Ruxolitinib + Enzalutamide for Prostate Cancer

Recruiting at 2 trial locations

Overseen By Cancer AnswerLine

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: University of Michigan Rogel Cancer Center

Must be taking: Androgen deprivation therapy

Must not be taking: Fluconazole, Strong CYP inhibitors

Disqualifiers: Brain metastasis, Seizures, Hypertension, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 6 months

39 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II tests the safety, side effects and best dose of ruxolitinib in combination with enzalutamide and how well it works in treating patients with prostate cancer that remains despite blocking hormone production (castration-resistant) and that has spread from where it first started to other places in the body (metastatic). Ruxolitinib, a kinase inhibitor, slows down the growth of the tumor by blocking the proteins, JAK1 and JAK2, tumors use to grow. Enzalutamide, an androgen receptor inhibitor, works by blocking the effects of androgen (a male reproductive hormone). This may help stop the growth and spread of tumor cells that need testosterone to grow. Giving ruxolitinib in combination with enzalutamide may be safe, tolerable, and/or effective in treating metastatic castration-resistant prostate cancer.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as fluconazole and any supplements containing androgens. If you are taking medications that strongly affect certain liver enzymes (CYP2C8, CYP3A4, CYP2C9, CYP2C19), you may need to stop them at least 7 days or 5 half-lives before starting the trial, unless a substitution is possible.

What data supports the effectiveness of the drug Enzalutamide for prostate cancer?

Research shows that Enzalutamide, an androgen receptor inhibitor, significantly improves survival rates and delays disease progression in men with metastatic castration-resistant prostate cancer, both after chemotherapy and in chemotherapy-naïve patients. ^{1 2 3 4 5}

Is the combination of Ruxolitinib and Enzalutamide generally safe for humans?

Ruxolitinib has been associated with some side effects, including infections, muscle and joint issues, blood clots, and skin cancers, based on data from its use in other conditions. However, it was generally well tolerated in a study with multiple myeloma patients. Enzalutamide, used for prostate cancer, is generally considered safe but can have side effects like fatigue, hot flashes, and high blood pressure. ^{6 7 8 9 10}

How does the drug combination of Ruxolitinib and Enzalutamide for prostate cancer differ from other treatments?

The combination of Ruxolitinib and Enzalutamide for prostate cancer is unique because Ruxolitinib, a JAK1/2 inhibitor, may enhance the effectiveness of Enzalutamide by targeting specific pathways involved in cancer cell survival, potentially offering a novel approach compared to standard treatments. ^{6 9 11 12 13}

Research Team

Zachery R. Reichert

Principal Investigator

University of Michigan Rogel Cancer Center

Eligibility Criteria

This trial is for men with prostate cancer that has spread and doesn't respond to hormone-blocking treatments. Participants should have a life expectancy of at least 3 months, good organ function, and no plans for other cancer therapies during the trial.

Inclusion Criteria

Ability to understand a written informed consent document, as determined by the study physician or designee

PSA must rise on two measurements at least 1 week apart in order to be eligible. Refer to PCWG3 for clarification

My latest treatment includes ADT and abiraterone, and I will sign consent within 30 days of stopping abiraterone.

Exclusion Criteria

I have not had a heart attack, stroke, or major blood clot in the last 6 months.

I cannot swallow pills or have a stomach condition that affects medication absorption.

Due to risk of tuberculosis (TB) reactivation, patients deemed at high risk by treating provider (e.g., close contact with someone with active TB, history of active/latent TB) should be excluded

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ruxolitinib and enzalutamide. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 6 months

Monthly visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 30 days after last dose

Long-term follow-up

Participants are monitored for progression-free survival and other long-term outcomes

Up to 2 years

Treatment Details

Interventions

• Enzalutamide
• Ruxolitinib

Trial Overview The study is testing the safety and effectiveness of combining two drugs: Ruxolitinib (which blocks proteins that help tumors grow) and Enzalutamide (which stops testosterone from helping tumor growth), in patients with advanced prostate cancer.

Participant Groups

Group I: Treatment (ruxolitinib, enzalutamide) Experimental Treatment 6 Interventions

Patients receive ruxolitinib PO BID and enzalutamide PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT and bone scan throughout the study. Patients may also undergo a tissue biopsy on study.

Enzalutamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in European Union as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in Canada as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in Japan as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Who Is Running the Clinical Trial?

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

Incyte Corporation

Industry 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

Enzalutamide (XTANDI) is an FDA-approved treatment for castration-resistant prostate cancer (CRPC) that effectively targets androgen receptor signaling, which is crucial for cancer progression.

In a Phase III clinical trial involving men with CRPC after chemotherapy, enzalutamide was well tolerated and significantly improved overall survival by 4.8 months, as indicated by reduced serum prostate-specific antigen (PSA) levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel anti-androgen with prolonged survival rate in CRPC patients. Dhingra, R., Sharma, T., Singh, S., et al.[2021]

In men with metastatic hormone-sensitive prostate cancer, enzalutamide, when combined with androgen-deprivation therapy, significantly prolonged radiographic progression-free survival compared to a placebo.

This finding highlights the efficacy of enzalutamide as an androgen-receptor inhibitor in improving outcomes for patients undergoing treatment for advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eyeing Enzalutamide for Hormone-Sensitive Prostate Cancer. [2020]

Enzalutamide significantly improved radiographic progression-free survival (rPFS) in men with chemotherapy-naïve metastatic castration-resistant prostate cancer across various disease subgroups, including nonvisceral and visceral disease, as well as low- and high-volume bone disease.

