Ruxolitinib Phosphate in Treating Patients With Chronic Neutrophilic Leukemia or Atypical Chronic Myeloid Leukemia

• Sponsor: OHSU Knight Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02092324
• Collaborator: (none)
• Enrollment: 51
• Locations: 7
• Arm: 1
• Actual Duration (Months): 66.6
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Neutrophilic Leukemia	Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: Ruxolitinib Phosphate	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. To determine the frequency of grade 3 or 4 hematologic and non-hematologic adverse events experienced by subjects during therapy with ruxolitinib.

2. 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.

3. To determine the maximum clinical responses for each subject and the median duration of maximum clinical responses.

4. To determine the mean % reduction of spleen size, estimated by volume using the conventional prolate ellipsoid method as measured by ultrasound compare to baseline.

5. 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).

6. To determine overall survival in subjects who complete a minimum of 1 dose of study drug.

7. To determine the proportion of subjects who discontinue after completion of > 3 cycles but < 6 cycles.

8. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prospective Evaluation of Ruxolitinib Efficacy for CNL/aCML Patients With Mutation of CSF3R
• Actual Study Start Date: Jul 8, 2014
• Actual Primary Completion Date: Nov 22, 2019
• Actual Study Completion Date: Jan 24, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (ruxolitinib phosphate) Patients receive ruxolitinib phosphate PO every other day, QD, or 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment ; Other: Questionnaire Administration; Ancillary studies; Drug: Ruxolitinib Phosphate; Given PO; Other Names: INCB-18424 Phosphate Jakafi

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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

3. 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).

4. 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

5. 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

6. 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

7. 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)

8. 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

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Cancer Institute Palo Alto	Palo Alto	California	United States	94304
2	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
3	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
4	OHSU Knight Cancer Institute	Portland	Oregon	United States	97239
5	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
6	M D Anderson Cancer Center	Houston	Texas	United States	77030
7	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• OHSU Knight Cancer Institute

Investigators

• Principal Investigator: Kim-Hien Dao, OHSU Knight Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 7, 2017

More Information

Additional Information:

• Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia
• An international consortium proposal of uniform response criteria for myelodysplastic/myeloprolierative neoplasms (MDS/MPN) in adults

Publications

• Savona MR, Malcovati L, Komrokji R, Tiu RV, Mughal TI, Orazi A, Kiladjian JJ, Padron E, Solary E, Tibes R, Itzykson R, Cazzola M, Mesa R, Maciejewski J, Fenaux P, Garcia-Manero G, Gerds A, Sanz G, Niemeyer CM, Cervantes F, Germing U, Cross NC, List AF; MDS/MPN International Working Group. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015 Mar 19;125(12):1857-65. doi: 10.1182/blood-2014-10-607341. Epub 2015 Jan 26.

• Responsible Party: Kim-Hien Dao, Principal Investigator, OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT02092324
• Other Study ID Numbers: IRB00010262; NCI-2014-00633; IRB00010262
• First Posted: Mar 20, 2014
• Last Update Posted: Nov 16, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Leukemia, Neutrophilic, Chronic

Study Results

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 Detail	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.

Arm/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day (QOD), or twice a day (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.
Period Title: Overall Study
STARTED	51
End of Cycle 6	25
Wildtype CSF3R	23
Mutant CSF3R	26
COMPLETED	32
NOT COMPLETED	19

