Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Chronic Neutrophilic Leukemia
Conditions
Brief summary
This phase II trial studies how well ruxolitinib phosphate works in treating patients with chronic neutrophilic leukemia (CNL) or atypical chronic myeloid leukemia (aCML). Ruxolitinib phosphate may stop the growth of cancer cells by blocking some of the enzymes needed for cells to reproduce. This trial also studies the genetic makeup of patients. Certain genes in cancer cells may determine how the cancer grows or spreads and how it may respond to different drugs. Studying how the genes associated with CNL and aCML respond to the study drug may help doctors learn more about CNL and aCML and improve the treatment for these diseases.
Detailed description
PRIMARY OBJECTIVES: I. To determine the proportion of patients with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) who have a hematologic response to ruxolitinib (ruxolitinib phosphate) (partial response \[PR\], complete response \[CR\], complete response, partial \[CRp\]). SECONDARY OBJECTIVES: I. To determine the frequency of grade 3 or 4 hematologic and non-hematologic adverse events experienced by subjects during therapy with ruxolitinib. II. To determine whether hematologic responses correlate with certain types of mutations in colony stimulating factor 3 receptor (CSF3R) and reduction in mutant CSF3R allele burden in the peripheral blood. III. To determine the maximum clinical responses for each subject and the median duration of maximum clinical responses. IV. To determine the mean % reduction of spleen size, estimated by volume using the conventional prolate ellipsoid method as measured by ultrasound compare to baseline. V. To determine the mean % reduction of total symptom score as measured by a modified Myeloproliferative Neoplasm Symptom Assessment Form version 2.0 (MPN-SAF) compared to start of study (day 1, cycle 1). VI. To determine overall survival in subjects who complete a minimum of 1 dose of study drug. VII. To determine the proportion of subjects who discontinue after completion of \> 3 cycles but \< 6 cycles. VIII. To determine the proportion of subjects who discontinue prior to completion of cycle 3. OUTLINE: Patients receive ruxolitinib phosphate orally (PO) every other day, once daily (QD), or twice daily (BID) on days 1-28. Each patient will be followed for a maximum of 96 weeks (24 cycles, 1 cycle is 4 weeks long). If the study drug continues to be effective, the patient may be eligible to continue on study drug past 24 cycles. After completion of study treatment, patients are followed up within 2 weeks and at 4-6 weeks.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
Given PO
Sponsors
OHSU Knight Cancer Institute
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
* Subjects must be newly diagnosed or previously diagnosed with CNL or aCML; all patients must have a bone marrow biopsy completed during the screening or baseline period if one has not been done within 90 days of day 1, cycle one * Subjects must have platelet count greater than 25,000 per microliter at baseline and at the start of study (day 1, cycle 1) visit * Subjects must be able to discontinue any drug treatment aimed at lowering disease burden in CNL or aCML; subjects should discontinue hydroxyurea to treat underlying CNL or aCML disease no later than day -7 (one week before starting ruxolitinib); for drugs that have more long-lasting effects on the marrow, such as thalidomide and its analogs, and interferon, subjects should discontinue these no later than day -28 * Subjects must be willing to accept/continue transfusions to treat low hemoglobin levels * Subjects must have a life expectancy of \> 6 months
Exclusion criteria
* Subjects unable to review and sign informed consent form * Females who are pregnant or breastfeeding, and males and females who cannot comply with requirements to avoid fathering a child or becoming pregnant * Subjects with known diagnosis of human immunodeficiency virus (HIV) or chronic active Hepatitis B or C; viral testing is not required; subjects with a history of Hepatitis B and/or C are allowed on trial if the virus is undetected at the time of enrollment * Subjects with inadequate liver (alanine aminotransferase \[ALT\]/serum glutamate pyruvate transaminase \[SGPT\] above 4 X upper limit of normal \[ULN\] or direct bilirubin 4 X ULN AND the lab abnormalities are felt to be due to underlying liver