INCA033989 for Myeloproliferative Disorder

(LIMBER Trial)

Recruiting at 13 trial locations

Overseen By Incyte Corporation Call Center (ex-US)

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Incyte Corporation

Must not be taking: Chemotherapy, Immunotherapy, Endocrine therapy, others

Disqualifiers: Hematological malignancy, Major bleeding, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

140 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called INCA033989 in patients with a type of blood cancer. The goal is to find the safest and most effective dose by checking for side effects and how well the drug works.

Will I have to stop taking my current medications?

The trial requires that you stop certain treatments, such as chemotherapy, immunosuppressive therapy, and some growth factors, at least 28 days before starting the study medication. It's best to discuss your specific medications with the trial team to see if they need to be paused.

What data supports the effectiveness of the drug INCA033989 for treating myeloproliferative disorders?

Research on similar drugs, like ruxolitinib, which target the JAK2 gene mutation common in myeloproliferative disorders, shows they can improve symptoms and quality of life by reducing spleen size and controlling blood cell levels. This suggests that INCA033989, if it works similarly, might also be effective in treating these conditions. ^{1 2 3 4 5}

What safety data exists for JAK2 inhibitors in treating myeloproliferative disorders?

JAK2 inhibitors, used in treating myeloproliferative disorders, have shown to be generally safe with few adverse events. Some side effects include headaches, elevated liver enzymes, and peripheral neuropathy (nerve damage causing tingling or numbness). Monitoring and managing these side effects are important during treatment. ^{1 2 6 7 8}

How is the drug INCA033989 different from other treatments for myeloproliferative disorders?

INCA033989 is unique because it is a JAK2 inhibitor, which targets the JAK2/STAT pathway involved in myeloproliferative disorders. This pathway is often overactive due to mutations, and INCA033989 aims to reduce this activity, potentially offering a more targeted approach compared to other treatments. ^{2 3 9 10 11}

Research Team

Incyte Medical Monitor

Principal Investigator

Incyte Corporation

Eligibility Criteria

This trial is for people who have been diagnosed with myeloproliferative neoplasms, specifically Myelofibrosis (MF) or Essential Thrombocythemia (ET), and are expected to live more than 6 months. They must be willing to undergo bone marrow biopsies and have a documented CALR exon-9 mutation.

Inclusion Criteria

My tests show a CALR exon-9 mutation.

I have been diagnosed with myelofibrosis or essential thrombocythemia.

I am willing to have bone marrow tests before and during the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

INCA033989 is administered in 28-day cycles to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) in participants with myelofibrosis (MF) and essential thrombocythemia (ET)

28 days

Dose Expansion

INCA033989 is administered at the RDE(s) identified during Dose Escalation in participants with myelofibrosis (MF) and essential thrombocythemia (ET)

Up to 3 years and 60 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years and 60 days

Treatment Details

Interventions

• INCA033989

Trial Overview The study tests INCA033989's safety and tolerability in patients with myeloproliferative disorders. It aims to find the highest dose patients can take without serious side effects (MTD) and suggest doses for future studies.

Participant Groups

Group I: Part 1b: Dose Expansion - with MF Experimental Treatment 1 Intervention

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

Group II: Part 1b: Dose Expansion - with ET Experimental Treatment 1 Intervention

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

Group III: Part 1a Dose Escalation Cohort Disease Group A - with MF Experimental Treatment 1 Intervention

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

Group IV: Part 1a Dose Escalation Cohort Disease Group A - with ET Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

Incyte Corporation

Lead Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

Myeloproliferative disorders (MPDs) can be classified into Philadelphia chromosome-positive (Ph(+)) and negative (Ph(-)) groups, with chronic myeloid leukemia (CML) being a Ph(+) disorder effectively treated with BCR-ABL kinase inhibitors that modify the disease course.

Recent discoveries of activating mutations in the JAK2 gene in Ph(-) MPD patients have opened new avenues for targeted therapies, highlighting JAK2 as a promising target for drug development in conditions like polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinase drug discovery approaches in chronic myeloproliferative disorders. Kumar, C., Purandare, AV., Lee, FY., et al.[2021]

JAK2 inhibitors have shown promising results in pre-clinical studies by effectively inhibiting the growth of cells with the JAK2V617F mutation at very low concentrations, indicating their potential as targeted therapies for myeloproliferative disorders (MPD).

These inhibitors have also demonstrated therapeutic efficacy in mouse models and can significantly suppress the growth of progenitor cells from MPD patients with JAK2V617F or MPLW515L/K mutations, suggesting they could be beneficial in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. Pardanani, A.[2013]

Ruxolitinib (RUX), a JAK2 inhibitor, has shown significant efficacy in treating myelofibrosis (MF) and polycythemia vera (PV), achieving a spleen volume response in over 60% of advanced MF patients and hematocrit control in about 60% of PV cases.

