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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1, Open-Label, Multicenter Study of INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms

Conditions
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Myeloproliferative Neoplasms

Intervention / Treatment
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* Drug: INCA033989
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1a Dose Escalation Cohort Disease Group A - with MF<br>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. | Drug: INCA033989<br>* INCA033989 will be administered at protocol defined dose.<br>|
| Experimental: Part 1a Dose Escalation Cohort Disease Group A - with ET<br>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. | Drug: INCA033989<br>* INCA033989 will be administered at protocol defined dose.<br>|
| Experimental: Part 1a: Dose Escalation Cohort Disease Group B - with TGB-MF SubOpt R<br>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. | Drug: INCA033989<br>* INCA033989 will be administered at protocol defined dose.<br>Drug: Ruxolitinib<br>* Rux will be administered according to Prescribing Information/SmPC.<br>* Other names: Jakafi;|
| Experimental: Part 1b: Dose Expansion - with MF<br>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. | Drug: INCA033989<br>* INCA033989 will be administered at protocol defined dose.<br>|
| Experimental: Part 1b: Dose Expansion - with TGB-MF SubOpt R<br>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. | Drug: INCA033989<br>* INCA033989 will be administered at protocol defined dose.<br>Drug: Ruxolitinib<br>* Rux will be administered according to Prescribing Information/SmPC.<br>* Other names: Jakafi;|
| Experimental: Part 1b: Dose Expansion - with ET<br>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. | Drug: INCA033989<br>* INCA033989 will be administered at protocol defined dose.<br>|
| Experimental: Part 1c: Dose Expansion<br>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. | Drug: INCA033989<br>* INCA033989 will be administered at protocol defined dose.<br>Drug: Ruxolitinib<br>* Rux will be administered according to Prescribing Information/SmPC.<br>* Other names: Jakafi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 28 days | 
| 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 | Up to 2 years and 30 days | 
| Number of participants with TEAEs leading to dose modification or discontinuation | Number of participants with TEAEs leading to dose modification or discontinuation. | Up to 2 years and 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 144 weeks | 
| 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. | Up to 144 weeks | 
| 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. | Up to 144 weeks | 
| Participants With ET: Response Rate | Defined as the proportion of participants with Complete Response or Partial Response when treated with study drug. | Up to 144 weeks | 
| Participants With ET: Mean change from baseline of total symptom score (TSS) | Mean change of TSS from baseline. | Up to 144 weeks | 
| Mean change in disease-related allele burden | Mean change in disease-related allele burden. | Up to 144 weeks | 
| Pharmacokinetics Parameter: Cmax of INCA33989 | Defined as maximum observed plasma concentration of INCA33989. | Up to approximately 2 years | 
| Pharmacokinetics Parameter: Tmax of INCA033989 | Defined as the time to reach the maximum plasma concentration of INCA33989. | Up to approximately 2 years | 
| Pharmacokinetics Parameter: Cmin of INCA33989 | Defined as the minimum observed plasma concentration of INCA33989. | Up to approximately 2 years | 
| Pharmacokinetics Parameter: AUC(0-t) of INCA33989 | Defined as the area under the concentration-time curve up to the last measurable concentration of INCA33989. | Up to approximately 2 years | 
| Pharmacokinetics Parameter: AUC 0-∞ of INCA33989 | Defined as the area under the concentration-time curve from 0 to infinity of INCA33989. | Up to approximately 2 years | 
| Pharmacokinetics Parameter: CL/F of INCA33989 | Defined as the apparent oral dose clearance of INCA33989. | Up to approximately 2 years | 
| Pharmacokinetics Parameter: Vz/F of INCA33989 | Defined as the apparent oral dose volume of distribution of INCA33989. | Up to approximately 2 years | 
| Pharmacokinetics Parameter: t1/2 of INCA33989 | Defined as the apparent terminal phase disposition half-life of INCA33989. | Up to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloproliferative Neoplasms, Ruxolitinib, Myelofibrosis, Essential thrombocythemia, CALR mutation, LIMBER