Clinical trial NCT02092324: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
Chronic Neutrophilic Leukemia
Lead sponsor: OHSU Knight Cancer Institute
Sponsor class: OTHER
First posted: 2014-03-20
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of First 25 Enrolled Patients With a Hematologic Response to Ruxolitinib (Complete Response (CR), Partial Response (PR))
timeFrame: Start of cycle 7
Secondary outcomes:
measure: Percentage of Participant With Any Hematologic Grade III or IV Adverse Events.
timeFrame: Up to 6 weeks after last dose of ruxolitinib phosphate
measure: Percentage of Participants With Any Non-hematologic Grade III or IV Adverse Events.
timeFrame: Up to 6 weeks after last dose of ruxolitinib phosphate
measure: Percentage of Participants Who Achieved Clinical Response of Partial Response or Better
timeFrame: Start of cycle 7
measure: Median Time on Study (Months) for Early Drop Offs
timeFrame: End of cycle 6
measure: Median Time on Study (Months) for All Enrolled Subjects
timeFrame: 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)
measure: Percentage of Participants With Early Drop Off (Prior to Completion of Cycle 3)
timeFrame: up to the end of cycle 3 (12 weeks)
measure: Percentage of Participants Who Reach Cycle 7
timeFrame: Start of cycle 7
measure: Percentage of Participants With Early Drop Off (After Completion of Cycle 3 and Prior to Completion of Cycle 6)
timeFrame: Between cycle 3 and cycle 6
measure: Maximum Clinical Responses
timeFrame: Up to 6 weeks after last dose of ruxolitinib phosphate
measure: Change in Spleen Size, Evaluated by Ultrasound
timeFrame: Measured on Day1 Cycle 1 and Day 1 Cycle 7
measure: Change in Symptom Score as Measured by a Modified Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF]
timeFrame: Measured at baseline and Day 1 Cycle 7
measure: Overall Survival in All Enrolled Patients
timeFrame: At stem-cell transplantation or up to 5 years after enrollment in the study
measure: Percentage of Patients Who Achieve Clinical Response of Partial Response or Better by CSF3R Mutation Status
timeFrame: Start of cycle 7
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford Cancer Institute Palo Alto
state: California
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Portland
country: United States
facility: OHSU Knight Cancer Institute
state: Oregon
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
Study officials:
affiliation: OHSU Knight Cancer Institute
name: Kim-Hien Dao
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.