INCA033989 + Ruxolitinib for Myeloproliferative Disorder

(LIMBER Trial)

Recruiting at33 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Incyte Corporation

Must not be taking: G-CSF, GM-CSF, TPO-R agonists

Disqualifiers: Hematological malignancy, Active malignancy, Cardiac disease, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called INCA033989, alone or with ruxolitinib, in patients with a type of blood cancer. The goal is to find the safest dose and see how well patients can tolerate it. Ruxolitinib is a medication used to treat myelofibrosis.

Do I need to stop my current medications to join the trial?

The trial requires that you stop certain medications before starting. Specifically, you must not have taken treatments like chemotherapy, immunotherapy, or certain other drugs within a specific time frame before the trial begins. It's best to discuss your current medications with the trial team to see if they are affected.

What data supports the effectiveness of the drug INCA033989 + Ruxolitinib for Myeloproliferative Disorder?

Ruxolitinib, a part of the treatment, has been shown to help control symptoms and reduce spleen size in patients with myeloproliferative disorders like polycythemia vera and myelofibrosis, especially when other treatments are not effective. It has been approved for use in these conditions based on studies showing its benefits in managing disease symptoms and improving patient outcomes. ^{1 2 3 4 5}

Is the combination of INCA033989 and Ruxolitinib safe for treating myeloproliferative disorders?

Ruxolitinib, also known as Jakafi or Jakavi, has been used for over a decade to treat myelofibrosis and other related conditions, with common side effects including anemia (low red blood cell count) and thrombocytopenia (low platelet count), which are generally manageable. No new safety concerns have been identified in recent studies, and the treatment is considered safe for use in patients with low platelet counts. ^{1 3 6 7 8}

What makes the drug INCA033989 + Ruxolitinib unique for treating myeloproliferative disorders?

The combination of INCA033989 with Ruxolitinib is unique because it targets the JAK-STAT signaling pathway, which is often dysregulated in myeloproliferative disorders. Ruxolitinib is already known for its effectiveness in reducing symptoms and spleen size in these conditions, and combining it with INCA033989 may enhance these effects, offering a potentially more effective treatment option. ^{1 2 3 5 9}

Research Team

Incyte Medical Monitor

Principal Investigator

Incyte Corporation

Eligibility Criteria

This trial is for people with myeloproliferative neoplasms who have a life expectancy over 6 months and measurable disease. They must be in good enough health to perform daily activities (ECOG score of 0-2) and willing to undergo bone marrow procedures. Participants should not have other active cancers, significant heart issues, or certain infections like HIV.

Inclusion Criteria

I have been diagnosed with myelofibrosis or essential thrombocythemia.

My tests show a CALR exon-9 mutation.

Life expectancy > 6 months

Exclusion Criteria

I do not have blood cancer, except for ET, PMF, or post-ET MF.

I have had an active cancer within the last 2 years.

Active HBV/HCV, HIV

Trial 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 and/or recommended dose for expansion

28 days

Dose Expansion

INCA033989 is administered at the recommended dose level as monotherapy or in combination with ruxolitinib

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years and 60 days

Treatment Details

Interventions

• INCA033989 (Monoclonal Antibodies)
• Ruxolitinib (Other)

Trial Overview The study tests INCA033989 alone or combined with Ruxolitinib to find the safest and most effective doses for treating myeloproliferative neoplasms. It aims to identify any dose-related toxicities and establish recommended dosages for further research.

Participant Groups

Group I: Part 1c: Dose Expansion Experimental Treatment 2 Interventions

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.

Group II: Part 1b: Dose Expansion - with TGB-MF SubOpt R Experimental Treatment 2 Interventions

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.

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

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.

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

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.

Group V: Part 1a: Dose Escalation Cohort Disease Group B - with TGB-MF SubOpt R Experimental Treatment 2 Interventions

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.

Group VI: 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 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.

Group VII: 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 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.

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

Ruxolitinib effectively reduces splenomegaly in patients with myeloproliferative neoplasms, showing a significant improvement with a relative risk of 49.12 based on a meta-analysis of randomized clinical trials.

