Phase 2 Study of Ruxolitinib Versus Anagrelide in Subjects With Essential Thrombocythemia Who Are Resistant to or Intolerant of Hydroxyurea (RESET-272)

• Sponsor: Incyte Corporation (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03123588
• Collaborator: (none)
• Enrollment: 12
• Locations: 26
• Arms: 2
• Actual Duration (Months): 32.6
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of ruxolitinib versus anagrelide in subjects with essential thrombocythemia who are resistant to or intolerant of hydroxyurea.

Condition or Disease	Intervention/Treatment	Phase
MPN (Myeloproliferative Neoplasms)	Drug: Ruxolitinib; Drug: Anagrelide; Drug: Placebo; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Double-Dummy Phase 2 Randomized Study to Evaluate the Efficacy and Safety of Ruxolitinib Versus Anagrelide in Subjects With Essential Thrombocythemia Who Are Resistant to or Intolerant of Hydroxyurea (RESET-272)
• Actual Study Start Date: Nov 14, 2017
• Actual Primary Completion Date: Aug 3, 2020
• Actual Study Completion Date: Aug 3, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A : Ruxolitinib and anagrelide placebo Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.	Drug: Ruxolitinib; Ruxolitinib administered orally twice daily (BID) at the protocol-defined starting dose.; Other Names: Jakafi INCB018424 ; Drug: Placebo; Anagrelide-placebo administered orally BID
Active Comparator: Group B : Anagrelide and Ruxolitinib PLacebo Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information.	Drug: Anagrelide; Anagrelide administered orally at a starting dose of 1 mg BID.; Drug: Placebo; Ruxolitinib-placebo administered orally BID.

Outcome Measures

Primary Outcome Measures

1. Proportion of Subjects Who Achieve Platelet and White Blood Cell (WBC) Control [52 weeks]

   Defined as proportion of subjects who achieve a simultaneous reduction of platelet counts to < 600 × 10^9/L with a reduction of WBC counts to < 10 × 10^9/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52.

Secondary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [Baseline through the end of randomized period -up to 14 months per participant]

   Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment.

2. Proportion of Subjects Who Achieve Complete Remission or Partial Remission [32 weeks]

   Defined as proportion of subjects who achieve CR or PR at Week 32 based on European LeukemiaNet (ELN) 2013 response criteria. Per ELN criteria: Complete Remission: durable resolution of disease related signs and symptoms, durable blood count normalization, absence of hemorrhagic or thrombotic events, absence of signs of progressive disease and bone marrow histological remission including disappearance of megakaryocyte hyperplasia and absence of reticulin fibrosis >Grade 1. Partial remission: durable resolution of disease related signs and symptoms, durable blood count normalization, absence of hemorrhagic or thrombotic events, absence of signs of progressive disease, persistance of megakaryocyte hyperplasia. No response: any response that does not satisfy partial remission. Progressive Disease: transformation in PET-MF, MDS or acute leukemia.

3. Time to Treatment Discontinuation [98 weeks]

   Defined as the time when treatment is discontinued

4. Duration of Response [142 weeks]

   Defined as measurement of response from the onset of response to the loss of response for responders.

5. Proportion of Subjects Who Achieve Reduction of Platelet Counts to < 600 × 10^9/L [Between 32 and 52 weeks]

   Defined as Proportion of subjects who achieve reduction of platelet counts to < 600 × 10^9/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52.

6. Proportion of Subjects Who Achieve a Reduction of WBC Counts to < 10 × 109/L [52 weeks]

   Defined as Proportion of subjects who achieve a reduction of WBC counts to < 10 × 109/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of essential thrombocythemia according to revised World Health Organization (WHO) 2016 criteria.

• Resistant to or intolerant of hydroxyurea, that is, fulfilling at least 1 of the following criteria:

• Platelet count > 600 × 10^9/L after 3 months of at least 2 g/day of hydroxyurea (2.5 g/day in subjects with a body weight over 80 kg) OR at the subject's maximally tolerated dose if that dose is < 2 g/day.

• Platelet count > 400 × 10^{9/L and WBC count < 2.5 × 10}9/L or hemoglobin < 10 g/dL at any dose of hydroxyurea.

• Presence of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of hydroxyurea.

• Hydroxyurea-related fever.

• Platelet count ≥ 650 × 10^9/L at screening.

• WBC ≥ 11.0 × 10^9/L at screening.

Exclusion Criteria:

• Subjects previously treated with anagrelide or Hydroxyurea (HU).

1. Prior anagrelide use is allowed provided the reason for discontinuation is not AE-related and anagrelide is stopped at least 28 days before the start of study medications (ie, Day 1).

2. Treatment with HU can be stopped at any time once one of the inclusion criteria for HU refractoriness or resistance have been met, and up to the day before the first dose of study treatment (ie, Day 1).

