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A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms (LIMBER)

Primary Purpose

Myeloproliferative Neoplasms

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
INCA033989
Ruxolitinib
Sponsored by
Incyte Corporation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myeloproliferative Neoplasms focused on measuring Myeloproliferative Neoplasms, Ruxolitinib, Myelofibrosis, Essential thrombocythemia, CALR mutation, LIMBER

Eligibility Criteria

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

Inclusion Criteria: Life expectancy > 6 months. Willingness to undergo a pretreatment and regular on-study BM biopsies and aspirates (as appropriate to disease). Existing documentation from a qualified local laboratory of CALR exon-9 mutation. Participants with MF and ET as defined in the protocol. Exclusion Criteria: Presence of any hematological malignancy other than ET, PMF, or post-ET MF. Active invasive malignancy over the previous 2 years. Active HBV/HCV, HIV. History of clinically significant or uncontrolled cardiac disease. Has undergone any prior allogenic or autologous stem-cell transplantation or such transplantation is planned. Laboratory values outside the Protocol-defined ranges. Participants undergoing treatment with G-CSF or GM-CSF, romiplostim, or eltrombopag at any time within 4 weeks before the first dose of study treatment. Prior history of major bleeding, or thrombosis within the last 3 months prior to study enrollment. Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, antibody, or hypomethylating agent used to treat the participant's disease within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment. For TGBs only: Undergoing treatment with a potent/strong inhibitor or inducer of CYP 3A4/5 within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment, or expected to receive such treatment during the study. Other protocol-defined Inclusion/Exclusion Criteria may apply.

Sites / Locations

  • Royal Brisbane and Women'S Hospital
  • Royal Adelaide HospitalRecruiting
  • The Alfred HospitalRecruiting
  • Peter Maccallum Cancer CentreRecruiting
  • Princess Margaret Cancer Center
  • Hopital Maisonneuve-Rosemont, Montreal, Qc
  • Sjaellands Universitetshospital
  • Vejle Hospital
  • Chu Nimes
  • Hospital Saint Louis
  • Institut Gustave Roussy
  • University Medical Center Rwth Aachen
  • Universitatsklinikum Halle (Saale)
  • Universitätsklinikum Ulm
  • L Azienda Ospedaliero-Universitaria Di Bologna Policlinico S. Orsola - Malpighi
  • Azienda Ospedaliero-Universitaria Careggi (Aouc)
  • Fondazione Irccs Ca Granda Ospedale Maggiore
  • Kagoshima University HospitalRecruiting
  • Osaka Metropolitan University Hospital
  • Nippon Medical School HospitalRecruiting
  • Mie University HospitalRecruiting
  • Hospital Universitario 12 de Octubre
  • Hospital Universitari I Politecnic La Fe
  • Guys and St Thomas Nhs Foundation Trust
  • The Christie Nhs Foundation Trust Uk
  • University of Oxford

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Part 1a Dose Escalation Cohort Disease Group A - with MF

Part 1a Dose Escalation Cohort Disease Group A - with ET

Part 1a: Dose Escalation Cohort Disease Group B - with TGB-MF SubOpt R

Part 1b: Dose Expansion - with MF

Part 1b: Dose Expansion - with TGB-MF SubOpt R

Part 1b: Dose Expansion - with ET

Part 1c: Dose Expansion

Arm Description

INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles as monotherapy to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with myelofibrosis (MF) will enroll in this group.

INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles as monotherapy to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with with essential thrombocythemia (ET) will enroll in this group.

INCA033989 will be administered at a protocol defined starting regimen in 28- day cycles and will allow for the evaluation of INCA033989 in combination with ruxolitinib to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with myelofibrosis (MF) exhibiting suboptimal response (SubOpt R) will enroll in this group.

INCA033989 will be administered as monotherapy at the RDE(s) identified during Part 1a. Participants with treatment group A (TGA) myelofibrosis MF will enroll in this group.