dysfunction) * Subjects with end stage renal function (creatinine clearance \[CrCl\] \< 15 mL/min or glomerular filtration rate \[GFR\] \<15 mL/min) regardless of whether hemodialysis is required * Subjects with clinically serious infections requiring ongoing antibiotic therapy * Subjects with severe (immediately life threatening) and recent (occurring within the last 3 months) cardiac dysfunction, pulmonary dysfunction, esophageal variceal bleeding, hemorrhagic strokes, or intracranial hemorrhage are not eligible for study participation * Subjects requiring therapeutic doses of anticoagulation or anti-platelet therapies (aspirin above 81 mg daily, Plavix or similar agents) AND platelet counts are below 50,000 on two different laboratory evaluations, separated by minimum of two weeks * Taking investigational or commercial agents or therapies with the intent to treat the subject's malignancy other than those therapies permitted * Subjects with invasive malignancy over the previous 2 years except treated early stage carcinomas of the skin, completely resected intraepithelial carcinoma of the cervix, and completely resected papillary thyroid and follicular thyroid cancers * Previous allergic reactions to janus kinase (JAK) inhibitors or excipients * Prior therapy with ruxolitinib or other JAK inhibitors * Subjects who have had major surgery within 4 weeks prior to entering the study * Subjects who are anticipated to receive a transplant within the first 6 months of treatment on trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of First 25 Enrolled Patients With a Hematologic Response to Ruxolitinib (Complete Response (CR), Partial Response (PR)) | Start of cycle 7 | A subject is defined as being responsive (responder) if he or she has achieved complete response (CR) or partial response (PR) at the beginning of cycle 7 compared to start of study (day 1,cycle 1). Subjects who do not reach the start of cycle 7 are counted as non-responders. Proportions with 95% exact confidence intervals will be computed. Protocol-defined Response evaluates changes in white blood cell count, absolute neutrophil count, marrow findings and spleen size to define response (attached protocol, Section 10.6, Clinical Response, Table 6 and Table). IWG-defined Response evaluates bone marrow cellularity and myeloblast percent, absence of osteopmyelofibrosis, peripheral blood elements (white blood cell, Neutrophil, Monocyte and platelet counts, hemoglobin density, percent blasts and Neutrophil precursors), symptom resolution, dysplasia, and spleen size to determine response (attached reference). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Any Non-hematologic Grade III or IV Adverse Events. | Up to 6 weeks after last dose of ruxolitinib phosphate | The frequency (percentage) of subjects with any non-hematologic grade III or IV adverse events according to CTCAE v4.0 |
| Percentage of Participants Who Achieved Clinical Response of Partial Response or Better | Start of cycle 7 | Compute the percent of patients with protocol-defined objective response (CR+PR) and IWG-defined objective response (CR+PR) at the start of cycle 7 among all enrolled patients (n = 49). Patients who withdrew prior to the end of cycle 6 are considered non-responders. Protocol-defined Response evaluates changes in white blood cell count, absolute neutrophil count, marrow findings and spleen size to define response (attached protocol, Section 10.6, Clinical Response, Table 6 and Table). IWG-defined Response evaluates bone marrow cellularity and myeloblast percent, absence of osteopmyelofibrosis, peripheral blood elements (white blood cell, Neutrophil, Monocyte and platelet counts, hemoglobin density, percent blasts and Neutrophil precursors), symptom resolution, dysplasia, and spleen size to determine response (attached reference). |
| Median Time on Study (Months) for Early Drop Offs | End of cycle 6 | Median and range of months on study for subjects who did not complete 6 cycles of Ruxolitinib |
| Median Time on Study (Months) for All Enrolled Subjects | Outcome is measured from the first dose of study drug. If study drug continues to be effective, patient may be eligible to continue on study drug past 24 cycles (up to 4.5 years) | Median and range of months on Ruxolitinib for all enrolled subjects |
| Percentage of Participants With Early Drop Off (Prior to Completion of Cycle 3) | up to the end of cycle 3 (12 weeks) | Percent (and 95% confidence interval) of subjects who discontinue Ruxolitinib prior to completion of cycle 3 |