• Inadequate liver function at screening and Day 1 (before drug administration) as demonstrated by:

• Total bilirubin > 1.5 × upper limit of normal (ULN)

• Aspartate aminotransferase or alanine aminotransferase > 1.5 × ULN

• Hepatocellular disease (eg, cirrhosis)

• Inadequate renal function at screening as demonstrated by creatinine clearance < 40 mL/min calculated by Cockcroft-Gault equation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Phoenix	Arizona	United States	85054
2	Pacific Shores Medical Group	Long Beach	California	United States	90813
3	University of Southern California	Los Angeles	California	United States	90033
4	Ventura County Hematology-Oncology Specialists	Oxnard	California	United States	93030
5	Compassionate Cancer Care Medical Group	Riverside	California	United States	92501
6	Innovative Clinical Research Institute	Whittier	California	United States	90603
7	Bond Clinic, PA	Winter Haven	Florida	United States	33880
8	Tift Regional	Tifton	Georgia	United States	31794
9	Edward Cancer Center	Naperville	Illinois	United States	60540
10	North Shore Cancer Research Association-Skokie	Skokie	Illinois	United States	60076
11	Southern Illinois University	Springfield	Illinois	United States	62702
12	Clinical Trials of SWLA LLC	Lake Charles	Louisiana	United States	70601
13	St. Agnes Hospital	Baltimore	Maryland	United States	21229
14	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
15	Summit Medical Group	Morristown	New Jersey	United States	07960
16	Montefiore Medical Center	Bronx	New York	United States	10467
17	Columbia Weill Cornell Cancer Centers - Herbert Irving Comprehensive Cancer Center (HICCC)	New York	New York	United States	10032
18	Waverly Hem Onc	Cary	North Carolina	United States	27518
19	Vidant Medical Center	Greenville	North Carolina	United States	27858
20	Gabrail Cancer Center- Canton Facility	Canton	Ohio	United States	44718
21	INTEGRIS Southwest Medical Center	Oklahoma City	Oklahoma	United States	73109
22	INTEGRIS Cancer Institute Proton Campus	Oklahoma City	Oklahoma	United States	73142
23	Kaiser Permanente Northwest	Portland	Oregon	United States	97227
24	Geisinger - Knapper Clinic	Danville	Pennsylvania	United States	17822
25	Prairie Lakes Health Care System Inc.	Watertown	South Dakota	United States	57201
26	Renovatio Clinical	The Woodlands	Texas	United States	77401

Sponsors and Collaborators

• Incyte Corporation

Investigators

• Study Director: Albert Assad, MD, Incyte Corporation

Study Documents (Full-Text)

• Study Protocol - Aug 2, 2019
• Statistical Analysis Plan - Sep 24, 2019

More Information

Publications

None provided.

• Responsible Party: Incyte Corporation
• ClinicalTrials.gov Identifier: NCT03123588
• Other Study ID Numbers: INCB 18424-272 (RESET-272)
• First Posted: Apr 21, 2017
• Last Update Posted: Nov 19, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Incyte Corporation: Essential thrombocythemia; hydroxyurea-resistant; hydroxyurea-intolerant; ruxolitinib; anagrelide
• Additional relevant MeSH terms: Myeloproliferative Disorders; Thrombocytosis; Thrombocythemia, Essential; Anagrelide

Study Results

Participant Flow

Recruitment Details	Approximately 120 participants were planned for enrollment and 12 participants were enrolled (6 in the ruxolitinib group and 6 in the anagrelide group). The first participant was dosed on 14 Nov 2017 and Last participant completed study on 03 Aug 2020
Pre-assignment Detail	Twelve participants were enrolled and randomized. One participant in the ruxolitinib group was enrolled in error and withdrawn from the study before receiving any dose of study drug.

Arm/Group Title	Group A : Ruxolitinib and Anagrelide Placebo	Group B : Anagrelide and Ruxolitinib Placebo
Arm/Group Description	Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.	Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information.
Period Title: Overall Study
STARTED	6	6
COMPLETED	0	0
NOT COMPLETED	6	6

Baseline Characteristics

Arm/Group Title	Group A : Ruxolitinib and Anagrelide Placebo	Group B : Anagrelide and Ruxolitinib Placebo	Total
Arm/Group Description	Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.	Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information.	Total of all reporting groups
Overall Participants	6	6	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.8 (13.04)	61.2 (16.77)	66.5 (15.37)
Sex: Female, Male (Count of Participants)
Female	5 83.3%	3 50%	8 66.7%
Male	1 16.7%	3 50%	4 33.3%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	6 100%	5 83.3%	11 91.7%
Not Reported	0 0%	1 16.7%	1 8.3%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	5 83.3%	6 100%	11 91.7%
Asian	1 16.7%	0 0%	1 8.3%