INCA033989 will be administered as an add-on therapy in combination with ruxolitinibat at the RDE(s) identified during Part 1a. Participants with treatment Group B (TGB) MF SubOpt R will enroll in this group.

INCA033989 will be administered as monotherapy at the RDE(s) identified during Part 1a. Participants with treatment group A (TGA) essential thrombocythemia (ET) will enroll in this group.

INCA033989 will be administered at the dose level found to exhibit an overall positive benefit/risk as monotherapy or as combination therapy with Ruxolitinib. Participants with myelofibrosis (MF) will enroll in this group. The participants enrolled in the monotherapy arm will be offered the option to crossover to combination therapy with ruxolitinib if a suboptimal response to monotherapy is observed after 12 weeks.

Outcomes

Primary Outcome Measures

Number of participants with Dose Limiting Toxicities (DLTs)
Dose-limiting toxicity will be defined as the occurrence of any of the toxicities as per protocol.
Number of participants with Treatment-emergent Adverse Events (TEAEs)
Defined as adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug monotherapy and in combination with ruxolitinib
Number of participants with TEAEs leading to dose modification or discontinuation
Number of participants with TEAEs leading to dose modification or discontinuation.

Secondary Outcome Measures

Participants with MF: Response using the revised IWG-MRT and ELN response criteria for MF
Defined as the percentage of participants with Response using the revised IWG-MRT and ELN response criteria.
Participants With MF: Percentage of participants achieving spleen volume reduction as defined in the protocol
Defined as percentage of participants with a protocol defined Spleen Volume Reduction.
Participants with MF with symptomatic anemia: Anemia Response
For non transfusion-dependent (TD) participants: An Hb increase relative to baseline as defined in the protocol if non-TD at baseline. For TD participants: Achieving transfusion independency (TI) as defined in the protocol.
Participants With ET: Response Rate
Defined as the proportion of participants with Complete Response or Partial Response when treated with study drug.
Participants With ET: Mean change from baseline of total symptom score (TSS)
Mean change of TSS from baseline.
Mean change in disease-related allele burden
Mean change in disease-related allele burden.
Pharmacokinetics Parameter: Cmax of INCA33989
Defined as maximum observed plasma concentration of INCA33989.
Pharmacokinetics Parameter: Tmax of INCA033989
Defined as the time to reach the maximum plasma concentration of INCA33989.
Pharmacokinetics Parameter: Cmin of INCA33989
Defined as the minimum observed plasma concentration of INCA33989.
Pharmacokinetics Parameter: AUC(0-t) of INCA33989
Defined as the area under the concentration-time curve up to the last measurable concentration of INCA33989.
Pharmacokinetics Parameter: AUC 0-∞ of INCA33989
Defined as the area under the concentration-time curve from 0 to infinity of INCA33989.
Pharmacokinetics Parameter: CL/F of INCA33989
Defined as the apparent oral dose clearance of INCA33989.
Pharmacokinetics Parameter: Vz/F of INCA33989
Defined as the apparent oral dose volume of distribution of INCA33989.
Pharmacokinetics Parameter: t1/2 of INCA33989
Defined as the apparent terminal phase disposition half-life of INCA33989.

Full Information

First Posted
June 21, 2023
Last Updated
October 19, 2023
Sponsor
Incyte Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT05936359
Brief Title
A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms
Acronym
LIMBER
Official Title
A Phase 1, Open-Label, Multicenter Study of INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 25, 2023 (Actual)
Primary Completion Date
February 29, 2028 (Anticipated)
Study Completion Date
February 29, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Incyte Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
This study is being conducted to evaluate the safety, tolerability, and dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE) of INCA033989 administered as a monotherapy or in combination with ruxolitinib in participants with myeloproliferative neoplasms.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myeloproliferative Neoplasms
Keywords
Myeloproliferative Neoplasms, Ruxolitinib, Myelofibrosis, Essential thrombocythemia, CALR mutation, LIMBER