Baseline Characteristics

Arm/Group Title	Wildtype CSF3R	Mutant CSF3R	Total
Arm/Group Description	Subjects with wild type granulocyte Colony Stimulating Factor Receptor 3 (CSF3R)	Subjects with mutant CSF3R	Total of all reporting groups
Overall Participants	23	26	49
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	72.8	73.0	72.8
Sex: Female, Male (Count of Participants)
Female	8 34.8%	12 46.2%	20 40.8%
Male	15 65.2%	14 53.8%	29 59.2%
Race/Ethnicity, Customized (Count of Participants)
White	21 91.3%	26 100%	47 95.9%
Black or African American	2 8.7%	0 0%	2 4.1%
Disease group (Count of Participants)
CNL	5 21.7%	17 65.4%	22 44.9%
aCML	18 78.3%	9 34.6%	27 55.1%
Splenomegaly at baseline (Count of Participants)
No Splenomegaly	6 26.1%	3 11.5%	9 18.4%
Splenomegaly	17 73.9%	23 88.5%	40 81.6%
Spleen volume by ultrasound (cm^3) [Median (Full Range) ]
Median (Full Range) [cm^3]	582.8	586.9	586.9
Palpable spleen length at left midcostochondral line (LMC) (cm) [Median (Full Range) ]
Median (Full Range) [cm]	9.0	5.0	5.8
White blood cell count (10^9 cells/L) [Median (Full Range) ]
Median (Full Range) [10^9 cells/L]	48.1	51.6	50.7
Absolute Neutrophil Count (ANC) (10^9 cells/L) [Median (Full Range) ]
Median (Full Range) [10^9 cells/L]	35.4	46.0	41.9
Hemoglobin (g/dL) [Median (Full Range) ]
Median (Full Range) [g/dL]	11.0	10.4	10.8
Platelets (10^9 cells/L) [Median (Full Range) ]
Median (Full Range) [10^9 cells/L]	134	125	130
Prior therapy (Count of Participants)
None	10 43.5%	8 30.8%	18 36.7%
Prior therapy	13 56.5%	18 69.2%	31 63.3%
Type of prior therapy (Count of Participants)
Hydroxyurea	11 47.8%	15 57.7%	26 53.1%
Hydroxyurea + Azacitidine	1 4.3%	0 0%	1 2%
Hydroxyurea + Dasatinib	1 4.3%	0 0%	1 2%
Decitabine	0 0%	2 7.7%	2 4.1%
Other (interferon)	0 0%	1 3.8%	1 2%
No prior treatment	10 43.5%	8 30.8%	18 36.7%
IPSS total score (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	2.0	2.5	2.0
MPN-SAF TSS (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	28.0	20.0	23.5
Prestudy disease duration, months (months) [Median (Full Range) ]
Median (Full Range) [months]	0.9	1.2	0.9

Outcome Measures

1. Primary Outcome

Title	Percentage of First 25 Enrolled Patients With a Hematologic Response to Ruxolitinib (Complete Response (CR), Partial Response (PR))
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	First 25 Enrolled Subjects
Arm/Group Description	First 25 enrolled subjects evaluated for protocol-defined objective response
Measure Participants	25
Protocol-defined Response	32 139.1%
IWG-defined Response	4 17.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First 25 Enrolled Subjects
	Comments	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).
	Type of Statistical Test	Superiority
	Comments	1-proportion test for greater than 10% difference.
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value for Protocol-defined objective response
	Method	binomial
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	First 25 Enrolled Subjects
	Comments	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).
	Type of Statistical Test	Superiority
	Comments	1-proportion test for greater than 10% difference
Statistical Test of Hypothesis	p-Value	0.90
	Comments	p-value is for IWG-defined objective response
	Method	binomial
	Comments

2. Secondary Outcome

Title	Percentage of Participant With Any Hematologic Grade III or IV Adverse Events.
Description	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

Outcome Measure Data

Analysis Population Description

All subjects receiving at least one dose of ruxolitinib

Arm/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	46.9 203.9%

3. Secondary Outcome

Title	Percentage of Participants With Any Non-hematologic Grade III or IV Adverse Events.
Description	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

Outcome Measure Data

Analysis Population Description

All subjects receiving at least one dose of ruxolitinib

Arm/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	69.4 301.7%

4. Secondary Outcome

Title	Percentage of Participants Who Achieved Clinical Response of Partial Response or Better
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	49
Protocol-defined Response	33 143.5%
IWG-defined Response	8 34.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First 25 Enrolled Subjects
	Comments
	Type of Statistical Test	Superiority
	Comments	Proportion estimated using Clopper-Pearson method. P-value is one-sided proportion test for greater than 10% response rate.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	p-value for protocol-defined objective response. p-value for IWG-defined objective response is 0.70
	Method	Clopper-Pearson method
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	First 25 Enrolled Subjects
	Comments
	Type of Statistical Test	Superiority
	Comments	Proportion estimated using Clopper-Pearson method. P-value is one-sided proportion test for greater than 10% response rate.
Statistical Test of Hypothesis	p-Value	0.70
	Comments	p-value for IWG-defined objective response
	Method	Clopper-Pearson method
	Comments

