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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Prospective Evaluation of Ruxolitinib Efficacy for CNL/aCML Patients With Mutation of CSF3R

Conditions
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Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Chronic Neutrophilic Leukemia

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Drug: Ruxolitinib Phosphate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ruxolitinib phosphate)<br>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<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Ruxolitinib Phosphate<br>* Given PO<br>* Other names: Jakafi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Start of cycle 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Up to 6 weeks after last dose of ruxolitinib phosphate | 
| 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 | Up to 6 weeks after last dose of ruxolitinib phosphate | 
| 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). | Start of cycle 7 | 
| 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 | End of cycle 6 | 
| Median Time on Study (Months) for All Enrolled Subjects | Median and range of months on Ruxolitinib 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) | 
| 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 | up to the end of cycle 3 (12 weeks) | 
| Percentage of Participants Who Reach Cycle 7 | Report percent (and 95% confidence interval) of subjects who start cycle 7(complete cycle 6) | Start of cycle 7 | 
| 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 | Between cycle 3 and cycle 6 | 
| 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. | Up to 6 weeks after last dose of ruxolitinib phosphate | 
| 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. | Measured on Day1 Cycle 1 and Day 1 Cycle 7 | 
| 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. | Measured at baseline and Day 1 Cycle 7 | 
| 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. | At stem-cell transplantation or up to 5 years after enrollment in the study | 
| 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. | Start of cycle 7 |