Ivosidenib + Ruxolitinib for Myeloproliferative Disorder

(MPN Trial)

Overseen By Clinical Trials Intake

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Must not be taking: Chemotherapy, Immunotherapy, CYP3A4 inducers

Disqualifiers: Active second malignancy, Uncontrolled illness, QTc ≥ 450 msec, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of combining two medications, ivosidenib (Tibsovo) and ruxolitinib (Jakafi, Jakavi, or Opzelura), for treating certain advanced blood disorders known as myeloproliferative neoplasms (MPNs) with a specific gene mutation. The study aims to determine the optimal dose of ruxolitinib when used with ivosidenib and to assess their combined efficacy. Suitable participants have been diagnosed with advanced MPNs with the IDH1 mutation and have experienced symptoms such as increased blasts (immature blood cells) in their blood or bone marrow. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on chemotherapy, radiation, or immunotherapy other than what's allowed in the protocol. You can continue taking hydroxyurea or steroids if you're already on them.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of ivosidenib and ruxolitinib has been tested for safety in people with blood disorders. In past studies, most patients managed this combination well. Ivosidenib is already approved for other uses, so its safety profile is well understood. Ruxolitinib has also been studied; it can be tolerated at certain doses but may cause side effects like low blood counts.

This trial is in an early stage, and the main goal is to find the safest dose for using these drugs together. While this provides some information about safety, researchers are still learning how well people can handle these drugs when combined. Participants in the trial will be closely monitored to ensure their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Ivosidenib and Ruxolitinib for treating myeloproliferative disorders because this duo targets the disease at a genetic level. Unlike traditional treatments like hydroxyurea or interferon, which primarily manage symptoms, Ivosidenib specifically inhibits mutant IDH1, a common driver in these disorders, potentially addressing the root cause. Ruxolitinib, on the other hand, is a JAK1/2 inhibitor, reducing the overproduction of blood cells and inflammation. Together, they offer a promising approach by combining genetic targeting with symptom management, which could lead to more effective and comprehensive treatment outcomes.

What evidence suggests that this trial's treatments could be effective for myeloproliferative disorder?

Research has shown that combining Ivosidenib and Ruxolitinib targets specific genetic changes in certain blood disorders. In studies with similar treatments, patients with advanced stages of these disorders showed promising results. For instance, one study found that a similar treatment helped nearly half of the patients improve. Some patients even experienced complete remission, with all signs of cancer disappearing, particularly those with genetic changes like IDH1. This trial will explore different dosage levels of the Ivosidenib and Ruxolitinib combination, which could effectively treat advanced stages of these blood disorders. ^{1 2 3 5 6}

Who Is on the Research Team?

Anand Patel

Principal Investigator

University of Chicago Medicine Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced blood cancers, specifically Myeloproliferative Neoplasms (MPNs), that have a mutation in the IDH1 gene. Participants should not have received certain treatments prior to joining and must meet specific health criteria.

Inclusion Criteria

I have chronic hepatitis B but it's under control with treatment.

It's been over 4 weeks since my last major surgery, radiation, or trial participation.

I agree to use birth control during the study.

Exclusion Criteria

I do not have any unmanaged ongoing illnesses.

I am not on any cancer treatments not listed in this study's protocol.

I have been treated with ivosidenib before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Ivosidenib and Ruxolitinib to determine the maximum tolerated dose and evaluate efficacy

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Ivosidenib
• Ruxolitinib

Trial Overview The study tests the combination of two drugs, Ruxolitinib and Ivosidenib, to find the highest dose patients can tolerate without severe side effects (MTD) and to assess how effective this combo is for treating advanced-phase Ph-negative MPNs with IDH1 mutation.

How Is the Trial Designed?

Group I: Dose Level 2 Experimental Treatment 2 Interventions

Ivosidenib 500mg daily + Ruxolitinib 20mg twice a day

Group II: Dose Level 1 Experimental Treatment 2 Interventions

Ivosidenib 500mg daily + Ruxolitinib 10mg twice a day

Group III: Dose Level -1 Experimental Treatment 2 Interventions

Ivosidenib 500mg daily + Ruxolitinib 5mg twice a day

Ivosidenib is already approved in United States, European Union for the following indications:

Approved in United States as Tibsovo for:

• Acute myeloid leukemia (AML) with IDH1 mutation

Approved in European Union as Tibsovo for:

• Acute myeloid leukemia (AML) with IDH1 mutation

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Published Research Related to This Trial

In a phase I/II study involving 27 patients with relapsed or refractory acute leukemias, ruxolitinib was found to be reasonably well tolerated, with the most common severe side effect being infections, particularly pneumonia.

