A Pilot Study of Ruxolitinib in Secondary Hemophagocytic Syndrome

Sponsor
University of Michigan Rogel Cancer Center (Other)
Overall Status
Completed
CT.gov ID
NCT02400463
Collaborator
(none)
6
1
1
47
0.1

Study Details

Study Description

Brief Summary

This is a pilot study to determine the efficacy of Ruxolitinib in secondary hemophagocytic syndrome. The primary objective is to assess the efficacy of ruxolitinib 15 mg PO twice daily in patients with HPS. The primary endpoint is overall survival at two months.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Hemophagocytic Syndrome (HPS) is a disorder characterized by pathological activation of the immune system resulting in a systemic disorder characterized by excessive cytokine production and macrophage activation, culminating in cytopenias and evidence of hemophagocytosis on tissue specimens. The disorder can be sporadic or familial due to one of several mutations and is primarily seen in the pediatric population, with a reported incidence of 1 case per 3000 admissions. The actual incidence in adults is unknown and can be rarely sporadic, or secondary to viral infections, malignancy, or autoimmune disease.

HPS is a universally fatal disease if untreated. In adults, the median survival has been reported to be less than 2 months if diagnosis and treatment is delayed. Adult patients are treated with pediatric protocols with early institution of etoposide and steroids and consolidation with allogeneic stem cell transplant in appropriately selected patients if a familial form is identified. Other treatment strategies have been attempted, including rituximab, infliximab, entaracept, tocilizumab, and alemtuzumab. These anecdotal reports highlight the therapeutic potential of cytokine-targeted therapies in this disorder.

This is a pilot study to determine the efficacy of Ruxolitinib in secondary hemophagocytic syndrome. The primary objective is to assess the efficacy of ruxolitinib 15 mg PO twice daily in patients with HPS. The primary endpoint is overall survival at two months.

Patients will receive Ruxolitinib at 15 mg twice daily orally either on an empty stomach or with food for 4 weeks (28 days) in a 4 week (28 day) cycle. Ruxolitinib will be administered in continuous 28-day cycles.

In the absence of treatment delays or cessation due to adverse events, treatment may continue indefinitely or until one of the following criteria applies:

  • Disease progression.

  • Intercurrent illness that prevents further administration of treatment.

  • The investigator considers it, for safety reasons, to be in the best interest of the patient.

  • Unacceptable adverse events such as any toxicity or other issue that causes a delay of study drug administration by more than 4 weeks.

  • General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.

  • Patient decision to withdraw from treatment (partial consent) or from the study (full consent.

  • Death.

Patients will be followed for toxicity for 30 days after treatment has been discontinued or until death, whichever occurs first.

Study Design

Study Type:
Interventional
Actual Enrollment :
6 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Pilot Study of Ruxolitinib in Secondary Hemophagocytic Syndrome
Actual Study Start Date :
Feb 5, 2016
Actual Primary Completion Date :
Oct 10, 2019
Actual Study Completion Date :
Jan 7, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ruxolitinib

Ruxolitinib 15 mg by mouth twice daily. For patients unable to ingest tablets, ruxolitinib suspended in water may be administered through a nasogastric (NG) or percutaneous endoscopy gastrostomy (PEG) tube.

Drug: Ruxolitinib

Outcome Measures

Primary Outcome Measures

  1. Overall Survival at 2 Months [2 Months]

    Number of Patients Alive at 2 Months after the first administration of ruxolitinib.

Secondary Outcome Measures

  1. Percentage of Patients With a Response to Treatment With Ruxolitinib [2 Months]

    Complete response is defined as complete normalization of all quantifiable symptoms and laboratory abnormalities. A partial response is defined as at least a 25% improvement in two or more quantifiable symptoms/laboratory markers.

  2. Duration of Response [Up to 3 years (Due to funding and other constraints, participant follow-up was discontinued in 2020. Thus, not all participants were followed for a full three years.)]

