Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care: (The RESPONSE Trial)

• Sponsor: Incyte Corporation
• Collaborator: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Incyte Corporation

Study Description

Brief Summary:

This pivotal phase III trial (CINC424B2301) is designed to compare the efficacy and safety of ruxolitinib (INC424) to Best Available Therapy (BAT) in participants with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea (HU).

Condition or disease	Intervention/treatment	Phase
Polycythemia Vera	Drug: ruxolitinib tablets; Other: Best Available Therapy (BAT)	Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Design

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	222 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Randomized, Open Label, Multicenter Phase III Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 Tablets Versus Best Available Care (The RESPONSE Trial)
Actual Study Start Date :	October 27, 2010
Actual Primary Completion Date :	January 15, 2014
Actual Study Completion Date :	February 9, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: ruxolitinib tablets; Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg once a day (QD) to 25 mg BID based on safety and efficacy	Drug: ruxolitinib tablets; Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy
Best Available Therapy; Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.	Other: Best Available Therapy (BAT); Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements.; Other Names: BAT could include:; Hydroxyurea; IFN/PEG-IFN; Pipobroman; Anagrelide; Lenalidomide; Pomalidomide; Observation only

Outcome Measures

Primary Outcome Measures :

1. The Percentage of Participants Achieving a Primary Response at Week 32 [ Time Frame: 32 Weeks ]
   Primary response was defined as having achieved hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and Spleen Volume Reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32).

Secondary Outcome Measures :

1. The Percentage of Participants Achieving a Durable Primary Response at Week 48 [ Time Frame: 48 Weeks ]
   Durable Primary Response was defined as any participant who achieved the primary outcome measure and who maintained their response up to 48 weeks after randomization.
2. The Percentage of Participants Achieving Complete Hematological Remission at Week 32 [ Time Frame: 32 Weeks ]
   Complete Hematological Remission at Week 32 was defined as any participant who achieved hematocrit control with a platelet count less than or equal to 400 X 10^9/L and a white blood cell count less than or equal to 10 X 10^9/L.
3. The Percentage of Participants Who Achieved a Durable Complete Hematological Remission at Week 48 [ Time Frame: 48 Weeks ]
   Durable Complete Hematological Remission was defined as any participant who achieved Complete Hematological Remission at Week 32 and maintained their response up to 48 weeks after randomization.
4. The Percentage of Participants Who Achieved a Durable Hematocrit Control at Week 48 [ Time Frame: 48 Weeks ]
   Durable Hematocrit Control was defined as any participant who achieved phlebotomy eligibility independence from Week 8 to Week 32 and maintained hematocrit control up to 48 weeks after randomization.
5. The Percentage of Participants Who Achieved Durable Spleen Volume Reduction at Week 48 [ Time Frame: 48 Weeks ]
   Durable Spleen Volume Reduction was defined as a participant who achieved at least 35% reduction from baseline in spleen volume at Week 32 and maintained that response 48 weeks after randomization.
6. Estimated Duration of the Primary Response [ Time Frame: Through study completion, analysis was conducted when all participants had completed the Week 80 visit or discontinued the study ]

   Duration of the primary response is defined as the time from the first occurrence when both components of the primary endpoint are met until the date of the first documented disease progression (end of response).

   Kaplan-Meier estimates are provided for duration of primary response.

7. The Percentage of Participants Who Achieved Overall Clinicohematologic Response at Week 32 [ Time Frame: 32 Weeks ]
   Overall Clinicohematologic Response is defined as any participant who achieved a complete or partial clinicohematologic response per the European LeukemiaNet modified criteria for response in polycythemia vera (PV). A Complete Response (CR) is defined as: hematocrit control, spleen volume reduction at least 35% from baseline, platelet count less than or equal to 400 x 10(9)/L, and white blood cell count less than or equal to 10 x 10(9)/L. A Partial Response (PR) is defined as hematocrit control or response in all 3 of the other criteria.
8. The Percentage of Participants Achieving a Durable Complete or Partial Clinicohematologic Response at Week 48 [ Time Frame: 48 Weeks ]
   Durable Complete or Partial Clinicohematologic Response was defined as any participant who achieved complete or partial clinicohematologic response per the European LeukemiaNet modified criteria for response in polycythemia vera at Week 32 and maintained that response 48 weeks after randomization.
9. Estimated Duration of the Complete Hematological Remission [ Time Frame: Through study completion, analysis was conducted when all participants had completed the Week 80 visit or discontinued the study ]

   Duration of the complete hematological remission is defined as the time from the first occurrence of complete hematological remission until the date of the first documented progression (end of response).

