% Reduction of MPN-SAF TSS Score | 2 Participants |
| Selinexor, All Patients | Change in Symptoms Score | < 50% Reduction of MPN-SAF TSS Score | 14 Participants |
Secondary
Overall Response
To further assess the efficacy and clinical activity of selinexor (by means of overall response) in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. Overall response according to the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) consensus criteria for treatment response in primary and secondary MF (post-PV and post-ET). The IWG-MRT response categories are CR (Complete Response), PR (Partial Response), CI (Clinical Improvement), Anemia Response, Spleen Response, Symptoms Response, Progressive Disease, Stable Disease, Relapse.
Time frame: Up to 24 months
Secondary
Overall Survival
Overall survival at 24 months from the initiation of study therapy.
Time frame: Up to 24 months
Secondary
Percent Change of Spleen Volume
To further assess the efficacy and clinical activity of selinexor (by means of overall response) in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. This outcome will report the mean percent change of spleen volume as measured by MRI or CT abdomen from baseline to after six cycles of treatment or end of treatment. Patients who did not complete six cycles of treatment received an MRI at discontinuation of therapy. Patients who died prior to completing six cycles of treatment or a follow-up scan were not included in this endpoint. The mean and standard will be reported for the change in spleen volume.
Time frame: Up to 5.5 months
Population: One participant did not reach this endpoint. This participant only completed a baseline disease assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Selinexor, All Patients | Percent Change of Spleen Volume | 2.96 percent (%) change of spleen volume | Standard Deviation 37.64 |