5. Secondary Outcome

Title	Median Time on Study (Months) for Early Drop Offs
Description	Median and range of months on study for subjects who did not complete 6 cycles of Ruxolitinib
Time Frame	End of cycle 6

Outcome Measure Data

Analysis Population Description

Enrolled subjects who received at least one dose of study drug but did not complete 6 full cycles of Ruxolitinib

Arm/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	17
Median (Full Range) [months]	2.4

6. Secondary Outcome

Title	Median Time on Study (Months) for All Enrolled Subjects
Description	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)

Outcome Measure Data

Analysis Population Description

Enrolled subjects who received at least one dose of Ruxolitinib

Arm/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	49
Median (Full Range) [months]	8.5

7. Secondary Outcome

Title	Percentage of Participants With Early Drop Off (Prior to Completion of Cycle 3)
Description	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)

Outcome Measure Data

Analysis Population Description

Enrolled subjects who received at least one dose of Ruxolitinib

Arm/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	16 69.6%

8. Secondary Outcome

Title	Percentage of Participants Who Reach Cycle 7
Description	Report percent (and 95% confidence interval) of subjects who start cycle 7(complete cycle 6)
Time Frame	Start of cycle 7

Outcome Measure Data

Analysis Population Description

Enrolled subjects who received at least one dose of Ruxolitinib

Arm/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	65 282.6%

9. Secondary Outcome

Title	Percentage of Participants With Early Drop Off (After Completion of Cycle 3 and Prior to Completion of Cycle 6)
Description	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

Outcome Measure Data

Analysis Population Description

Enrolled subjects who received at least one dose of Ruxolitinib

Arm/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	49
Number (95% Confidence Interval) [percentage of participants]	18 78.3%

10. Secondary Outcome

Title	Maximum Clinical Responses
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	49
Complete Response (CR)	8 34.8%
Partial Response (PR)	24 104.3%
Stable Disease (SD)	29 126.1%
Progressive Disease (PD)	37 160.9%

11. Secondary Outcome

Title	Change in Spleen Size, Evaluated by Ultrasound
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	32
Median (Full Range) [cm^3]	-219.7

12. Secondary Outcome

Title	Change in Symptom Score as Measured by a Modified Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF]
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	28
Median (Full Range) [score on a scale]	-3.0

13. Secondary Outcome

Title	Overall Survival in All Enrolled Patients
Description	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

Outcome Measure Data

Analysis Population Description

Enrolled subjects receiving at least one dose of Ruxolitinib except 9 subjects who were censored at the time of stem-cell transplant

Arm/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
Measure Participants	49
Median (95% Confidence Interval) [months]	17.9