   Kaplan-Meier estimates are provided for duration of complete hematological remission.

10. Duration of the Absence of Phlebotomy Eligibility [ Time Frame: 256 Weeks ]
    Duration of the absence of phlebotomy eligibility is defined as the time from the first occurrence of absence of phlebotomy eligibility until the date of the first documented progression.
11. Duration of Reduction in Spleen Volume [ Time Frame: 256 Weeks ]
    Duration of spleen volume reduction is defined as the time from the first occurrence of a >=35% reduction from baseline in spleen volume until the date of the first documented progression.
12. Duration of The Overall Clinicohematologic Response [ Time Frame: 256 Weeks ]
    Duration of the overall clinicohematologic response was defined as the time from the first occurrence of complete response (CR) or partial response (PR) until the date of the first documented disease progression.

Eligibility Criteria

Layout table for eligibility information

Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Participants diagnosed with PV for at least 24 weeks prior to screening according to the 2008 World Health Organization criteria
• Participants resistant to or intolerant of hydroxyurea
• Participants with a phlebotomy requirement
• Participants with splenomegaly (palpable or non-palpable) and a spleen volume, as measured by MRI (or CT in applicable participants ), of greater than or equal to 450 cubic centimeters
• Participants with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Exclusion Criteria:

• Women who are pregnant or nursing
• Participants with inadequate liver or renal function
• Participants with significant bacterial, fungal, parasitic, or viral infection requiring treatment
• Participants with an active malignancy within the past 5 years, excluding specific skin cancers
• Participants with known active hepatitis or HIV positivity
• Participants who have previously received treatment with a JAK inhibitor
• Participants being treated with any investigational agent

Contacts and Locations

  Show 102 Study Locations

Sponsors and Collaborators

Incyte Corporation

Novartis Pharmaceuticals

Investigators

Layout table for investigator information

Study Director:	Srdan Verstovsek, MD,PhD	M.D. Anderson Cancer Center
Study Director:	Mark Jones, MD	Incyte Corporation

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kiladjian JJ, Guglielmelli P, Griesshammer M, Saydam G, Masszi T, Durrant S, Passamonti F, Jones M, Zhen H, Li J, Gadbaw B, Perez Ronco J, Khan M, Verstovsek S. Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies. Ann Hematol. 2018 Apr;97(4):617-627. doi: 10.1007/s00277-017-3225-1. Epub 2018 Feb 2.

Verstovsek S, Harrison CN, Kiladjian JJ, Miller C, Naim AB, Paranagama DC, Habr D, Vannucchi AM. Markers of iron deficiency in patients with polycythemia vera receiving ruxolitinib or best available therapy. Leuk Res. 2017 May;56:52-59. doi: 10.1016/j.leukres.2017.01.032. Epub 2017 Jan 31.

Verstovsek S, Vannucchi AM, Griesshammer M, Masszi T, Durrant S, Passamonti F, Harrison CN, Pane F, Zachee P, Kirito K, Besses C, Hino M, Moiraghi B, Miller CB, Cazzola M, Rosti V, Blau I, Mesa R, Jones MM, Zhen H, Li J, Francillard N, Habr D, Kiladjian JJ. Ruxolitinib versus best available therapy in patients with polycythemia vera: 80-week follow-up from the RESPONSE trial. Haematologica. 2016 Jul;101(7):821-9. doi: 10.3324/haematol.2016.143644. Epub 2016 Apr 21.

Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, Harrison CN, Pane F, Zachee P, Mesa R, He S, Jones MM, Garrett W, Li J, Pirron U, Habr D, Verstovsek S. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015 Jan 29;372(5):426-35. doi: 10.1056/NEJMoa1409002.

Layout table for additonal information

Responsible Party:	Incyte Corporation
ClinicalTrials.gov Identifier:	NCT01243944 History of Changes
Other Study ID Numbers:	CINC424B2301
First Posted:	November 19, 2010
Results First Posted:	March 6, 2015
Last Update Posted:	March 6, 2019
Last Verified:	February 2019

Keywords provided by Incyte Corporation:

INCB018424

Additional relevant MeSH terms:

Layout table for MeSH terms

Polycythemia; Polycythemia Vera; Hematologic Diseases; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Neoplasms; Bone Marrow Diseases; Myeloproliferative Disorders; Lenalidomide; Pomalidomide; Hydroxyurea; Janus Kinase Inhibitors	Immunologic Factors; Physiological Effects of Drugs; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antineoplastic Agents; Antisickling Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Protein Kinase Inhibitors