| Percentage of Participants Who Reach Cycle 7 | Start of cycle 7 | Report percent (and 95% confidence interval) of subjects who start cycle 7(complete cycle 6) |
| Percentage of Participant With Any Hematologic Grade III or IV Adverse Events. | Up to 6 weeks after last dose of ruxolitinib phosphate | The frequency (percentage) of subjects with any hematologic \[thrombocytopenia, anemia or neutropenia\] grade III or IV adverse events according to CTCAE v4.0 |
| Maximum Clinical Responses | Up to 6 weeks after last dose of ruxolitinib phosphate | Percent (and 95% confidence interval) of subjects' maximum or best protocol-defined response \[CR \> PR \> SD \> PD\]. Protocol-defined Response combines changes in white blood cell count, absolute neutrophil count, marrow findings and spleen size to define response (attached protocol, Section 10.6, Clinical Response, Table 6 and Table). Duration of maximum response was not available from the final data set. PR requires \> 50% reduction in white blood cell and absolute neutrophil counts, \> 50% reduction in granulocytic hyperplasia (CNL) or granulocytic dyspoiesis (aCML), and \> 25% reduction in spleen size. |
| Change in Spleen Size, Evaluated by Ultrasound | Measured on Day1 Cycle 1 and Day 1 Cycle 7 | Change in spleen size (median, range) evaluated by ultrasound at the start of cycle 7 (day 1, cycle 7) and the start of study (day 1, cycle 1). Spleen volume is calculated by the conventional prolate ellipsoid method. Measure spleen width, thickness and maximum length in centimeters. Multiply width by thickness by max length by 0.524 to get the total spleen volume in cm\^3. Spleen size is only one component of protocol-defined response and cannot be used to independently assess response. (see section 10.6, Clinical Response, Table 6 of attached study protocol) Change in spleen size is the difference between measurements: value at Day 1 Cycle 7 minus the value at Day 1 Cycle 1. |
| Change in Symptom Score as Measured by a Modified Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF] | Measured at baseline and Day 1 Cycle 7 | Myeloproliferative Neoplasm Symptom Assessment Form Total symptom score (MPN-SAF TSS) ranges from 0 (no symptoms) to 10 (worst imaginable symptoms). The score is a sum of 10 independent measurements, generating a final score ranging from 0 - 100 and collected at baseline and on day 1, cycle 7. Change in total symptom score (TSS Median, range) is reported for those achieving day 1, cycle 7 AND responding to all 10 survey questions at baseline and Day 1, Cycle 7. Change in TSS is calculated as score on Day 1 Cycle 7 minus score at baseline. |
| Overall Survival in All Enrolled Patients | At stem-cell transplantation or up to 5 years after enrollment in the study | Kaplan-Meier methods will be used to estimate overall survival for all enrolled patients receiving at least one dose of Ruxolitinib. |
| Percentage of Patients Who Achieve Clinical Response of Partial Response or Better by CSF3R Mutation Status | Start of cycle 7 | Compute the percent (and 95% confidence interval) of patients with protocol-defined objective response (CR+PR) and IWG-defined objective response (CR+PR) at the start of cycle 7 among all enrolled patients (n = 49). Protocol-defined Response combines changes in white blood cell count, absolute neutrophil count, marrow findings and spleen size to define response (attached protocol, Section 10.6, Clinical Response, Table 6 and Table). IWG-defined Response evaluates bone marrow cellularity and myeloblast percent, absence of osteopmyelofibrosis, peripheral blood elements (white blood cell, Neutrophil, Monocyte and platelet counts, hemoglobin density, percent blasts and Neutrophil precursors), symptom resolution, dysplasia, and spleen size to determine response (attached reference). Patients who withdraw prior to the start of cycle 7 are considered non-responders. |
| Percentage of Participants With Early Drop Off (After Completion of Cycle 3 and Prior to Completion of Cycle 6) | Between cycle 3 and cycle 6 | Percent (and 95% confidence interval) of subjects who discontinue after completion of 3 cycles but prior to completion of 6 cycles |
Countries
United States
Participant flow
Recruitment details
The first patient was enrolled July 8, 2014 and recruitment ended in September 2019, across seven medical centers in the US.
Pre-assignment details
Two subjects who were enrolled were shortly determined to be misdiagnosed and were not evaluable bringing the total eligible subjects to 49. An additional subject was not evaluable for the primary endpoint because of missing bone marrow (BM) biopsy data.
Participants by arm
| Arm | Count |
|---|---|
| Wildtype CSF3R Subjects with wild type granulocyte Colony Stimulating Factor Receptor 3 (CSF3R) | 23 |
| Mutant CSF3R Subjects with mutant CSF3R | 26 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lack of Efficacy | 6 |
| Overall Study | Misdiagnosis | 2 |
| Overall Study | Physician Decision | 7 |
| Overall Study | Proceed to Transplant | 3 |
Baseline characteristics
| Characteristic | Total | Wildtype CSF3R | Mutant CSF3R |
|---|---|---|---|
| Absolute Neutrophil Count (ANC) | 41.9 10^9 cells/L | 35.4 10^9 cells/L | 46.0 10^9 cells/L |
| Age, Continuous | 72.8 years | 72.8 years | 73.0 years |
| Disease group aCML | 27 Participants | 18 Participants | 9 Participants |
| Disease group CNL | 22 Participants | 5 Participants | 17 Participants |
| Hemoglobin | 10.8 g/dL | 11.0 g/dL | 10.4 g/dL |
| IPSS total score | 2.0 units on a scale | 2.0 units on a scale | 2.5 units on a scale |
| MPN-SAF TSS | 23.5 units on a scale | 28.0 units on a scale | 20.0 units on a scale |
| Palpable spleen length at left midcostochondral line (LMC) | 5.8 cm | 9.0 cm | 5.0 cm |
| Platelets | 130 10^9 cells/L | 134 10^9 cells/L | 125 10^9 cells/L |
| Prestudy disease duration, months | 0.9 months | 0.9 months | 1.2 months |
| Prior therapy None | 18 Participants | 10 Participants | 8 Participants |
| Prior therapy Prior therapy | 31 Participants | 13 Participants | 18 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 47 Participants | 21 Participants | 26 Participants |
| Sex: Female, Male Female | 20 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Male | 29 Participants | 15 Participants | 14 Participants |
| Spleen volume by ultrasound | 586.9 cm^3 | 582.8 cm^3 | 586.9 cm^3 |
| Splenomegaly at baseline No Splenomegaly | 9 Participants | 6 Participants | 3 Participants |
| Splenomegaly at baseline Splenomegaly | 40 Participants | 17 Participants | 23 Participants |
| Type of prior therapy Decitabine | 2 Participants | 0 Participants | 2 Participants |
| Type of prior therapy Hydroxyurea | 26 Participants | 11 Participants | 15 Participants |
| Type of prior therapy Hydroxyurea + Azacitidine | 1 Participants | 1 Participants | 0 Participants |
| Type of prior therapy Hydroxyurea + Dasatinib | 1 Participants | 1 Participants | 0 Participants |
| Type of prior therapy No prior treatment | 18 Participants | 10 Participants | 8 Participants |
| Type of prior therapy Other (interferon) | 1 Participants | 0 Participants | 1 Participants |
| White blood cell count | 50.7 10^9 cells/L | 48.1 10^9 cells/L | 51.6 10^9 cells/L |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 36 / 49 |
| other Total, other adverse events | 27 / 49 |
| serious Total, serious adverse events | 30 / 49 |
Outcome results
Primary
Percentage of First 25 Enrolled Patients With a Hematologic Response to Ruxolitinib (Complete Response (CR), Partial Response (PR))
A subject is defined as being responsive (responder) if he or she has achieved complete response (CR) or partial response (PR) at the beginning of cycle 7 compared to start of study (day 1,cycle 1). Subjects who do not reach the start of cycle 7 are counted as non-responders. Proportions with 95% exact confidence intervals will be computed. Protocol-defined Response evaluates changes in white blood cell count, absolute neutrophil count, marrow findings and spleen size to define response (attached protocol, Section 10.6, Clinical Response, Table 6 and Table). IWG-defined Response evaluates bone marrow cellularity and myeloblast percent, absence of osteopmyelofibrosis, peripheral blood elements (white blood cell, Neutrophil, Monocyte and platelet counts, hemoglobin density, percent blasts and Neutrophil precursors), symptom resolution, dysplasia, and spleen size to determine response (attached reference).