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
225 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Part 1a Dose Escalation Cohort Disease Group A - with MF
Arm Type
Experimental
Arm Description
INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles as monotherapy to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with myelofibrosis (MF) will enroll in this group.
Arm Title
Part 1a Dose Escalation Cohort Disease Group A - with ET
Arm Type
Experimental
Arm Description
INCA033989 will be administered at a protocol defined starting regimen in 28-day cycles as monotherapy to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with with essential thrombocythemia (ET) will enroll in this group.
Arm Title
Part 1a: Dose Escalation Cohort Disease Group B - with TGB-MF SubOpt R
Arm Type
Experimental
Arm Description
INCA033989 will be administered at a protocol defined starting regimen in 28- day cycles and will allow for the evaluation of INCA033989 in combination with ruxolitinib to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE[s]). Participants with myelofibrosis (MF) exhibiting suboptimal response (SubOpt R) will enroll in this group.
Arm Title
Part 1b: Dose Expansion - with MF
Arm Type
Experimental
Arm Description
INCA033989 will be administered as monotherapy at the RDE(s) identified during Part 1a. Participants with treatment group A (TGA) myelofibrosis MF will enroll in this group.
Arm Title
Part 1b: Dose Expansion - with TGB-MF SubOpt R
Arm Type
Experimental
Arm Description
INCA033989 will be administered as an add-on therapy in combination with ruxolitinibat at the RDE(s) identified during Part 1a. Participants with treatment Group B (TGB) MF SubOpt R will enroll in this group.
Arm Title
Part 1b: Dose Expansion - with ET
Arm Type
Experimental
Arm Description
INCA033989 will be administered as monotherapy at the RDE(s) identified during Part 1a. Participants with treatment group A (TGA) essential thrombocythemia (ET) will enroll in this group.
Arm Title
Part 1c: Dose Expansion
Arm Type
Experimental
Arm Description
INCA033989 will be administered at the dose level found to exhibit an overall positive benefit/risk as monotherapy or as combination therapy with Ruxolitinib. Participants with myelofibrosis (MF) will enroll in this group. The participants enrolled in the monotherapy arm will be offered the option to crossover to combination therapy with ruxolitinib if a suboptimal response to monotherapy is observed after 12 weeks.
Intervention Type
Drug
Intervention Name(s)
INCA033989
Intervention Description
INCA033989 will be administered at protocol defined dose.
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Other Intervention Name(s)
Jakafi
Intervention Description
Rux will be administered according to Prescribing Information/SmPC.
Primary Outcome Measure Information:
Title
Number of participants with Dose Limiting Toxicities (DLTs)
Description
Dose-limiting toxicity will be defined as the occurrence of any of the toxicities as per protocol.
Time Frame
Up to 28 days
Title
Number of participants with Treatment-emergent Adverse Events (TEAEs)
Description
Defined as adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug monotherapy and in combination with ruxolitinib
Time Frame
Up to 2 years and 30 days
Title
Number of participants with TEAEs leading to dose modification or discontinuation
Description
Number of participants with TEAEs leading to dose modification or discontinuation.
Time Frame
Up to 2 years and 30 days
Secondary Outcome Measure Information:
Title
Participants with MF: Response using the revised IWG-MRT and ELN response criteria for MF
Description
Defined as the percentage of participants with Response using the revised IWG-MRT and ELN response criteria.
Time Frame
Up to 144 weeks
Title
Participants With MF: Percentage of participants achieving spleen volume reduction as defined in the protocol
Description
Defined as percentage of participants with a protocol defined Spleen Volume Reduction.
Time Frame
Up to 144 weeks
Title
Participants with MF with symptomatic anemia: Anemia Response
Description
For non transfusion-dependent (TD) participants: An Hb increase relative to baseline as defined in the protocol if non-TD at baseline. For TD participants: Achieving transfusion independency (TI) as defined in the protocol.
