A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms
- Conditions
- Myeloproliferative Neoplasms
- Interventions
- Drug: INCA033989Drug: Ruxolitinib
- Registration Number
- NCT05936359
- Lead Sponsor
- Incyte Corporation
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 225
- 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.
- 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, GM-CSF, or TPO-R agonists 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 1a Dose Escalation Cohort Disease Group A - with MF INCA033989 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. Part 1a Dose Escalation Cohort Disease Group A - with ET INCA033989 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. Part 1a: Dose Escalation Cohort Disease Group B - with TGB-MF SubOpt R INCA033989 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. Part 1b: Dose Expansion - with MF INCA033989 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. Part 1b: Dose Expansion - with TGB-MF SubOpt R INCA033989 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. Part 1b: Dose Expansion - with TGB-MF SubOpt R Ruxolitinib 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. Part 1b: Dose Expansion - with ET INCA033989 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. Part 1c: Dose Expansion INCA033989 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. Part 1c: Dose Expansion Ruxolitinib 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. Part 1a: Dose Escalation Cohort Disease Group B - with TGB-MF SubOpt R Ruxolitinib 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.
- Primary Outcome Measures
Name Time Method Number of participants with Dose Limiting Toxicities (DLTs) Up to 28 days Dose-limiting toxicity will be defined as the occurrence of any of the toxicities as per protocol.
Number of participants with TEAEs leading to dose modification or discontinuation Up to 3 years and 60 days Number of participants with TEAEs leading to dose modification or discontinuation.
Number of participants with Treatment-emergent Adverse Events (TEAEs) Up to 3 years and 60 days 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
- Secondary Outcome Measures
Name Time Method Participants With MF: Percentage of participants achieving spleen volume reduction as defined in the protocol Up to 3 years and 60 days Defined as percentage of participants with a protocol defined Spleen Volume Reduction.
Participants with MF with symptomatic anemia: Anemia Response Up to 3 years and 60 days 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 Up to 3 years and 60 days Defined as the proportion of participants with Complete Response or Partial Response when treated with study drug.
Mean change in disease-related allele burden Up to 3 years and 60 days Mean change in disease-related allele burden.
Pharmacokinetics Parameter: Cmin of INCA33989 Up to 3 years and 60 days Defined as the minimum observed plasma concentration of INCA33989.
Pharmacokinetics Parameter: AUC(0-t) of INCA33989 Up to 3 years and 60 days Defined as the area under the concentration-time curve up to the last measurable concentration of INCA33989.
Pharmacokinetics Parameter: Vz/F of INCA33989 Up to 3 years and 60 days Defined as the apparent oral dose volume of distribution of INCA33989.
Pharmacokinetics Parameter: t1/2 of INCA33989 Up to 3 years and 60 days Defined as the apparent terminal phase disposition half-life of INCA33989.
Pharmacokinetics Parameter: Cmax of INCA33989 Up to 3 years and 60 days Defined as maximum observed plasma concentration of INCA33989.
Pharmacokinetics Parameter: Tmax of INCA033989 Up to 3 years and 60 days Defined as the time to reach the maximum plasma concentration of INCA33989.
Pharmacokinetics Parameter: AUC 0-∞ of INCA33989 Up to 3 years and 60 days Defined as the area under the concentration-time curve from 0 to infinity of INCA33989.
Participants with MF: Response using the revised IWG-MRT and ELN response criteria for MF Up to 3 years and 60 days Defined as the percentage of participants with Response using the revised IWG-MRT and ELN response criteria.
Pharmacokinetics Parameter: CL/F of INCA33989 Up to 3 years and 60 days Defined as the apparent oral dose clearance of INCA33989.
Participants With ET: Mean change from baseline of total symptom score (TSS) Up to 3 years and 60 days Mean change of TSS from baseline.
Trial Locations
- Locations (29)
Aou Policlinico S. Orsola-Malpighi Bologna
🇮🇹Bologna, Italy
Royal Brisbane and Women'S Hospital
🇦🇺Herston, Queensland, Australia
Peter Maccallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
The Alfred Hospital
🇦🇺Melbourne, Victoria, Australia
Princess Margaret Cancer Center
🇨🇦Toronto, Ontario, Canada
Hopital Maisonneuve-Rosemont, Montreal, Qc
🇨🇦Montreal, Quebec, Canada
Odense University Hospital
🇩🇰Odense C, Denmark
Sjaellands Universitetshospital
🇩🇰Roskilde, Denmark
Vejle Hospital
🇩🇰Vejle, Denmark
Institut Bergonie
🇫🇷Bordeaux, France
Chu Nimes
🇫🇷Nimes, France
University Medical Center Rwth Aachen
🇩🇪Aachen, Germany
Universitatsklinikum Halle (Saale)
🇩🇪Halle, Germany
Universitatsklinikum Ulm
🇩🇪ULM, Germany
Azienda Ospedaliero-Universitaria Careggi (Aouc)
🇮🇹Firenze, Italy
Hospital Saint Louis
🇫🇷Paris, France
Institut Gustave Roussy
🇫🇷Villejuif Cedex, France
Fondazione Irccs Ca Granda Ospedale Maggiore
🇮🇹Milan, Italy
National Cancer Center Hospital East
🇯🇵Chiba, Japan
Kagoshima University Hospital
🇯🇵Kagoshima, Japan
Osaka Metropolitan University Hospital
🇯🇵Osaka, Japan
Nippon Medical School Hospital
🇯🇵Tokyo, Japan
Mie University Hospital
🇯🇵TSU, Japan
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitari I Politecnic La Fe
🇪🇸Valencia, Spain
Guys and St Thomas Nhs Foundation Trust
🇬🇧London, United Kingdom
The Christie Nhs Foundation Trust Uk
🇬🇧Manchester, United Kingdom
University of Oxford
🇬🇧Oxford, United Kingdom
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia