Tivozanib + Enzalutamide for Prostate Cancer

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must be taking: Androgen deprivation therapy

Must not be taking: Enzalutamide, TOK-001, ARN-509

Disqualifiers: Brain metastases, Seizure history, Cardiovascular disease, Active infection, Second primary malignancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

Duration: 2 years

5 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational combination of drugs to learn whether they work in treating a specific cancer. "Investigational" means that the combination of drugs is still being studied and that research doctors are trying to find out more about it, such as the safest dose to use and the side effects they may cause. It also means that the FDA has not yet approved the combination. The two drugs being tested in this study are tivozanib and enzalutamide. Enzalutamide has been approved by the FDA for treatment of prostate cancer. On the other hand, tivozanib is still investigational, and has not been tested in a combination with enzalutamide before. Enzalutamide is an androgen receptor antagonist (it blocks the activity of the male sex hormones). Prostate cancers are initially dependent on the male hormone testosterone for growth. Hormonal therapies that lower testosterone or block the ability of testosterone to act at the level of the prostate cancer are currently among the most effective treatments for prostate cancers taht have spread to other body organs (metastasized). The effectiveness of hormonal treatments, however, is not permanent, and over time many prostate cancers progress in spite of these treatments. Enzalutamide is a drug that has been proven to help delay the progression of advanced prostate cancer on average for about 8 months. Tivozanib is an anti-angiogenesis medicine that fights different types of cancer by blocking the blood supply to the tumor, so that the tumor does not receive the nutrients it needs to grow. The main goal of this study is to determine whether the combination of tivozanib and enzalutamide is more effective in delaying the progression of disease than when enzalutamide is given alone. This study will also determine whether treatment with the combination of the tivozanib and enzalutamide will have more side effects then treatment with enzalutamide alone.

Will I have to stop taking my current medications?

The trial requires that you stop taking other hormonal agents like antiandrogens or ketoconazole at least two weeks before joining. If you've had chemotherapy, it must be stopped at least three weeks before starting the trial. The protocol does not specify other medications, so it's best to discuss with the trial team.

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

Research shows that Enzalutamide, a drug that blocks certain signals in cancer cells, significantly improves survival and delays disease progression in men with different types of prostate cancer, including those who haven't had chemotherapy yet. ^{1 2 3 4 5}

Is the combination of Tivozanib and Enzalutamide safe for humans?

Enzalutamide has been associated with some side effects, including severe thrombocytopenia (a condition where you have a low blood platelet count) and seizures in some patients with prostate cancer. It is important to discuss potential risks with your healthcare provider. ^{6 7 8 9 10}

How is the drug combination of Tivozanib and Enzalutamide unique for prostate cancer treatment?

The combination of Tivozanib and Enzalutamide is unique because it pairs an androgen receptor inhibitor (Enzalutamide) with a VEGF receptor inhibitor (Tivozanib), potentially offering a novel approach by targeting both hormone signaling and blood vessel growth in prostate cancer, which is different from standard treatments that typically focus on one pathway. ^{2 5 6 11 12}

Research Team

Dror Michaelson, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Men with metastatic prostate cancer that's resistant to hormone therapy and have had docetaxel-based chemotherapy in the past year can join. They must be able to swallow capsules, not have a major illness or surgery recently, no active infections or second cancers (except certain skin/breast cancers), and agree to use contraception.

Inclusion Criteria

Life expectancy of at least 12 weeks

Must agree to use adequate contraception prior to study entry and for the duration of study participation

My prostate cancer has spread, as shown on scans.

Exclusion Criteria

Receiving any other investigational anticancer agents

I have previously been treated with enzalutamide, TOK-001, or ARN-509.

I have had more than two chemotherapy treatments for advanced prostate cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tivozanib daily for 21 days followed by a 7-day break, and enzalutamide daily for 28 days in 4-week cycles

2 years

Clinic visits at the beginning of each 4-week cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a final study visit 4 weeks after stopping the study drug

4 weeks

1 final visit (in-person)

Treatment Details

Interventions

• Enzalutamide
• Tivozanib

Trial Overview The trial is testing if combining tivozanib (a drug that cuts off blood supply to tumors) with enzalutamide (an FDA-approved drug for prostate cancer) is more effective than enzalutamide alone in slowing down cancer progression.

Participant Groups

Group I: Experimental Treatment Arm Experimental Treatment 2 Interventions

Tivozanib, taken daily for 21 days followed by a 7 day break Enzalutamide taken daily for 28 days

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?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

National Comprehensive Cancer Network

Collaborator

Trials

121

Recruited

7,400+

Findings from Research

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]

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]

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]

The ENZAMET phase III trial demonstrated that adding enzalutamide to standard treatment significantly prolongs survival in men with metastatic hormone-sensitive prostate cancer.

Enzalutamide is more effective than older nonsteroidal antiandrogen drugs, highlighting its potential as a superior treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide Bests Older NSAAs in mHSPC. [2021]

In the PREVAIL trial, enzalutamide significantly improved both radiographic progression-free survival and overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (CRPC), demonstrating its efficacy as a treatment option.

Enzalutamide was well tolerated and delayed the need for chemotherapy and decline in health-related quality of life, making it a convenient choice for patients who are asymptomatic or mildly symptomatic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide: a review of its use in chemotherapy-naïve metastatic castration-resistant prostate cancer. Keating, GM.[2021]

Enzalutamide is an effective androgen receptor inhibitor that improves overall survival in patients with metastatic castration-resistant prostate cancer, showing a 4.8-month survival benefit in those previously treated with docetaxel, as demonstrated in the Phase III AFFIRM trial.

The FDA has expanded enzalutamide's approval to include first-line treatment for metastatic castration-resistant prostate cancer in patients who have not yet received chemotherapy, and it is associated with an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide for patients with metastatic castration-resistant prostate cancer. Ramadan, WH., Kabbara, WK., Al Basiouni Al Masri, HS.[2020]

A 76-year-old man developed severe thrombocytopenia after 13 days of enzalutamide treatment for castration-resistant prostate cancer, indicating that this side effect can occur early in therapy.

After discontinuing enzalutamide, the patient's platelet count recovered, and he was able to restart the medication without recurrence of thrombocytopenia; however, he later experienced a seizure, suggesting that enzalutamide may also be associated with neurological adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide-induced severe thrombocytopenia complicated by a seizure in a 76-year-old man with castration-resistant prostate cancer. Murata, M., Takizawa, I., Maruyama, R., et al.[2022]

In a study of 137 chemo-naïve patients with metastatic castration-resistant prostate cancer, Enzalutamide (EZ) showed a significantly higher PSA response rate compared to Abiraterone (AA) in the first line of treatment (95.9% vs 67%).

Both AA and EZ had comparable toxicity rates and progression-free survival (PFS) outcomes, indicating that both treatments are effective and well-tolerated options for managing mCRPC without chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing lines of therapy in castration-resistant prostate cancer: real-life snapshot from a multicenter cohort. Ferriero, M., Mastroianni, R., De Nunzio, C., et al.[2021]

In a study involving 249 men with metastatic castrate-resistant prostate cancer, patient preference between darolutamide and enzalutamide was balanced, with no significant preference for either treatment (p = 0.92).

Darolutamide was associated with less fatigue and a moderate improvement in episodic memory compared to enzalutamide, suggesting it may offer a better quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA. Colomba, E., Jonas, SF., Eymard, JC., et al.[2023]

In a phase III trial involving 1,150 men with metastatic hormone-sensitive prostate cancer, enzalutamide combined with androgen deprivation therapy significantly reduced the risk of radiographic progression or death compared to placebo, with a hazard ratio of 0.39, indicating a strong efficacy.

The safety profile of enzalutamide was consistent with previous studies, showing similar rates of grade 3 or greater adverse events between the enzalutamide and placebo groups (24.3% vs. 25.6%), suggesting it is a safe treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. Armstrong, AJ., Szmulewitz, RZ., Petrylak, DP., et al.[2021]

Combining atezolizumab, an anti-PD-L1 immunotherapy, with enzalutamide, an androgen receptor antagonist, did not improve survival rates in patients with metastatic prostate cancer.

Further research is needed to understand the mechanisms of resistance to immunotherapy in the prostate tumor microenvironment, which may help improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. Siddiqui, BA., Subudhi, SK., Sharma, P.[2023]

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]

References

1. 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]

2. 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]

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

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

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

Enzalutamide Bests Older NSAAs in mHSPC. [2021]

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

Enzalutamide: a review of its use in chemotherapy-naïve metastatic castration-resistant prostate cancer. [2021]

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

Enzalutamide for patients with metastatic castration-resistant prostate cancer. [2020]

7. Australia pubmed.ncbi.nlm.nih.gov

Enzalutamide-induced severe thrombocytopenia complicated by a seizure in a 76-year-old man with castration-resistant prostate cancer. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Managing lines of therapy in castration-resistant prostate cancer: real-life snapshot from a multicenter cohort. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA. [2023]

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

ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. [2021]

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

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. [2023]

12. Netherlands pubmed.ncbi.nlm.nih.gov

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