While RUX is effective with mild toxicity, long-term treatment may lead to a loss of spleen volume response in MF patients, and monitoring for side effects like decreased hemoglobin/platelet levels and skin tumors is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of JAK2 inhibitors in MPNs 7 years after approval. Passamonti, F., Maffioli, M.[2021]

In a study of 356 patients with myeloproliferative disorders (MPD), 28.5% experienced thromboembolic events and 22.8% had hemorrhagic complications, highlighting the significant risks associated with these conditions.

Conversions between different types of MPD, such as from essential thrombocythemia (ET) to myelofibrosis (MF) or acute leukemia, occurred in a small percentage of patients, indicating the potential for disease progression in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications and conversions in myeloproliferative disorders: an analysis of 356 cases. Wang, Y., Zuo, A., Liu, Y., et al.[2004]

The JAK2V617F mutation is common in patients with myeloproliferative neoplasms, leading to the development of targeted therapies like ruxolitinib, which has been approved for treating intermediate- or high-risk myelofibrosis and significantly improves patients' quality of life.

While ruxolitinib helps reduce symptoms and may extend survival in advanced myelofibrosis, it does not cure the disease, highlighting the need for new treatments and combination therapies to enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic advances in myeloproliferative neoplasms: the role of new-small molecule inhibitors. Verstovsek, S.[2023]

In a Phase 1/2 trial involving 60 patients with myelofibrosis, the JAK1/2 inhibitor CYT387 demonstrated significant efficacy, achieving anemia and spleen response rates of 59% and 48%, respectively, while also improving constitutional symptoms.

CYT387 was well tolerated, with the maximum-tolerated dose identified as 300 mg/day, and most adverse effects were manageable, including reversible headaches and mild peripheral neuropathy in 22% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Pardanani, A., Laborde, RR., Lasho, TL., et al.[2021]

Fedratinib, a selective JAK2 inhibitor, was approved by the FDA for treating intermediate-2 or high-risk myelofibrosis (MF) based on phase II and phase III trials, showing significant reductions in spleen size and symptom burden compared to placebo.

While fedratinib is effective, it has notable side effects including anemia and gastrointestinal issues, and carries a black box warning for encephalopathy, which occurred in about 1% of patients, necessitating careful monitoring of thiamine levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis. Bewersdorf, JP., Jaszczur, SM., Afifi, S., et al.[2020]

JAK2 inhibitors have shown effectiveness in treating Philadelphia chromosome negative myeloproliferative disorders (MPDs), particularly myelofibrosis, by reducing symptoms like splenomegaly and improving daily activity with minimal adverse effects.

These inhibitors work by blocking JAK2-driven signaling pathways, leading to decreased cell proliferation and survival in JAK2-activated cells, and have demonstrated a partial reduction in the disease burden associated with the JAK2V617F mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases. Hitoshi, Y., Lin, N., Payan, DG., et al.[2021]

TG101348, a selective JAK2 inhibitor, demonstrated significant therapeutic effects in a mouse model of myeloproliferative disease caused by the JAK2V617F mutation, including reduced hematocrit and leukocyte counts.

The treatment showed no apparent toxicities and did not affect T cell numbers, indicating a favorable safety profile while effectively targeting the disease at the molecular level.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Wernig, G., Kharas, MG., Okabe, R., et al.[2022]

The case study of a patient with 8p11 myeloproliferative syndrome revealed distinct clinical features such as hyperleukocytosis and widespread adenopathy, linked to the ins(13;8)(q12;p11p23)/ZNF198-FGFR1 genetic alteration.

Molecular analysis confirmed a fusion between the ZNF198 and FGFR1 genes, resulting in a chimeric protein that activates FGFR1's tyrosine kinase, suggesting a mechanism for the disease's aggressive nature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical and gene involved of one case of 8p11 myeloproliferative syndrome with ins(13;8)(q12;p11p23)]. Zhou, F., Chen, S., Chao, H., et al.[2020]

INCB018424, a JAK2 inhibitor, has shown significant clinical activity in treating myelofibrosis (MF), leading to rapid reductions in spleen size and improvements in symptoms for patients taking 10-25 mg twice daily.

The treatment was generally well tolerated, with reversible thrombocytopenia occurring in 30% of patients at the higher dose, while it was not observed at the lower dose, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK2 inhibitors: A reality? A hope? Apostolidou, E., Kantarjian, HM., Verstovsek, S.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Kinase drug discovery approaches in chronic myeloproliferative disorders. [2021]

2. England pubmed.ncbi.nlm.nih.gov

JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

The role of JAK2 inhibitors in MPNs 7 years after approval. [2021]

4. China pubmed.ncbi.nlm.nih.gov

Complications and conversions in myeloproliferative disorders: an analysis of 356 cases. [2004]

5. United States pubmed.ncbi.nlm.nih.gov

Therapeutic advances in myeloproliferative neoplasms: the role of new-small molecule inhibitors. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. [2021]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis. [2020]

8. Japan pubmed.ncbi.nlm.nih.gov

The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. [2022]

10. China pubmed.ncbi.nlm.nih.gov

[Clinical and gene involved of one case of 8p11 myeloproliferative syndrome with ins(13;8)(q12;p11p23)]. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

JAK2 inhibitors: A reality? A hope? [2023]