Ruxolitinib + Duvelisib for Lymphoma

Recruiting at 8 trial locations

Overseen By Steven M. Horwitz, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Immunosuppressants, Corticosteroids, CYP3A inducers

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of combining two drugs, ruxolitinib and duvelisib, for treating certain types of lymphoma, including NK-cell and T-cell lymphomas that have returned or resisted previous treatments. Researchers aim to observe how different doses of duvelisib affect participants while maintaining a consistent dose of ruxolitinib. The trial includes several parts, such as adjusting doses and expanding to include more specific lymphoma types. Ideal participants have confirmed mature T-cell lymphomas, like T-cell prolymphocytic leukemia or T-follicular helper lymphomas, and have experienced relapse or progression after previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this novel combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you may need to stop using certain medications that strongly affect liver enzymes (CYP3A) at least 2 weeks before starting the trial. It's best to discuss your current medications with the trial team.

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

Research has shown that combining the drugs ruxolitinib and duvelisib raises some safety concerns. In an earlier study, two patients experienced serious side effects when taking duvelisib at 25 mg twice a day with ruxolitinib at 20 mg twice a day, indicating that some people might not tolerate these doses well.

Another study found this drug combination effective in targeting specific cancer pathways, but it did not focus on safety. This trial is in an early stage, so researchers are still carefully studying safety.

For those considering joining this trial, it's important to understand that this phase will help determine how well people can tolerate these drugs together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Ruxolitinib and Duvelisib for treating lymphoma because it targets the JAK/STAT signaling pathway, a key driver in many lymphomas. This is different from traditional chemotherapy, which can be less targeted and often comes with significant side effects. Ruxolitinib and Duvelisib are both oral medications, making them more convenient and potentially less invasive than intravenous treatments. Additionally, the dose-escalation design allows for personalized dosing, which could lead to better outcomes and fewer side effects for patients.

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

Research has shown that combining ruxolitinib and duvelisib might help treat certain types of lymphoma. In this trial, participants will receive these drugs together, which block the JAK and PI3K pathways involved in the growth of some cancer cells. This treatment has shown potential benefits, particularly for patients with T-follicular helper (TFH) lymphomas or T-cell lymphomas. Specifically, individuals with certain genetic markers responded well to this drug combination, suggesting effectiveness for others with similar conditions. Overall, the evidence supports further study of this treatment for relapsed or hard-to-treat NK-cell or T-cell lymphoma. ^{1 2 4 6 7}

Who Is on the Research Team?

Alison Moskowitz, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with certain types of T-cell lymphoma or leukemia, who've had at least one prior therapy (treatment-naive allowed for some conditions), can join this trial. They must be able to swallow pills, have a specific level of organ function, and not be pregnant or breastfeeding. Contraception is required during the study.

Inclusion Criteria

My lymphoma is a type of T-cell lymphoma confirmed by tests.

I have a specific type of T-cell lymphoma.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

I am currently being treated for another type of cancer.

I have had surgery or a condition that affects how drugs are absorbed in my body.

Specific criteria for patients with HIV infection or chronic hepatitis B or C

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ruxolitinib and duvelisib with dose-escalation to determine safety and optimal dosing

8 weeks

Regular visits for safety assessments

Cohort Expansion

Further expansion for patients with T-PLL and TFH lymphomas to evaluate disease control rate

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Duvelisib
• Ruxolitinib

Trial Overview The trial tests Ruxolitinib at a fixed dose and Duvelisib at varying doses in people with relapsed/refractory NK-cell or T-cell lymphoma to determine their safety and effects.

How Is the Trial Designed?

Group I: Ruxolitinib and Duvelisib Experimental Treatment 2 Interventions

Ruxolitinib 20mg BID plus Duvelisib 25mg, 50mg, or 75mg BID. Patients will be instructed to take duvelisib and ruxolitinib by mouth every 12 hours, the same time each day, +/- 2 hours. Duvelisib and ruxolitinib will be provided via the institutional investigational pharmacy. The researchers will utilize a dose-escalation standard 3+3 design in which we evaluate 3 doses of duvelisib (25mg BID, 50mg BID, and 75mg BID) in combination with ruxolitinib 20mg BID. A minus-1 dose level of duvelisib (15mg BID) can be used if de-escalation is needed. The cohort expansion phase will have two treatment groups JAK/STAT activation or mutation present or JAK/STAT activation or mutation absent or unknown. Upon discussion with PI, the treating physician may increase dose up to 20 mg of ruxotlinib and/or 25 mg of duvelisib when deemed clinically favorable. T-prolymphocytic leukemia (T-PLL) and T-follicular helper (TFH) lymphoma expansion: Further expansion for patients with T-PLL and TFH lymphomas.