Time Frame
Up to 144 weeks
Title
Participants With ET: Response Rate
Description
Defined as the proportion of participants with Complete Response or Partial Response when treated with study drug.
Time Frame
Up to 144 weeks
Title
Participants With ET: Mean change from baseline of total symptom score (TSS)
Description
Mean change of TSS from baseline.
Time Frame
Up to 144 weeks
Title
Mean change in disease-related allele burden
Description
Mean change in disease-related allele burden.
Time Frame
Up to 144 weeks
Title
Pharmacokinetics Parameter: Cmax of INCA33989
Description
Defined as maximum observed plasma concentration of INCA33989.
Time Frame
Up to approximately 2 years
Title
Pharmacokinetics Parameter: Tmax of INCA033989
Description
Defined as the time to reach the maximum plasma concentration of INCA33989.
Time Frame
Up to approximately 2 years
Title
Pharmacokinetics Parameter: Cmin of INCA33989
Description
Defined as the minimum observed plasma concentration of INCA33989.
Time Frame
Up to approximately 2 years
Title
Pharmacokinetics Parameter: AUC(0-t) of INCA33989
Description
Defined as the area under the concentration-time curve up to the last measurable concentration of INCA33989.
Time Frame
Up to approximately 2 years
Title
Pharmacokinetics Parameter: AUC 0-∞ of INCA33989
Description
Defined as the area under the concentration-time curve from 0 to infinity of INCA33989.
Time Frame
Up to approximately 2 years
Title
Pharmacokinetics Parameter: CL/F of INCA33989
Description
Defined as the apparent oral dose clearance of INCA33989.
Time Frame
Up to approximately 2 years
Title
Pharmacokinetics Parameter: Vz/F of INCA33989
Description
Defined as the apparent oral dose volume of distribution of INCA33989.
Time Frame
Up to approximately 2 years
Title
Pharmacokinetics Parameter: t1/2 of INCA33989
Description
Defined as the apparent terminal phase disposition half-life of INCA33989.
Time Frame
Up to approximately 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Life expectancy > 6 months. Willingness to undergo a pretreatment and regular on-study BM biopsies and aspirates (as appropriate to disease). Existing documentation from a qualified local laboratory of CALR exon-9 mutation. Participants with MF and ET as defined in the protocol. Exclusion Criteria: Presence of any hematological malignancy other than ET, PMF, or post-ET MF. Active invasive malignancy over the previous 2 years. Active HBV/HCV, HIV. History of clinically significant or uncontrolled cardiac disease. Has undergone any prior allogenic or autologous stem-cell transplantation or such transplantation is planned. Laboratory values outside the Protocol-defined ranges. Participants undergoing treatment with G-CSF or GM-CSF, romiplostim, or eltrombopag at any time within 4 weeks before the first dose of study treatment. Prior history of major bleeding, or thrombosis within the last 3 months prior to study enrollment. Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, antibody, or hypomethylating agent used to treat the participant's disease within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment. For TGBs only: Undergoing treatment with a potent/strong inhibitor or inducer of CYP 3A4/5 within 14 days or 5 half-lives (whichever is longer) before the first dose of study treatment, or expected to receive such treatment during the study. Other protocol-defined Inclusion/Exclusion Criteria may apply.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Incyte Corporation Call Center (US)
Phone
1.855.463.3463
Email
medinfo@incyte.com
First Name & Middle Initial & Last Name or Official Title & Degree
Incyte Corporation Call Center (ex-US)
Phone
+800 00027423
Email
eumedinfo@incyte.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Incyte Medical Monitor
Organizational Affiliation
Incyte Corporation
Official's Role
Study Director
Facility Information:
Facility Name
Royal Brisbane and Women'S Hospital
City
Herston
State/Province
Queensland
ZIP/Postal Code
04029
Country
Australia
Individual Site Status
Not yet recruiting
Facility Name
Royal Adelaide Hospital
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
05000
Country
Australia
Individual Site Status
Recruiting
Facility Name