Time frame: Start of cycle 7
Population: First 25 enrolled subjects enrolled, received at least one dose of study drug, and were evaluated for protocol-defined and International Working Group (IWG) defined objective response
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First 25 Enrolled Subjects | Percentage of First 25 Enrolled Patients With a Hematologic Response to Ruxolitinib (Complete Response (CR), Partial Response (PR)) | Protocol-defined Response | 32 percentage of participants |
| First 25 Enrolled Subjects | Percentage of First 25 Enrolled Patients With a Hematologic Response to Ruxolitinib (Complete Response (CR), Partial Response (PR)) | IWG-defined Response | 4 percentage of participants |
Comparison: Proportion estimated using Clopper-Pearson method. P-value is one-sided proportion test for greater than 10% response rate (based on Simon's 2-stage).p-value: 0.002binomial
Comparison: Proportion estimated using Clopper-Pearson method. P-value is one-sided proportion test for greater than 10% response rate (based on Simon's 2-stage).p-value: 0.9binomial
Secondary
Change in Spleen Size, Evaluated by Ultrasound
Change in spleen size (median, range) evaluated by ultrasound at the start of cycle 7 (day 1, cycle 7) and the start of study (day 1, cycle 1). Spleen volume is calculated by the conventional prolate ellipsoid method. Measure spleen width, thickness and maximum length in centimeters. Multiply width by thickness by max length by 0.524 to get the total spleen volume in cm\^3. Spleen size is only one component of protocol-defined response and cannot be used to independently assess response. (see section 10.6, Clinical Response, Table 6 of attached study protocol) Change in spleen size is the difference between measurements: value at Day 1 Cycle 7 minus the value at Day 1 Cycle 1.
Time frame: Measured on Day1 Cycle 1 and Day 1 Cycle 7
Population: Enrolled subjects receiving at least one dose of Ruxolitinib, completed 6 cycles of study drug and a had 3-dimensional spleen measurements at baseline and the start of cycle 7.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| First 25 Enrolled Subjects | Change in Spleen Size, Evaluated by Ultrasound | -219.7 cm^3 |
Secondary
Change in Symptom Score as Measured by a Modified Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF]
Myeloproliferative Neoplasm Symptom Assessment Form Total symptom score (MPN-SAF TSS) ranges from 0 (no symptoms) to 10 (worst imaginable symptoms). The score is a sum of 10 independent measurements, generating a final score ranging from 0 - 100 and collected at baseline and on day 1, cycle 7. Change in total symptom score (TSS Median, range) is reported for those achieving day 1, cycle 7 AND responding to all 10 survey questions at baseline and Day 1, Cycle 7. Change in TSS is calculated as score on Day 1 Cycle 7 minus score at baseline.
Time frame: Measured at baseline and Day 1 Cycle 7
Population: Enrolled subjects who received at least one dose of Ruxolitinib, completed 6 cycles of study drug and responded to all 10 survey questions at baseline and start of cycle 7.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| First 25 Enrolled Subjects | Change in Symptom Score as Measured by a Modified Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF] | -3.0 score on a scale |
Secondary
Maximum Clinical Responses
Percent (and 95% confidence interval) of subjects' maximum or best protocol-defined response \[CR \> PR \> SD \> PD\]. Protocol-defined Response combines changes in white blood cell count, absolute neutrophil count, marrow findings and spleen size to define response (attached protocol, Section 10.6, Clinical Response, Table 6 and Table). Duration of maximum response was not available from the final data set. PR requires \> 50% reduction in white blood cell and absolute neutrophil counts, \> 50% reduction in granulocytic hyperplasia (CNL) or granulocytic dyspoiesis (aCML), and \> 25% reduction in spleen size.