    Duration will be calculated from the date of the determination of partial response or better until the date of progression, death, or additional non-protocol therapy.

  3. Progression Free Survival Time [Up to 3 years (Due to funding and other constraints, participant follow-up was discontinued in 2020. Thus, not all participants were followed for a full three years.)]

    Progressive Disease is defined as at least a 50% worsening in two or more quantifiable laboratory markers. Calculated from the first administration of ruxolitinib until the date of progression or death.

  4. Regimen Related Toxicities [Up to 30 days after last treatment administration]

    Incidence and grade of adverse events (AEs) unlikely, possibly or probably related to treatment (tx) with ruxolitinib. Graded per Common Terminology Criteria for Adverse Events (CTCAE) v.4. Grade refers to the severity of the AE, from mild (grade 1) to life-threatening (grade 4).

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Patients, or their legally authorized representative, must voluntarily provide written IRB-approved informed consent.

  • Males and females, 18 years of age or older at the time of enrollment.

  • Patients must meet the diagnostic criteria for HPS (at least 5 of the following): fever, splenomegaly, cytopenia involving ≥2 cell lines (Hemoglobin <9 g/dL; platelets <100,000/μL; absolute neutrophil count <1000/μL), hypertriglyceridemia or hypofibrinogenemia, tissue demonstration of hemophagocytosis, low or absent NK (Natural Killer) cell activity, serum ferritin ≥3000 ug/L, soluble IL-2 receptor (CD25) >2400 U/mL.

  • In the investigator's opinion, the patient has the ability to participate fully in the study, and comply with all its requirements.

Exclusion Criteria:
  • CNS (Central Nervous System) involvement

  • Malabsorption

  • Known secondary HPS (Hemophagocytic Syndrome) that is otherwise treatable (e.g. non-Hodgkin's lymphoma).

  • Pregnant or lactating female: all females of child-bearing potential must have a negative serum pregnancy test within 7 days of treatment; lactating females must discontinue breast feeding.

  • Estimated creatinine clearance <15mL/min

  • Has received any prior systemic therapy, excluding corticosteroids, within 7 days (or 5 half-lives) of treatment.

  • No active malignancy at the time of enrollment, except nonmelanoma skin cancers or carcinoma in situ. Patients with a prior history of malignancy are eligible if their malignancy has been definitely treated or is in remission and does not require ongoing adjuvant or cancer-directed therapies.

  • Active hepatitis B or hepatitis C or known HIV infection

  • Known (and biopsy-confirmed) liver cirrhosis; or, a reported history of liver cirrhosis with a Model for End-stage Liver Disease (MELD) score >20.

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Michigan Comprehensive Cancer Center Ann Arbor Michigan United States 48109

Sponsors and Collaborators

  • University of Michigan Rogel Cancer Center

Investigators

  • Principal Investigator: Ryan Wilcox, M.D., Int Med-Hematology/Oncology - Faculty and Staff

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
University of Michigan Rogel Cancer Center
ClinicalTrials.gov Identifier:
NCT02400463
Other Study ID Numbers:
  • UMCC 2014.112
  • HUM00092921
First Posted:
Mar 27, 2015
Last Update Posted:
Jan 25, 2021
Last Verified:
Jan 1, 2021
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Ruxolitinib
Arm/Group Description Ruxolitinib 15 mg by mouth twice daily. For patients unable to ingest tablets, ruxolitinib suspended in water may be administered through a nasogastric (NG) or percutaneous endoscopy gastrostomy (PEG) tube.
Period Title: Overall Study
STARTED 6
COMPLETED 6
NOT COMPLETED 0