Duvelisib is already approved in United States for the following indications:

Approved in United States as Copiktra for:

• Relapsed or refractory chronic lymphocytic leukemia (CLL)
• Relapsed or refractory small lymphocytic lymphoma (SLL)

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

Ruxolitinib, a JAK-2 inhibitor used for treating myeloproliferative neoplasms, is generally associated with very rare skin toxicity, but an unusual case of erythematous skin eruption with necrotic centers was observed in a patient with primary myelofibrosis.

This case highlights the need for increased awareness of potential skin side effects from ruxolitinib, especially as JAK-2 inhibitors may be used more widely in dermatological treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erythematous skin lesions with necrotic centers on lower extremities due to the use of ruxolitinib for primary myelofibrosis. Dasanu, CA.[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]

Duvelisib, a dual inhibitor of PI3Kδ and PI3Kγ, was tested on 30 pediatric acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) and was found to be well-tolerated, but showed limited efficacy with only one objective response despite reducing leukemia cells in some cases.

The study revealed no clear relationship between the drug's effectiveness and the expression or mutation status of PI3Kδ or PI3Kγ, indicating that duvelisib's action may not be dependent on these factors in the context of ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo activity of the dual PI3Kδ and PI3Kγ inhibitor duvelisib against pediatric acute lymphoblastic leukemia xenografts. Randall, J., Evans, K., Watts, B., et al.[2023]

Ruxolitinib is a selective oral inhibitor of JAK1 and JAK2 that effectively reduces spleen size and alleviates symptoms in patients with myelofibrosis, showing a 41.9% spleen-volume response rate compared to only 0.7% for placebo in a Phase III trial.

Patients taking ruxolitinib also experienced significant improvements in their overall quality of life and symptom scores, with 45.9% showing a ≥ 50% improvement compared to 5.3% for placebo, although the treatment was associated with thrombocytopenia as a dose-limiting toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Ostojic, A., Vrhovac, R., Verstovsek, S.[2021]

Duvelisib is a dual inhibitor of PI3Kδ and PI3Kγ, approved by the FDA in 2018 for treating adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) after at least two prior therapies.

It has also received accelerated approval for relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies, highlighting its efficacy in difficult-to-treat blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duvelisib: A 2018 Novel FDA-Approved Small Molecule Inhibiting Phosphoinositide 3-Kinases. Rodrigues, DA., Sagrillo, FS., Fraga, CAM.[2020]

Ruxolitinib is an effective oral treatment for intermediate- or high-risk myelofibrosis, targeting JAK1 and JAK2 to reduce spleen size and improve symptoms, as demonstrated in Phase III trials with significant improvements in quality of life and overall survival.

The treatment has a manageable safety profile, with common side effects including anemia and thrombocytopenia, and requires dosage adjustments based on platelet counts, allowing for personalized patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. Swaim, SJ.[2021]

Ruxolitinib is an effective treatment for patients with polycythaemia vera (PV) who do not respond well to hydroxyurea, showing superior results in reducing hematocrit and spleen size after 32 weeks in the phase III RESPONSE trial.

The drug is generally well tolerated, with manageable side effects like mild to moderate anemia and thrombocytopenia, making it a valuable option for PV patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: A Review in Polycythaemia Vera. McKeage, K.[2021]

Duvelisib, an oral dual inhibitor, showed a 47.3% overall response rate in a phase II trial involving 129 patients with indolent non-Hodgkin lymphoma (iNHL) who were refractory to previous treatments, indicating its efficacy as a new treatment option.

The treatment had a manageable safety profile, with common side effects including diarrhea and neutropenia, affecting a significant portion of patients, but overall it provided clinically meaningful activity for those with limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma. Flinn, IW., Miller, CB., Ardeshna, KM., et al.[2020]

Duvelisib is an oral small-molecule inhibitor of phosphatidylinositol-3 kinase that received its first global approval in the USA in September 2018 for treating adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) after at least two prior therapies.

It also received accelerated approval for treating adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies, indicating its efficacy in multiple hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duvelisib: First Global Approval. Blair, HA.[2019]

Ruxolitinib is a well-absorbed tyrosine kinase inhibitor with 95% bioavailability, primarily metabolized in the liver, and its pharmacokinetics can vary based on factors like gender and body weight.