One patient achieved a complete response with incomplete recovery of peripheral blood (CRp) at the highest dose of 200 mg b.i.d., indicating potential efficacy in this heavily pretreated population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Pemmaraju, N., Kantarjian, H., Kadia, T., et al.[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]

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, approved by the FDA for treating high and intermediate risk myelofibrosis, provides relief from symptoms and splenomegaly but does not improve survival or reverse bone marrow fibrosis, making it suitable only for select patients.

While ruxolitinib can alleviate constitutional symptoms, it carries significant side effects like anemia and gastrointestinal issues, which must be weighed against its benefits when considering treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths. Tefferi, A.[2022]

Ruxolitinib treatment in patients with myelofibrosis (MF) significantly reduced spleen size and improved symptoms compared to placebo, demonstrating its efficacy in managing this condition.

In a study of 236 JAK2p.V617F-positive patients, ruxolitinib therapy led to reductions in the JAK2 mutation allele burden, with better outcomes observed in patients who started treatment earlier, indicating the importance of timely intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. Deininger, M., Radich, J., Burn, TC., et al.[2021]

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 II study, ruxolitinib, starting at a low dose of 5 mg twice daily, showed significant efficacy in myelofibrosis patients with low platelet counts (50-100 × 10^9/L), with 62% of patients achieving stable doses of 10 mg twice daily by week 24, and median reductions in spleen volume and symptoms of 24.2% and 43.8%, respectively.

While some patients experienced thrombocytopenia requiring dose adjustments, the treatment was generally manageable, with mean hemoglobin levels remaining stable, indicating that ruxolitinib can be safely administered to this subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. Talpaz, M., Paquette, R., Afrin, L., et al.[2021]

In a study of 219 patients with myelofibrosis, ruxolitinib demonstrated a significant efficacy advantage over the best available therapy, with 28% of patients achieving at least a 35% reduction in spleen volume at 48 weeks, compared to 0% in the control group.

Ruxolitinib not only reduced spleen size but also improved overall quality of life and disease symptoms, with manageable side effects, primarily hematologic issues like thrombocytopenia and anemia, indicating it is a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. Harrison, C., Kiladjian, JJ., Al-Ali, HK., et al.[2022]

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, a JAK inhibitor approved for myelofibrosis, does not cure the disease, highlighting the need for new therapies with different mechanisms of action.

Several promising new agents, including heat shock protein inhibitors and monoclonal antibodies, are being tested in clinical trials and may help overcome resistance to JAK2 inhibitors and address challenges like bone marrow fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is next beyond janus kinase 2 inhibitors for primary myelofibrosis? Santos, FP., Verstovsek, S.[2023]

The study highlights the potential of targeting the PI3K pathway alongside JAK inhibitors like ruxolitinib to address treatment resistance in myeloproliferative neoplasms (MPNs), particularly myelofibrosis.

Combining the PI3Kδ inhibitor parsaclisib with ruxolitinib may enhance treatment efficacy and improve outcomes for patients who do not respond adequately to JAK inhibitors, suggesting a promising new therapeutic strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the PI3K pathway in myeloproliferative neoplasms. Gerds, AT., Bartalucci, N., Assad, A., et al.[2022]

Citations

1. withpower.com withpower.com/trial/phase-1-myeloproliferative-neoplasms-mpns-4-2024-15e58

Ivosidenib + Ruxolitinib for Myeloproliferative Disorder The combination of Ivosidenib and Ruxolitinib is unique because it targets specific genetic mutations and pathways involved in myeloproliferative disorders.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10410182/

Treating accelerated and blast phase myeloproliferative ... In a multicenter phase II study of 25 patients with MPN AP/BP treated with ruxolitinib at an induction dose of 25 mg twice daily and then 10 mg twice daily in ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-09318

Ivosidenib in Combination with Ruxolitinib for the ... This phase Ib trial tests the safety, side effects, and best dose of ivosidenib in combination with ruxolitinib and studies how well it works in treating ...

4. nature.com nature.com/articles/s41408-023-00878-8

Blast phase myeloproliferative neoplasm In a phase 2 study of ruxolitinib plus decitabine in patients with either MPN-BP or MPN-AP, the overall response rate was 44% (CR/CRi/partial ...

5. ashpublications.org ashpublications.org/bloodadvances/article/4/21/5336/469754/Outcome-of-patients-with-IDH1-2-mutated-post

Outcome of patients with IDH1/2-mutated post ... Complete remission was achieved in 3/7 patients (1 attaining MRD–) with new IDH1/2-mutated post–MPN AML treated with IDH1/2-i combinations.

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265025000655

SOHO State of the Art Updates and Next Questions Median OS for all patients was 7.9 months and the overall response rate (ORR) was 53%. ... A subsequent phase 2 study evaluated responses of 25 patients with MPN ...