Outcome Measures

1. Primary Outcome

Title	Proportion of Subjects Who Achieve Platelet and White Blood Cell (WBC) Control
Description	Defined as proportion of subjects who achieve a simultaneous reduction of platelet counts to < 600 × 10^9/L with a reduction of WBC counts to < 10 × 10^9/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population will include subjects randomized in the study

Arm/Group Title	Group A : Ruxolitinib and Anagrelide Placebo	Group B : Anagrelide and Ruxolitinib PLacebo
Arm/Group Description	Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.	Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information.
Measure Participants	6	6
Number [proportion of participants]	0 0%	0.17 2.8%

2. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment.
Time Frame	Baseline through the end of randomized period -up to 14 months per participant

Outcome Measure Data

Analysis Population Description

The safety population includes all randomized subjects who received at least 1 dose of study drug. AE has been summarized only in randomized period. End of randomized period is defined as the earliest of discontinuation or the individual unblinding date.

Arm/Group Title	Group A : Ruxolitinib and Anagrelide Placebo	Group B : Anagrelide and Ruxolitinib PLacebo
Arm/Group Description	Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.	Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information.
Measure Participants	5	6
Number [participants]	5 83.3%	4 66.7%

3. Secondary Outcome

Title	Proportion of Subjects Who Achieve Complete Remission or Partial Remission
Description	Defined as proportion of subjects who achieve CR or PR at Week 32 based on European LeukemiaNet (ELN) 2013 response criteria. Per ELN criteria: Complete Remission: durable resolution of disease related signs and symptoms, durable blood count normalization, absence of hemorrhagic or thrombotic events, absence of signs of progressive disease and bone marrow histological remission including disappearance of megakaryocyte hyperplasia and absence of reticulin fibrosis >Grade 1. Partial remission: durable resolution of disease related signs and symptoms, durable blood count normalization, absence of hemorrhagic or thrombotic events, absence of signs of progressive disease, persistance of megakaryocyte hyperplasia. No response: any response that does not satisfy partial remission. Progressive Disease: transformation in PET-MF, MDS or acute leukemia.
Time Frame	32 weeks

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population will include subjects randomized in the study

Arm/Group Title	Group A : Ruxolitinib and Anagrelide Placebo	Group B : Anagrelide and Ruxolitinib Placebo
Arm/Group Description	Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.	Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information.
Measure Participants	6	6
Number [proportion of participants]	0 0%	0.17 2.8%

4. Secondary Outcome

Title	Time to Treatment Discontinuation
Description	Defined as the time when treatment is discontinued
Time Frame	98 weeks

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population will include subjects randomized in the study

Arm/Group Title	Group A : Ruxolitinib and Anagrelide Placebo	Group B : Anagrelide and Ruxolitinib Placebo
Arm/Group Description	Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.	Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information.
Measure Participants	5	6
Mean (Standard Deviation) [Days]	261.2 (238.85)	437.2 (183.99)

5. Secondary Outcome

Title	Duration of Response
Description	Defined as measurement of response from the onset of response to the loss of response for responders.
Time Frame	142 weeks

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population who are responders

Arm/Group Title	Group A : Ruxolitinib and Anagrelide Placebo	Group B : Anagrelide and Ruxolitinib PLacebo
Arm/Group Description	Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.	Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information.
Measure Participants	0	1
Number [Days]	442

6. Secondary Outcome

Title	Proportion of Subjects Who Achieve Reduction of Platelet Counts to < 600 × 10^9/L
Description	Defined as Proportion of subjects who achieve reduction of platelet counts to < 600 × 10^9/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52.
Time Frame	Between 32 and 52 weeks

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population will include subjects randomized in the study

Arm/Group Title	Group A : Ruxolitinib and Anagrelide Placebo	Group B : Anagrelide and Ruxolitinib Placebo
Arm/Group Description	Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.	Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information.
Measure Participants	5	6
Number [Proportion of participants]	0 0%	0.50 8.3%

7. Secondary Outcome

Title	Proportion of Subjects Who Achieve a Reduction of WBC Counts to < 10 × 109/L
Description	Defined as Proportion of subjects who achieve a reduction of WBC counts to < 10 × 109/L for at least 80% of biweekly measurements for a consecutive 12-week period between Weeks 32 and 52.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population will include subjects randomized in the study

Arm/Group Title	Group A : Ruxolitinib and Anagrelide Placebo	Group B : Anagrelide and Ruxolitinib PLacebo
Arm/Group Description	Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.	Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information.
Measure Participants	5	6
Number [Proportion of participants]	0 0%	0.33 5.5%