Baseline Characteristics

Arm/Group Title Ruxolitinib
Arm/Group Description Ruxolitinib 15 mg by mouth twice daily. For patients unable to ingest tablets, ruxolitinib suspended in water may be administered through a nasogastric (NG) or percutaneous endoscopy gastrostomy (PEG) tube.
Overall Participants 6
Age (years) [Median (Full Range) ]
Median (Full Range) [years]
38
Sex: Female, Male (Count of Participants)
Female
4
66.7%
Male
2
33.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
0
0%
Not Hispanic or Latino
6
100%
Unknown or Not Reported
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
Asian
0
0%
Native Hawaiian or Other Pacific Islander
0
0%
Black or African American
0
0%
White
6
100%
More than one race
0
0%
Unknown or Not Reported
0
0%

Outcome Measures

1. Primary Outcome
Title Overall Survival at 2 Months
Description Number of Patients Alive at 2 Months after the first administration of ruxolitinib.
Time Frame 2 Months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Ruxolitinib
Arm/Group Description Ruxolitinib 15 mg by mouth twice daily. For patients unable to ingest tablets, ruxolitinib suspended in water may be administered through a nasogastric (NG) or percutaneous endoscopy gastrostomy (PEG) tube.
Measure Participants 6
Count of Participants [Participants]
6
100%
2. Secondary Outcome
Title Percentage of Patients With a Response to Treatment With Ruxolitinib
Description Complete response is defined as complete normalization of all quantifiable symptoms and laboratory abnormalities. A partial response is defined as at least a 25% improvement in two or more quantifiable symptoms/laboratory markers.
Time Frame 2 Months

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Ruxolitinib
Arm/Group Description Ruxolitinib 15 mg by mouth twice daily. For patients unable to ingest tablets, ruxolitinib suspended in water may be administered through a nasogastric (NG) or percutaneous endoscopy gastrostomy (PEG) tube.
Measure Participants 6
Number [percentage of participants]
100
1666.7%
3. Secondary Outcome
Title Duration of Response
Description Duration will be calculated from the date of the determination of partial response or better until the date of progression, death, or additional non-protocol therapy.
Time Frame Up to 3 years (Due to funding and other constraints, participant follow-up was discontinued in 2020. Thus, not all participants were followed for a full three years.)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Ruxolitinib
Arm/Group Description Ruxolitinib 15 mg by mouth twice daily. For patients unable to ingest tablets, ruxolitinib suspended in water may be administered through a nasogastric (NG) or percutaneous endoscopy gastrostomy (PEG) tube.
Measure Participants 6
Median (Full Range) [months]
17.25
4. Secondary Outcome
Title Progression Free Survival Time
Description Progressive Disease is defined as at least a 50% worsening in two or more quantifiable laboratory markers. Calculated from the first administration of ruxolitinib until the date of progression or death.
Time Frame Up to 3 years (Due to funding and other constraints, participant follow-up was discontinued in 2020. Thus, not all participants were followed for a full three years.)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Ruxolitinib
Arm/Group Description Ruxolitinib 15 mg by mouth twice daily. For patients unable to ingest tablets, ruxolitinib suspended in water may be administered through a nasogastric (NG) or percutaneous endoscopy gastrostomy (PEG) tube.
Measure Participants 6
Median (Full Range) [months]
17.25
5. Secondary Outcome
Title Regimen Related Toxicities
Description Incidence and grade of adverse events (AEs) unlikely, possibly or probably related to treatment (tx) with ruxolitinib. Graded per Common Terminology Criteria for Adverse Events (CTCAE) v.4. Grade refers to the severity of the AE, from mild (grade 1) to life-threatening (grade 4).
Time Frame Up to 30 days after last treatment administration

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Ruxolitinib
Arm/Group Description Ruxolitinib 15 mg by mouth twice daily. For patients unable to ingest tablets, ruxolitinib suspended in water may be administered through a nasogastric (NG) or percutaneous endoscopy gastrostomy (PEG) tube.
Measure Participants 6
Grade 1
5
Grade 2
3
Grade 3
1
Grade 4
1

