Ivosidenib + Ruxolitinib for Myeloproliferative Disorder

(MPN Trial)

Overseen By Clinical Trials Intake

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

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

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this research is to gather information on the safety and effectiveness determining maximum tolerated dose (MTD) of ruxolitinib in combination with ivosidenib in IDH1-mutated advanced-phase Ph-negative MPNs while evaluate the efficacy of ruxolitinib in combination with ivosidenib in IDH1-mutated advanced-phase Ph-negative MPNs.

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.

What data supports the effectiveness of the drug combination Ivosidenib and Ruxolitinib for treating myeloproliferative disorders?

Ruxolitinib, a drug that blocks certain proteins (JAK1 and JAK2) involved in blood cell production, has shown effectiveness in reducing symptoms and improving survival in patients with myelofibrosis, a type of myeloproliferative disorder. It is approved for patients who do not respond well to other treatments, and studies have shown it can help control blood cell levels and reduce spleen size. ^{1 2 3 4 5}

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

Ruxolitinib, used in treating myeloproliferative disorders, commonly causes anemia (low red blood cells) and thrombocytopenia (low platelets), but these side effects are usually manageable and rarely lead to stopping treatment. No new safety concerns have been identified in large studies, and non-blood-related side effects like infections are generally mild. ^{2 6 7 8 9}

How is the drug combination of Ivosidenib and Ruxolitinib unique for treating myeloproliferative disorders?

The combination of Ivosidenib and Ruxolitinib is unique because it targets specific genetic mutations and pathways involved in myeloproliferative disorders. Ruxolitinib is a JAK1 and JAK2 inhibitor that helps manage symptoms and reduce spleen size in conditions like myelofibrosis, while Ivosidenib targets IDH1 mutations, potentially offering a novel approach for patients with specific genetic profiles. ^{2 4 7 10 11}

Research Team

Anand Patel

Principal Investigator

University of Chicago Medicine Comprehensive Cancer Center

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Ivosidenib (Targeted Therapy)
• Ruxolitinib (Targeted Therapy)

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.

Participant Groups

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

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Findings from Research

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]

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]

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]

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]

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]

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, 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 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]

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]

References

1. United States 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. [2021]

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

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. [2021]

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

What is next beyond janus kinase 2 inhibitors for primary myelofibrosis? [2023]

4. France pubmed.ncbi.nlm.nih.gov

[Not Available]. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Targeting the PI3K pathway in myeloproliferative neoplasms. [2022]

6. 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]

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

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

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

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

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

The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis. [2021]

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

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

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

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. [2022]