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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two drugs, tivozanib and enzalutamide, to determine if they can more effectively delay the progression of prostate cancer that has metastasized. Enzalutamide (Xtandi) is already approved for treating prostate cancer, while tivozanib (Fotivda) is under study for its ability to block the tumor's blood supply. The goal is to assess whether this combination is more effective and has acceptable side effects compared to enzalutamide alone. Men with metastatic prostate cancer unresponsive to hormone therapy may qualify if they have previously received certain types of chemotherapy. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research shows that enzalutamide is generally safe for treating prostate cancer, reducing the risk of disease progression or death by 81% compared to a placebo. This indicates a strong safety record.

Other studies have examined enzalutamide combined with tivozanib. This combination was generally well-tolerated, but the benefits for overall survival were not clear for everyone. Tivozanib is still under study to confirm its safety and effectiveness, as it works by stopping blood flow to tumors.

In this clinical trial, researchers aim to assess the safety of combining these two drugs and whether it causes more side effects than enzalutamide alone. Since tivozanib is still being researched, its safety profile is less understood compared to enzalutamide. This trial is crucial for identifying any potential side effects when these drugs are used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Tivozanib and Enzalutamide for prostate cancer because it targets the disease in a novel way. Most standard treatments focus on hormone pathways or chemotherapy, but Tivozanib is a VEGF receptor tyrosine kinase inhibitor, which means it helps cut off the blood supply tumors need to grow, potentially enhancing the effects of Enzalutamide, an androgen receptor inhibitor. This dual action could make the treatment more effective than using Enzalutamide alone, offering a new hope for better outcomes in prostate cancer therapy.

What evidence suggests that the combination of tivozanib and enzalutamide could be an effective treatment for prostate cancer?

Research has shown that enzalutamide, which participants in this trial will receive, effectively treats advanced prostate cancer. It can delay cancer progression by about 8 months on average and significantly improves survival rates compared to other treatments.

Tivozanib, also part of the treatment in this trial, is an experimental drug that cuts off the blood supply to tumors. Although not yet approved for prostate cancer, it has shown promise in shrinking tumors in other cancers, such as kidney cancer. The trial aims to enhance treatment effectiveness by combining tivozanib with enzalutamide, attacking the cancer in two ways: blocking hormone action and starving the tumor. ^{6 7 8 9 10}

Who Is on the Research Team?

Dror Michaelson, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 (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 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]

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]

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 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]

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 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]

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]

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]

Citations

1. pfizer.com pfizer.com/news/press-release/press-release-detail/astellas-and-pfizers-xtanditm-enzalutamide-shows-long-term

Astellas and Pfizer's XTANDI™ (enzalutamide) Shows ... OS at 96 months was 50% with XTANDI and 40% for NSAA; progression-free survival (PFS) also favored XTANDI over NSAA (HR: 0.49; 95% CI, 0.42-0.57) ...

2. targetedonc.com targetedonc.com/shorts/a-13-year-old-drug-s-persisting-power-in-prostate-cancer

A 13-Year-Old Drug's Persisting Power in Prostate Cancer Two-year OS rates were 80% vs 63%. The treatment also yielded a record 57.1% pathological pCR. ... Clinical Trial Achieves 60% Reduction in the Risk of Tumor ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2510310?query=featured_home

Improved Survival with Enzalutamide in Biochemically ... In this trial, enzalutamide plus leuprolide led to significantly longer overall survival than leuprolide alone among patients with castration- ...

4. xtandihcp.com xtandihcp.com/cspc/efficacy

Efficacy CSPC | HCP Site | XTANDI® (enzalutamide) XTANDI (single agent) significantly improved metastasis-free survival vs placebo + GnRH therapy* · Number of events: 63 (17.7%) with XTANDI (single agent) vs 92 ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40660075/

The efficacy and safety of enzalutamide in metastatic ... Results: The data of 2275 patients were analyzed eventually. Enzalutamide reduced the risk of death by 33% compared to the control. Specifically ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01885949?tab=table

Tivozanib + Enzalutamide in Adv Prostate Cancer 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- ...

7. withpower.com withpower.com/trial/phase-3-prostatic-neoplasms-5-2013-e1fe0

Tivozanib + Enzalutamide for Prostate Cancer The treatment was well tolerated, showing clinically significant benefits in overall survival (OS) for most subgroups, although the results were less definitive ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4492664/

Enzalutamide for the treatment of metastatic castration ... Enzalutamide resulted in an 81% reduction in the risk of radiographic progression or death as compared with placebo (HR 0.19, P<0.001) with a median rPFS not ...

9. pfizer.com pfizer.com/news/press-release/press-release-detail/xtandir-plus-leuprolide-reduced-risk-death-40-vs-leuprolide

XTANDI® Plus Leuprolide Reduced Risk of Death by 40% ... The probability of survival at 8 years was an unprecedented 78.9% with XTANDI plus leuprolide versus 69.5% with leuprolide, in men with ...

10. valueinhealthjournal.com valueinhealthjournal.com/article/S1098-3015(18)30392-9/pdf

Efficacy and Safety of Enzalutamide in Metastatic Prostate ... The objective of this review is to evaluate the efficacy and safety of enzalutamide. (ENZ) versus placebo in metastatic prostate cancer (mPCa) patients. METHODS ...