Adverse Events

Time Frame Up to 30 days after last treatment administration (13.5 months)
Adverse Event Reporting Description
Arm/Group Title Ruxolitinib
Arm/Group Description Ruxolitinib 15 mg by mouth twice daily. For patients unable to ingest tablets, ruxolitinib suspended in water may be administered through a nasogastric (NG) or percutaneous endoscopy gastrostomy (PEG) tube.
All Cause Mortality
Ruxolitinib
Affected / at Risk (%) # Events
Total 0/6 (0%)
Serious Adverse Events
Ruxolitinib
Affected / at Risk (%) # Events
Total 2/6 (33.3%)
Blood and lymphatic system disorders
Febrile neutropenia 1/6 (16.7%) 1
Musculoskeletal and connective tissue disorders
Arthritis 1/6 (16.7%) 1
Back pain 1/6 (16.7%) 1
Other (Not Including Serious) Adverse Events
Ruxolitinib
Affected / at Risk (%) # Events
Total 6/6 (100%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders - Other, specify 2/6 (33.3%) 2
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify 1/6 (16.7%) 1
Endocrine disorders
Cushingoid 1/6 (16.7%) 1
Gastrointestinal disorders
Abdominal pain 2/6 (33.3%) 2
Constipation 2/6 (33.3%) 2
Dysphagia 1/6 (16.7%) 1
Gastrointestinal disorders - Other, specify 1/6 (16.7%) 1
Nausea 2/6 (33.3%) 3
General disorders
Fatigue 3/6 (50%) 4
Fever 1/6 (16.7%) 2
General disorders and administration site conditions - Other, specify 2/6 (33.3%) 4
Localized edema 3/6 (50%) 3
Non-cardiac chest pain 1/6 (16.7%) 1
Pain 1/6 (16.7%) 3
Infections and infestations
Infections and infestations - Other, specify 2/6 (33.3%) 2
Sinusitis 1/6 (16.7%) 1
Skin infection 1/6 (16.7%) 2
Tooth infection 1/6 (16.7%) 1
Upper respiratory infection 1/6 (16.7%) 1
Vaginal infection 1/6 (16.7%) 1
Injury, poisoning and procedural complications
Ankle fracture 1/6 (16.7%) 1
Investigations
Cholesterol high 1/6 (16.7%) 1
Musculoskeletal and connective tissue disorders
Arthralgia 1/6 (16.7%) 1
Back pain 1/6 (16.7%) 3
Chest wall pain 1/6 (16.7%) 1
Pain in extremity 1/6 (16.7%) 2
Nervous system disorders
Dizziness 1/6 (16.7%) 1
Headache 4/6 (66.7%) 6
Peripheral sensory neuropathy 1/6 (16.7%) 1
Psychiatric disorders
Agitation 1/6 (16.7%) 1
Anxiety 1/6 (16.7%) 1
Depression 1/6 (16.7%) 1
Insomnia 2/6 (33.3%) 2
Psychiatric disorders - Other, specify 1/6 (16.7%) 1
Reproductive system and breast disorders
Irregular menstruation 1/6 (16.7%) 1
Respiratory, thoracic and mediastinal disorders
Nasal congestion 1/6 (16.7%) 1
Pneumonitis 2/6 (33.3%) 2
Sore throat 1/6 (16.7%) 1
Skin and subcutaneous tissue disorders
Alopecia 1/6 (16.7%) 1
Erythroderma 1/6 (16.7%) 1
Rash maculo-papular 2/6 (33.3%) 4
Vascular disorders
Hot flashes 1/6 (16.7%) 1
Hypertension 1/6 (16.7%) 1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.

Results Point of Contact

Name/Title Ryan Wilcox
Organization University of Michigan Rogel Cancer Center
Phone 734-615-1482
Email rywilcox@umich.edu
Responsible Party:
University of Michigan Rogel Cancer Center
ClinicalTrials.gov Identifier:
NCT02400463
Other Study ID Numbers:
  • UMCC 2014.112
  • HUM00092921
First Posted:
Mar 27, 2015
Last Update Posted:
Jan 25, 2021
Last Verified:
Jan 1, 2021