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

Primary Purpose

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

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Laboratory Biomarker Analysis

Quality-of-Life Assessment

Questionnaire Administration

Ruxolitinib Phosphate

About this trial

This is an interventional treatment trial for Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Stanford Cancer Institute Palo Alto
Emory University Hospital/Winship Cancer Institute
Washington University School of Medicine
OHSU Knight Cancer Institute
UT Southwestern/Simmons Cancer Center-Dallas
M D Anderson Cancer Center
Huntsman Cancer Institute/University of Utah

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (ruxolitinib phosphate)

Arm 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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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

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

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).

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

Median Time on Study (Months) for All Enrolled Subjects

Median and range of months on Ruxolitinib for all enrolled subjects

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

Percentage of Participants Who Reach Cycle 7

Report percent (and 95% confidence interval) of subjects who start cycle 7(complete cycle 6)

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

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT02092324

First Posted

March 18, 2014

Last Updated

October 22, 2020

Sponsor

OHSU Knight Cancer Institute

1. Study Identification

Unique Protocol Identification Number

NCT02092324

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2020

Overall Recruitment Status

Completed

Study Start Date

July 8, 2014 (Actual)

Primary Completion Date

November 22, 2019 (Actual)

Study Completion Date

January 24, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

OHSU Knight Cancer Institute

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

51 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (ruxolitinib phosphate)

Arm Type

Experimental

Arm Description

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Intervention Type

Other

Intervention Name(s)

Quality-of-Life Assessment

Other Intervention Name(s)

Quality of Life Assessment

Intervention Description

Ancillary studies

Intervention Type

Other

Intervention Name(s)

Questionnaire Administration

Intervention Description

Ancillary studies

Intervention Type

Drug

Intervention Name(s)

Ruxolitinib Phosphate

Other Intervention Name(s)

INCB-18424 Phosphate, Jakafi

Intervention Description

Given PO

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Start of cycle 7

Secondary Outcome Measure Information:

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

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

Title

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

Description

Time Frame

Start of cycle 7

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

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)

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)

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

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

Title

Maximum Clinical Responses

Description

Time Frame

Up to 6 weeks after last dose of ruxolitinib phosphate

Title

Change in Spleen Size, Evaluated by Ultrasound

Description

Time Frame

Measured on Day1 Cycle 1 and Day 1 Cycle 7

Title

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

Description

Time Frame

Measured at baseline and Day 1 Cycle 7

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

Title

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

Description

Time Frame

Start of cycle 7

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kim-Hien Dao

Organizational Affiliation

OHSU Knight Cancer Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

Stanford Cancer Institute Palo Alto

City

Palo Alto

State/Province

California

ZIP/Postal Code

94304

Country

United States

Facility Name

Emory University Hospital/Winship Cancer Institute

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Washington University School of Medicine

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Facility Name

OHSU Knight Cancer Institute

City

Portland

State/Province

Oregon

ZIP/Postal Code

97239

Country

United States

Facility Name

UT Southwestern/Simmons Cancer Center-Dallas

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390

Country

United States

Facility Name

M D Anderson Cancer Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Huntsman Cancer Institute/University of Utah

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84112

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

25624319

Citation

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.

Results Reference

background

PubMed Identifier

31880950

Citation

Dao KT, Gotlib J, Deininger MMN, Oh ST, Cortes JE, Collins RH Jr, Winton EF, Parker DR, Lee H, Reister A, Schultz, Savage S, Stevens, Brockett C, Subbiah N, Press RD, Raess PW, Cascio M, Dunlap J, Chen Y, Degnin C, Maxson JE, Tognon CE, Macey T, Druker BJ, Tyner JW. Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia. J Clin Oncol. 2020 Apr 1;38(10):1006-1018. doi: 10.1200/JCO.19.00895. Epub 2019 Dec 27.

Results Reference

result

PubMed Identifier

25180155

Citation

Dao KH, Solti MB, Maxson JE, Winton EF, Press RD, Druker BJ, Tyner JW. Significant clinical response to JAK1/2 inhibition in a patient with CSF3R-T618I-positive atypical chronic myeloid leukemia. Leuk Res Rep. 2014 Aug 1;3(2):67-9. doi: 10.1016/j.lrr.2014.07.002. eCollection 2014.

Results Reference

derived

Links:

URL

https://pubmed.ncbi.nlm.nih.gov/25624319/

Description

An international consortium proposal of uniform response criteria for myelodysplastic/myeloprolierative neoplasms (MDS/MPN) in adults

Learn more about this trial

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

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