While ruxolitinib is effective, it is associated with an increased incidence of anemia, indicating potential safety concerns that need to be addressed in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and Effectiveness of Ruxolitinib for Treatment of Myeloproliferative Neoplasm: A Meta-Analysis]. Yang, ZR., Zhu, HY.[2021]

Ruxolitinib is an effective treatment for patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea, as demonstrated in the phase 3 RESPONSE study, which showed improvements in hematocrit control, splenomegaly reduction, and alleviation of disease symptoms.

In patients with myelofibrosis (MF), ruxolitinib has been shown to reduce splenomegaly and improve symptoms and survival, based on the phase 3 COMFORT-I and COMFORT-II studies, although there are still unmet needs regarding cytopenias and disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Not Available]. Soret, J., Kiladjian, JJ.[2021]

Ruxolitinib is an effective oral JAK1 and JAK2 inhibitor that has been shown to significantly reduce spleen size and improve symptoms in patients with myelofibrosis (MF), based on randomized phase III studies.

The treatment is generally well-tolerated, with manageable side effects like anemia and thrombocytopenia, leading to its approval by the FDA for intermediate or high-risk myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. Mascarenhas, J., Mughal, TI., Verstovsek, S.[2021]

Ruxolitinib is highly effective for controlling hematocrit levels in patients with polycythemia vera (PV), with 93.8% of first-line and 88.2% of second-line therapy patients achieving control within a median of 2.2 months.

The treatment is generally well tolerated, with only rare adverse effects reported, such as mild anemia and thrombocytopenia, and no thromboembolic events occurring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Ruxolitinib in Polycythemia Vera]. Chang, L., Duan, MH.[2022]

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]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been the standard treatment for intermediate or high-risk myelofibrosis (MF) since its FDA approval in 2011, demonstrating significant efficacy in improving patient outcomes based on data from the phase 3 COMFORT trials.

The review highlights the importance of dose optimization and management of common side effects, such as anemia and thrombocytopenia, to maximize the safety and clinical benefits of ruxolitinib, supported by findings from subsequent trials like JUMP, ROBUST, EXPAND, and REALISE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. Verstovsek, S., Mesa, RA., Livingston, RA., et al.[2023]

Ruxolitinib, a JAK1/JAK2 inhibitor, was evaluated in a large phase 3b study (N = 2233) for treating myelofibrosis, including patients with low platelet counts, showing significant reductions in spleen size and symptoms.

The safety profile of ruxolitinib was consistent with previous studies, with common adverse events like anemia and thrombocytopenia, but these rarely led to treatment discontinuation, indicating it is a viable option for patients with low platelet counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. Al-Ali, HK., Griesshammer, M., Foltz, L., et al.[2021]

In a phase 3 study involving 222 patients with polycythemia vera, ruxolitinib significantly outperformed standard therapy, achieving hematocrit control in 60% of patients and a 35% reduction in spleen volume in 38% of patients, compared to only 20% and 1% respectively in the standard therapy group.

Ruxolitinib also led to a higher rate of complete hematologic remission (24% vs. 9%) and a greater reduction in total symptom scores (49% vs. 5%), while maintaining a manageable safety profile with low rates of severe anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib versus standard therapy for the treatment of polycythemia vera. Vannucchi, AM., Kiladjian, JJ., Griesshammer, M., et al.[2022]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, effectively managed dose-dependent cytopenias in patients with intermediate- or high-risk myelofibrosis through dose adjustments, as demonstrated in the COMFORT-I trial with 309 participants.

Titrated doses of ruxolitinib of 10 mg BID or higher led to significant improvements in myelofibrosis-related symptoms and reductions in spleen volume by week 24, indicating its efficacy in treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Verstovsek, S., Gotlib, J., Gupta, V., et al.[2021]

References

1. China pubmed.ncbi.nlm.nih.gov

[Safety and Effectiveness of Ruxolitinib for Treatment of Myeloproliferative Neoplasm: A Meta-Analysis]. [2021]

2. France pubmed.ncbi.nlm.nih.gov

[Not Available]. [2021]

3. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. [2021]

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

[Efficacy and Safety of Ruxolitinib in Polycythemia Vera]. [2022]

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

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

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

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. [2021]

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

Ruxolitinib versus standard therapy for the treatment of polycythemia vera. [2022]

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

Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. [2021]