Adverse Events

Time Frame	Baseline through the end of randomized period -up to 14 months per participant
Adverse Event Reporting Description	The safety population includes all randomized subjects who received at least 1 dose of study drug. AE has been summarized only in randomized period. End of randomized period is defined as the earliest of discontinuation or the individual unblinding date.
Arm/Group Title	Group A : Ruxolitinib and Anagrelide Placebo		Group B : Anagrelide and Ruxolitinib Placebo
Arm/Group Description	Ruxolitinib or placebo will be administered orally twice a day at a starting dose of 10 mg.		Anagrelide or placebo will be administered orally twice a day at a starting dose of 1 mg. Use of anagrelide will be consistent with approved prescribing information
All Cause Mortality
	Group A : Ruxolitinib and Anagrelide Placebo		Group B : Anagrelide and Ruxolitinib Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/6 (0%)
Serious Adverse Events
	Group A : Ruxolitinib and Anagrelide Placebo		Group B : Anagrelide and Ruxolitinib Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		1/6 (16.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-small cell lung cancer	0/5 (0%)	0	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	Group A : Ruxolitinib and Anagrelide Placebo		Group B : Anagrelide and Ruxolitinib Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		4/6 (66.7%)
Blood and lymphatic system disorders
Anaemia	2/5 (40%)	2	0/6 (0%)	0
Cardiac disorders
Palpitations	0/5 (0%)	0	1/6 (16.7%)	1
Tachycardia paroxysmal	0/5 (0%)	0	1/6 (16.7%)	1
Ear and labyrinth disorders
Ear discomfort	1/5 (20%)	1	0/6 (0%)	0
Tinnitus	1/5 (20%)	1	0/6 (0%)	0
Eye disorders
Vitreous floaters	1/5 (20%)	1	0/6 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/5 (0%)	0	1/6 (16.7%)	1
Abdominal pain upper	1/5 (20%)	1	0/6 (0%)	0
Diarrhoea	0/5 (0%)	0	2/6 (33.3%)	3
Gastrooesophageal reflux disease	1/5 (20%)	1	0/6 (0%)	0
Nausea	1/5 (20%)	1	2/6 (33.3%)	2
General disorders
Fatigue	3/5 (60%)	3	0/6 (0%)	0
Oedema peripheral	0/5 (0%)	0	2/6 (33.3%)	2
Pyrexia	1/5 (20%)	1	0/6 (0%)	0
Infections and infestations
Bronchitis	1/5 (20%)	2	1/6 (16.7%)	1
Fungal infection	0/5 (0%)	0	1/6 (16.7%)	1
Upper respiratory tract infection	1/5 (20%)	1	0/6 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/5 (0%)	0	1/6 (16.7%)	1
Fall	1/5 (20%)	1	1/6 (16.7%)	1
Muscle strain	0/5 (0%)	0	1/6 (16.7%)	1
Skin abrasion	0/5 (0%)	0	1/6 (16.7%)	1
Investigations
Aspartate aminotransferase increased	1/5 (20%)	2	0/6 (0%)	0
Blood creatinine	0/5 (0%)	0	1/6 (16.7%)	1
Weight decreased	1/5 (20%)	1	0/6 (0%)	0
Weight increased	0/5 (0%)	0	1/6 (16.7%)	1
Metabolism and nutrition disorders
Decreased appetite	1/5 (20%)	1	0/6 (0%)	0
Hyperkalaemia	0/5 (0%)	0	1/6 (16.7%)	1
Hyperuricaemia	1/5 (20%)	1	0/6 (0%)	0
Hyponatraemia	1/5 (20%)	2	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/5 (0%)	0	1/6 (16.7%)	1
Back pain	1/5 (20%)	1	0/6 (0%)	0
Musculoskeletal pain	0/5 (0%)	0	1/6 (16.7%)	1
Myalgia	1/5 (20%)	1	0/6 (0%)	0
Nervous system disorders
Dizziness	1/5 (20%)	1	0/6 (0%)	0
Hypoaesthesia	1/5 (20%)	1	1/6 (16.7%)	1
Psychiatric disorders
Depression	1/5 (20%)	1	0/6 (0%)	0
Insomnia	1/5 (20%)	1	0/6 (0%)	0
Renal and urinary disorders
Micturition urgency	1/5 (20%)	1	0/6 (0%)	0
Nephrolithiasis	0/5 (0%)	0	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/5 (20%)	1	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Night sweats	1/5 (20%)	2	0/6 (0%)	0
Onycholysis	1/5 (20%)	1	0/6 (0%)	0
Pruritus	1/5 (20%)	1	2/6 (33.3%)	2
Rash	0/5 (0%)	0	1/6 (16.7%)	1
Skin ulcer	1/5 (20%)	1	0/6 (0%)	0
Vascular disorders
Hypotension	1/5 (20%)	1	0/6 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Clinical Study Agreement