The drug's effectiveness can be influenced by liver and renal function, necessitating dose adjustments, and while model-informed precision dosing could enhance treatment personalization, more research is needed before it can be routinely implemented.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review. Appeldoorn, TYJ., Munnink, THO., Morsink, LM., et al.[2023]

Ruxolitinib, a selective JAK1 and JAK2 inhibitor, significantly reduced spleen volume in patients with myelofibrosis compared to placebo in a 24-week trial, demonstrating its efficacy as the first approved treatment for this condition.

The drug was generally well-tolerated, with manageable side effects like thrombocytopenia and anemia, indicating a favorable safety profile for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: in the treatment of myelofibrosis. Yang, LP., Keating, GM.[2022]

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]

Duvelisib, a dual inhibitor of PI3K-δ and PI3K-γ, demonstrated single-agent activity in 14 out of 20 tested hematologic malignancy cell lines, with a median growth inhibition concentration (GI50) of 0.59 μM, indicating its potential efficacy as a treatment.

Combining duvelisib with dexamethasone or ibrutinib not only prevented the reactivation of the AKT signaling pathway but also led to significant tumor growth inhibition in xenograft models, suggesting that these combinations could enhance therapeutic outcomes in hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies. Faia, K., White, K., Murphy, E., et al.[2023]

Ruxolitinib, a JAK1/JAK2 inhibitor, effectively inhibits STAT signaling and shows significant anti-proliferative effects on Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBL) cells in vitro, indicating its potential as a targeted therapy.

In vivo studies demonstrated that ruxolitinib significantly inhibited tumor progression and improved survival rates in xenograft models of HL and PMBL, suggesting it could be a valuable adjuvant treatment for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib significantly enhances in vitro apoptosis in Hodgkin lymphoma and primary mediastinal B-cell lymphoma and survival in a lymphoma xenograft murine model. Lee, S., Shah, T., Yin, C., et al.[2019]

Ruxolitinib, an oral JAK1/2 inhibitor, is effective in reducing spleen size and symptom burden in patients with intermediate and high-risk myelofibrosis, making it a valuable treatment option before hematopoietic stem cell transplantation (HSCT).

The impact of ruxolitinib on HSCT outcomes is not well understood, and there is significant variability in how it is used in patients transitioning to HSCT, highlighting the need for more research to guide treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peritransplantation Use of Ruxolitinib in Myelofibrosis. Ibrahim, U., Petrone, GEM., Mascarenhas, J., et al.[2021]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/463/531152/Dual-Targeted-Therapy-with-Ruxolitinib-Plus

Dual-Targeted Therapy with Ruxolitinib Plus Duvelisib for T ... In part II, we assessed efficacy in 2 expansion cohorts for pts with lymphoma characterized by presence of genetic or immunohistochemical JAK/ ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8718625/

A phase 2 biomarker-driven study of ruxolitinib ... Peripheral T-cell lymphoma (PTCL) is a heterogeneous category composed of many subtypes, and biomarkers to inform targeted therapy are needed.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124032105

Dual-Targeted Therapy with Ruxolitinib Plus Duvelisib for T ... We conducted a phase I study assessing dual-targeting of JAK and PI3K with ruxolitinib plus duvelisib for PTCL or CTCL.

4. pharmacytimes.com pharmacytimes.com/view/dual-targeted-therapy-with-ruxolitinib-and-duvelisib-optimizing-treatment-for-t-cell-lymphomas-through-pharmacist-collaboration

Dual-Targeted Therapy With Ruxolitinib and Duvelisib Moskowitz emphasized that patients most likely to benefit from this combination are those with T-follicular helper (TFH) lymphomas or T-cell ...

5. lymphomahub.com lymphomahub.com/medical-information/the-efficacy-and-safety-of-the-jak-12-inhibitor-ruxolitinib-in-tcl

The efficacy and safety of the JAK 1/2 inhibitor ruxolitinib in ... The results of a phase II trial (NCT02974647) were recently published by Moskowitz et al.1 in Blood, which investigated the efficacy and safety ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2473952925003398

Real-world evidence of duvelisib and romidepsin in ... A previous phase 1/2 study of duvelisib/romidepsin (duv/romi) reported an overall response rate (ORR) of 58% and a complete response rate (CRR) ...

7. biospace.com biospace.com/press-releases/new-combination-data-of-secura-bios-copiktra-duvelisib-presented-at-the-2024-american-society-of-hematology-meeting

New Combination Data of Secura Bio's COPIKTRA® ... Results demonstrated an overall response rate (ORR) of 45%, a complete response (CR) rate of 22%, and a partial response (PR) rate of 22%. ORR ...