14. Secondary Outcome

Title	Percentage of Patients Who Achieve Clinical Response of Partial Response or Better by CSF3R Mutation Status
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Wildtype CSF3R	Mutant CSF3R
Arm/Group Description	Subjects with wildtype CSF3R	Subjects with mutant CSF3R
Measure Participants	22	26
Protocol-defined Response	9 39.1%	54 207.7%
IWG-defined Response	0 0%	15 57.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First 25 Enrolled Subjects, Mutant CSF3R
	Comments	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 response
	Type of Statistical Test	Equivalence
	Comments	2-sample test for equality of proportions with continuity correction (Pearson's chi-square test statistic)
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value for protocol-defined objective response.
	Method	Chi-squared, Corrected
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	First 25 Enrolled Subjects, Mutant CSF3R
	Comments	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 response
	Type of Statistical Test	Equivalence
	Comments	2-sample test for equality of proportions with continuity correction (Pearson's chi-square)
Statistical Test of Hypothesis	p-Value	0.1
	Comments	p-value for IWG-defined objective response = 0.1
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Adverse Events (AE) were collected from first dose of ruxolitinib until 30 days after last dose. Any AEs occurring more than 30 days after the last dose of study drug and believed related to study drug were reported. Study drug was administered up to 96 weeks. Patients receiving ongoing clinical benefit were eligible to continue receiving study drug (up to 5 years).
Arm/Group Title	Treatment (Ruxolitinib Phosphate)
Arm/Group Description	Patients receive ruxolitinib phosphate PO every other day, QD, or 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. Laboratory Biomarker Analysis: Correlative studies Quality-of-Life Assessment: Ancillary studies Questionnaire Administration: Ancillary studies Ruxolitinib Phosphate: Given PO
All Cause Mortality
	Treatment (Ruxolitinib Phosphate)
	Affected / at Risk (%)	# Events
Total	36/49 (73.5%)
Serious Adverse Events
	Treatment (Ruxolitinib Phosphate)
	Affected / at Risk (%)	# Events
Total	30/49 (61.2%)
Blood and lymphatic system disorders
Anemia	4/49 (8.2%)	4
Blood and lymphatic system disorders - Other, Specify	1/49 (2%)	1
Febrile neutropenia	1/49 (2%)	1
Leukocytosis	4/49 (8.2%)	5
Cardiac disorders
Cardiac arrest	1/49 (2%)	1
Cardiac disorders - Other, Specify	1/49 (2%)	1
Chest pain - cardiac	1/49 (2%)	1
Heart failure	4/49 (8.2%)	4
Sinus bradycardia	1/49 (2%)	1
Eye disorders
Retinal detachment	1/49 (2%)	1
Uveitis	1/49 (2%)	1
Gastrointestinal disorders
Abdominal pain	1/49 (2%)	1
Constipation	1/49 (2%)	1
Gastrointestinal disorders - Other, Specify	2/49 (4.1%)	2
Lower gastrointestinal hemorrhage	1/49 (2%)	1
General disorders
Death NOS	3/49 (6.1%)	3
Fatigue	2/49 (4.1%)	2
Fever	1/49 (2%)	1
Infections and infestations
Infections and infestations - Other, Specify	2/49 (4.1%)	2
Lung infection	6/49 (12.2%)	6
Sepsis	1/49 (2%)	4
Skin infection	2/49 (4.1%)	2
Upper respiratory infection	3/49 (6.1%)	6
Urinary tract infection	2/49 (4.1%)	4
Injury, poisoning and procedural complications
Hip fracture	1/49 (2%)	1
Postoperative hemorrhage	1/49 (2%)	1
Investigations
Platelet count decreased	2/49 (4.1%)	2
Metabolism and nutrition disorders
Dehydration	1/49 (2%)	2
Hypoglycemia	1/49 (2%)	1
Musculoskeletal and connective tissue disorders
Avascular necrosis	1/49 (2%)	1
Back pain	2/49 (4.1%)	2
Generalized muscle weakness	1/49 (2%)	1
Muscle weakness lower limb	1/49 (2%)	2
Neck pain	1/49 (2%)	1
Pain in extremity	1/49 (2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Specify	1/49 (2%)	1
Nervous system disorders
Cognitive disturbance	1/49 (2%)	1
Dizziness	1/49 (2%)	1
Syncope	1/49 (2%)	1
Transient ischemic attacks	1/49 (2%)	1
Psychiatric disorders
Anxiety	1/49 (2%)	1
Delirium	1/49 (2%)	1
Renal and urinary disorders
Acute kidney injury	3/49 (6.1%)	3
Hematuria	1/49 (2%)	1
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	1/49 (2%)	1
Dyspnea	1/49 (2%)	1
Epistaxis	1/49 (2%)	1
Pneumonitis	5/49 (10.2%)	5
Respiratory failure	1/49 (2%)	1
Stridor	1/49 (2%)	1
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, Specify	1/49 (2%)	1
Vascular disorders
Hematoma	3/49 (6.1%)	3
Vascular disorders - Other, Specify	1/49 (2%)	2
Other (Not Including Serious) Adverse Events
	Treatment (Ruxolitinib Phosphate)
	Affected / at Risk (%)	# Events
Total	27/49 (55.1%)
Blood and lymphatic system disorders
Anemia	16/49 (32.7%)	28
Leukocytosis	4/49 (8.2%)	5
Gastrointestinal disorders
Diarrhea	1/49 (2%)	2
General disorders
Fatigue	2/49 (4.1%)	3
Investigations
Lymphocyte count decreased	3/49 (6.1%)	5
Platelet count decreased	7/49 (14.3%)	11
Metabolism and nutrition disorders
Hyponatremia	3/49 (6.1%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.