The Alfred Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
03004
Country
Australia
Individual Site Status
Recruiting
Facility Name
Peter Maccallum Cancer Centre
City
North Melbourne
State/Province
Victoria
ZIP/Postal Code
03051
Country
Australia
Individual Site Status
Recruiting
Facility Name
Princess Margaret Cancer Center
City
Toronto
State/Province
Ontario
ZIP/Postal Code
MG5 2R2
Country
Canada
Individual Site Status
Not yet recruiting
Facility Name
Hopital Maisonneuve-Rosemont, Montreal, Qc
City
Montreal
ZIP/Postal Code
QC H1T 2M4
Country
Canada
Individual Site Status
Not yet recruiting
Facility Name
Sjaellands Universitetshospital
City
Roskilde
ZIP/Postal Code
04000
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Name
Vejle Hospital
City
Vejle
ZIP/Postal Code
07100
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Name
Chu Nimes
City
Nimes
ZIP/Postal Code
30029
Country
France
Individual Site Status
Not yet recruiting
Facility Name
Hospital Saint Louis
City
Paris
ZIP/Postal Code
75010
Country
France
Individual Site Status
Not yet recruiting
Facility Name
Institut Gustave Roussy
City
Villejuif Cedex
ZIP/Postal Code
94805
Country
France
Individual Site Status
Not yet recruiting
Facility Name
University Medical Center Rwth Aachen
City
Aachen
ZIP/Postal Code
D-52074
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
Universitatsklinikum Halle (Saale)
City
Halle
ZIP/Postal Code
06120
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
Universitätsklinikum Ulm
City
ULM
ZIP/Postal Code
89081
Country
Germany
Individual Site Status
Not yet recruiting
Facility Name
L Azienda Ospedaliero-Universitaria Di Bologna Policlinico S. Orsola - Malpighi
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Individual Site Status
Not yet recruiting
Facility Name
Azienda Ospedaliero-Universitaria Careggi (Aouc)
City
Firenze
ZIP/Postal Code
50134
Country
Italy
Individual Site Status
Not yet recruiting
Facility Name
Fondazione Irccs Ca Granda Ospedale Maggiore
City
Milan
ZIP/Postal Code
20122
Country
Italy
Individual Site Status
Not yet recruiting
Facility Name
Kagoshima University Hospital
City
Kagoshima
ZIP/Postal Code
890-8520
Country
Japan
Individual Site Status
Recruiting
Facility Name
Osaka Metropolitan University Hospital
City
Osaka
ZIP/Postal Code
545-8586
Country
Japan
Individual Site Status
Not yet recruiting
Facility Name
Nippon Medical School Hospital
City
Tokyo
ZIP/Postal Code
113-8603
Country
Japan
Individual Site Status
Recruiting
Facility Name
Mie University Hospital
City
TSU
ZIP/Postal Code
514-0001
Country
Japan
Individual Site Status
Recruiting
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Individual Site Status
Not yet recruiting
Facility Name
Hospital Universitari I Politecnic La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Individual Site Status
Not yet recruiting
Facility Name
Guys and St Thomas Nhs Foundation Trust
City
London
ZIP/Postal Code
SE1 9RT
Country
United Kingdom
Individual Site Status
Not yet recruiting
Facility Name
The Christie Nhs Foundation Trust Uk
City
Manchester
ZIP/Postal Code
M20 4BV
Country
United Kingdom
Individual Site Status
Not yet recruiting
Facility Name
University of Oxford
City
Oxford
ZIP/Postal Code
OX3 7LE
Country
United Kingdom
Individual Site Status
Not yet recruiting

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Incyte shares data with qualified external researchers after a research proposal is submitted. These requests are reviewed and approved by a review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The trial data availability is according to the criteria and process described on https://www.incyte.com/our-company/compliance-and-transparency
IPD Sharing Time Frame
Data will be shared after the primary publication or 2 years after the study has ended for market authorized products and indications.
IPD Sharing Access Criteria
Data from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.incyteclinicaltrials.com website. For approved requests, the researchers will be granted access to anonymized data under the terms of a data sharing agreement.
IPD Sharing URL
https://www.incyte.com/our-company/compliance-and-transparency

Learn more about this trial

A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms

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