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

Incyte

Status and phase: Enrolling; Phase 1

Conditions: Myeloproliferative Neoplasms

Treatments: Drug: INCA033989; Drug: Ruxolitinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT05936359

INCA 33989-101

2022-502514-86-00 (Registry Identifier)

Details and patient eligibility

About

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.

Enrollment: 225 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No 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, 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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225 participants in 7 patient groups

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

Experimental group

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.

Treatment:

Drug: INCA033989

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

Experimental group

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.

Treatment:

Drug: INCA033989

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

Experimental group

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.

Treatment:

Drug: Ruxolitinib

Drug: INCA033989

Part 1b: Dose Expansion - with MF

Experimental group

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.

Treatment:

Drug: INCA033989

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

Experimental group

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.

Treatment:

Drug: Ruxolitinib

Drug: INCA033989

Part 1b: Dose Expansion - with ET

Experimental group

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.

Treatment:

Drug: INCA033989

Part 1c: Dose Expansion

Experimental group

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.

Treatment:

Drug: Ruxolitinib

Drug: INCA033989