Time frame: Up to 6 weeks after last dose of ruxolitinib phosphate
Population: All enrolled subjects who received at least one dose of ruxolitinib. Subject who withdraw prior to disease response evaluation are considered non-responders (PD). One subject who was inevaluable for response was included in the denominator.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First 25 Enrolled Subjects | Maximum Clinical Responses | Complete Response (CR) | 8 percentage of participants |
| First 25 Enrolled Subjects | Maximum Clinical Responses | Partial Response (PR) | 24 percentage of participants |
| First 25 Enrolled Subjects | Maximum Clinical Responses | Stable Disease (SD) | 29 percentage of participants |
| First 25 Enrolled Subjects | Maximum Clinical Responses | Progressive Disease (PD) | 37 percentage of participants |
Secondary
Median Time on Study (Months) for All Enrolled Subjects
Median and range of months on Ruxolitinib for all enrolled subjects
Time frame: Outcome is measured from the first dose of study drug. If study drug continues to be effective, patient may be eligible to continue on study drug past 24 cycles (up to 4.5 years)
Population: Enrolled subjects who received at least one dose of Ruxolitinib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| First 25 Enrolled Subjects | Median Time on Study (Months) for All Enrolled Subjects | 8.5 months |
Secondary
Median Time on Study (Months) for Early Drop Offs
Median and range of months on study for subjects who did not complete 6 cycles of Ruxolitinib
Time frame: End of cycle 6
Population: Enrolled subjects who received at least one dose of study drug but did not complete 6 full cycles of Ruxolitinib
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| First 25 Enrolled Subjects | Median Time on Study (Months) for Early Drop Offs | 2.4 months |
Secondary
Overall Survival in All Enrolled Patients
Kaplan-Meier methods will be used to estimate overall survival for all enrolled patients receiving at least one dose of Ruxolitinib.
Time frame: At stem-cell transplantation or up to 5 years after enrollment in the study
Population: Enrolled subjects receiving at least one dose of Ruxolitinib except 9 subjects who were censored at the time of stem-cell transplant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| First 25 Enrolled Subjects | Overall Survival in All Enrolled Patients | 17.9 months |
Secondary
Percentage of Participants Who Achieved Clinical Response of Partial Response or Better
Compute the percent of patients with protocol-defined objective response (CR+PR) and IWG-defined objective response (CR+PR) at the start of cycle 7 among all enrolled patients (n = 49). Patients who withdrew prior to the end of cycle 6 are considered non-responders. Protocol-defined Response evaluates changes in white blood cell count, absolute neutrophil count, marrow findings and spleen size to define response (attached protocol, Section 10.6, Clinical Response, Table 6 and Table). IWG-defined Response evaluates bone marrow cellularity and myeloblast percent, absence of osteopmyelofibrosis, peripheral blood elements (white blood cell, Neutrophil, Monocyte and platelet counts, hemoglobin density, percent blasts and Neutrophil precursors), symptom resolution, dysplasia, and spleen size to determine response (attached reference).
Time frame: Start of cycle 7
Population: All enrolled subjects who receive at least one dose of ruxolitinib. Subjects who withdraw prior to the start of cycle 7 are considered non-responders.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First 25 Enrolled Subjects | Percentage of Participants Who Achieved Clinical Response of Partial Response or Better | Protocol-defined Response | 33 percentage of participants |
| First 25 Enrolled Subjects | Percentage of Participants Who Achieved Clinical Response of Partial Response or Better | IWG-defined Response | 8 percentage of participants |
p-value: <0.0001Clopper-Pearson method
p-value: 0.7Clopper-Pearson method
Secondary
Percentage of Participants Who Reach Cycle 7
Report percent (and 95% confidence interval) of subjects who start cycle 7(complete cycle 6)
Time frame: Start of cycle 7
Population: Enrolled subjects who received at least one dose of Ruxolitinib
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First 25 Enrolled Subjects | Percentage of Participants Who Reach Cycle 7 | 65 percentage of participants |
Secondary
Percentage of Participants With Any Non-hematologic Grade III or IV Adverse Events.
The frequency (percentage) of subjects with any non-hematologic grade III or IV adverse events according to CTCAE v4.0
Time frame: Up to 6 weeks after last dose of ruxolitinib phosphate
Population: All subjects receiving at least one dose of ruxolitinib
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First 25 Enrolled Subjects | Percentage of Participants With Any Non-hematologic Grade III or IV Adverse Events. | 69.4 percentage of participants |
Secondary
Percentage of Participants With Early Drop Off (After Completion of Cycle 3 and Prior to Completion of Cycle 6)
Percent (and 95% confidence interval) of subjects who discontinue after completion of 3 cycles but prior to completion of 6 cycles
Time frame: Between cycle 3 and cycle 6
Population: Enrolled subjects who received at least one dose of Ruxolitinib
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First 25 Enrolled Subjects | Percentage of Participants With Early Drop Off (After Completion of Cycle 3 and Prior to Completion of Cycle 6) | 18 percentage of participants |
Secondary
Percentage of Participants With Early Drop Off (Prior to Completion of Cycle 3)
Percent (and 95% confidence interval) of subjects who discontinue Ruxolitinib prior to completion of cycle 3
Time frame: up to the end of cycle 3 (12 weeks)
Population: Enrolled subjects who received at least one dose of Ruxolitinib
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First 25 Enrolled Subjects | Percentage of Participants With Early Drop Off (Prior to Completion of Cycle 3) | 16 percentage of participants |
Secondary
Percentage of Participant With Any Hematologic Grade III or IV Adverse Events.
The frequency (percentage) of subjects with any hematologic \[thrombocytopenia, anemia or neutropenia\] grade III or IV adverse events according to CTCAE v4.0
Time frame: Up to 6 weeks after last dose of ruxolitinib phosphate
Population: All subjects receiving at least one dose of ruxolitinib
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| First 25 Enrolled Subjects | Percentage of Participant With Any Hematologic Grade III or IV Adverse Events. | 46.9 percentage of participants |
Secondary
Percentage of Patients Who Achieve Clinical Response of Partial Response or Better by CSF3R Mutation Status
Compute the percent (and 95% confidence interval) of patients with protocol-defined objective response (CR+PR) and IWG-defined objective response (CR+PR) at the start of cycle 7 among all enrolled patients (n = 49). Protocol-defined Response combines changes in white blood cell count, absolute neutrophil count, marrow findings and spleen size to define response (attached protocol, Section 10.6, Clinical Response, Table 6 and Table). IWG-defined Response evaluates bone marrow cellularity and myeloblast percent, absence of osteopmyelofibrosis, peripheral blood elements (white blood cell, Neutrophil, Monocyte and platelet counts, hemoglobin density, percent blasts and Neutrophil precursors), symptom resolution, dysplasia, and spleen size to determine response (attached reference). Patients who withdraw prior to the start of cycle 7 are considered non-responders.
Time frame: Start of cycle 7
Population: All enrolled patients receiving at least one dose ruxolitinib and are evaluated for response at the start of cycle 7. Patients who withdraw prior to the start of cycle 7 are considered non-responders. One wildtype CSF3R patient was deemed inevaluable for response and was excluded from response evaluation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First 25 Enrolled Subjects | Percentage of Patients Who Achieve Clinical Response of Partial Response or Better by CSF3R Mutation Status | Protocol-defined Response | 9 percentage of participants |
| First 25 Enrolled Subjects | Percentage of Patients Who Achieve Clinical Response of Partial Response or Better by CSF3R Mutation Status | IWG-defined Response | 0 percentage of participants |
| Mutant CSF3R | Percentage of Patients Who Achieve Clinical Response of Partial Response or Better by CSF3R Mutation Status | Protocol-defined Response | 54 percentage of participants |
| Mutant CSF3R | Percentage of Patients Who Achieve Clinical Response of Partial Response or Better by CSF3R Mutation Status | IWG-defined Response | 15 percentage of participants |
Comparison: 2-sample test for equality of proportions with continuity correction (Pearson's chi-square test statistic) comparing Wildtype and Mutant CSF3R status for protocol-defined objective responsep-value: 0.003Chi-squared, Corrected
Comparison: 2-sample test for equality of proportions with continuity correction (Pearson's chi-square test statistic) comparing Wildtype and Mutant CSF3R status for IWG-defined objective responsep-value: 0.1Fisher Exact