The treatment was well tolerated, showing clinically significant benefits in overall survival (OS) for most subgroups, although the results were less definitive for patients with visceral disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer. Evans, CP., Higano, CS., Keane, T., et al.[2022]

Enzalutamide is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC), approved for use both after chemotherapy and before chemotherapy, significantly improving patient survival.

The STRIVE Phase II clinical trial demonstrated that enzalutamide outperforms bicalutamide in patients with nonmetastatic and mCRPC who have not responded to androgen deprivation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of enzalutamide on the treatment of prostate cancer. Nadal, R., Bellmunt, J.[2021]

In a long-term study of 67 patients with hormone-naïve prostate cancer, enzalutamide monotherapy resulted in a 100% prostate-specific antigen (PSA) response rate at 97 weeks for those who remained on treatment, indicating its strong efficacy.

The treatment was well-tolerated with minimal negative effects on total-body bone mineral density, although common side effects included gynecomastia and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results. Tombal, B., Borre, M., Rathenborg, P., et al.[2021]

In a study involving 29 patients with multiple myeloma who had undergone extensive prior treatments, the combination of ruxolitinib and methylprednisolone showed a 31% overall response rate, indicating significant clinical activity in this heavily-treated population.

The treatment was well tolerated, with a median duration of response of 13.1 months and median progression-free survival of 3.4 months, suggesting that JAK inhibitors may be a promising option for patients with multiple myeloma, including those with high-risk cytogenetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma. Berenson, JR., Martinez, D., Safaie, T., et al.[2023]

A study analyzing 126,815 safety reports found that the JAK inhibitors ruxolitinib, tofacitinib, and baricitinib are associated with increased risks of infectious adverse events, particularly viral, fungal, and mycobacterial infections.

Tofacitinib specifically showed a significant association with gastrointestinal perforation events, while no significant increase in major cardiovascular events was observed, indicating a need for careful monitoring of these risks in patients using JAK inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database. Hoisnard, L., Lebrun-Vignes, B., Maury, S., et al.[2023]

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]

Janus kinase inhibitors (JAKi) are commonly used for treating immune-mediated inflammatory diseases like psoriatic arthritis, but recent studies have raised safety concerns, particularly in patients over 50 with cardiac risk factors.

This review summarizes the latest safety data for various JAKi, including tofacitinib and upadacitinib, and discusses findings from an oral surveillance study to provide context for these safety issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Janus Kinase Inhibitors: Safety in Patients With Psoriatic Arthritis. Nash, P.[2022]

Ruxolitinib, when combined with lenalidomide and methylprednisolone, shows potential to overcome resistance to lenalidomide in patients with relapsed/refractory multiple myeloma, achieving a clinical benefit rate of 49% and an overall response rate of 36% in a Phase I trial with 49 participants.

The trial demonstrated that ruxolitinib was safe, with no dose-limiting toxicities reported, although some patients experienced grade 3 or 4 adverse events, including anemia and decreased lymphocyte count, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of ruxolitinib, steroids and lenalidomide for relapsed/refractory multiple myeloma patients. Berenson, JR., Kim, C., Bujarski, S., et al.[2022]

Ruxolitinib is the first targeted therapy approved for treating high- or intermediate-risk myelofibrosis, specifically addressing symptoms like splenomegaly, which is an enlarged spleen.

The authors emphasize the need for pharmacobiological assessments and understanding the risk profile of ruxolitinib in myeloproliferative neoplasms (MPNs) to optimize its clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacobiological Approach for the Clinical Development of Ruxolitinib in Myeloproliferative Neoplasms. Eliaçık, E., Işık, A., Aksu, S., et al.[2021]

Ruxolitinib shows significant cytotoxic effects on multiple myeloma cells (ARH-77) with an IC50 value of 20.03 μM, indicating its potential as a targeted therapy for this type of cancer.

The drug effectively reduces the expression of key genes in the IL-6/JAK/STAT pathway, which is linked to poor prognosis in multiple myeloma, and induces autophagy in both cancerous and healthy cells, suggesting a mechanism of action that could be beneficial in treating this malignancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib Regulates the Autophagy Machinery in Multiple Myeloma Cells. Kusoglu, A., Bagca, BG., Ay, NPO., et al.[2021]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel anti-androgen with prolonged survival rate in CRPC patients. [2021]

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

Eyeing Enzalutamide for Hormone-Sensitive Prostate Cancer. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer. [2022]

4. England pubmed.ncbi.nlm.nih.gov

The evolving role of enzalutamide on the treatment of prostate cancer. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results. [2021]

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

Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma. [2023]

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

Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database. [2023]

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

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

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

Ruxolitinib synergizes with DMF to kill via BIM+BAD-induced mitochondrial dysfunction and via reduced SOD2/TRX expression and ROS. [2023]

10. Canada pubmed.ncbi.nlm.nih.gov

Janus Kinase Inhibitors: Safety in Patients With Psoriatic Arthritis. [2022]

11. England pubmed.ncbi.nlm.nih.gov

A phase 1 study of ruxolitinib, steroids and lenalidomide for relapsed/refractory multiple myeloma patients. [2022]

12. Turkey pubmed.ncbi.nlm.nih.gov

Pharmacobiological Approach for the Clinical Development of Ruxolitinib in Myeloproliferative Neoplasms. [2021]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Ruxolitinib Regulates the Autophagy Machinery in Multiple Myeloma Cells. [2021]