Testosterone + ZEN-3694 + Enzalutamide for Prostate Cancer

Overseen By Sin Chan, MS

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must be taking: Androgen ablative therapy

Must not be taking: Opioid pain medications, Anticoagulants

Disqualifiers: Seizure history, Uncontrolled infection, 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: Unknown

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This research is being done to determine if receiving the combination of testosterone and ZEN-3694 followed by the combination of enzalutamide plus ZEN-3694 will decrease the size of tumors in patients with prostate cancer that has become resistant to castration and other therapies. The investigators also want to determine if dosing first with the combination of testosterone and ZEN-3694 may cause enzalutamide and ZEN-3694 to work more effectively.

Will I have to stop taking my current medications?

Participants must stop taking second-generation AR-axis inhibitors like Abiraterone, Enzalutamide, Darolutamide, or Apalutamide for at least 2 weeks before starting the trial. Attempts should also be made to reduce or stop prednisone, but if symptoms persist, the lowest possible dose can be continued.

What data supports the effectiveness of the drug combination of Testosterone, ZEN-3694, and Enzalutamide for prostate cancer?

Research shows that Enzalutamide, when used with other treatments, can significantly improve survival in men with different types of prostate cancer, including those resistant to standard hormone therapy. This suggests that combining Enzalutamide with other drugs like Testosterone and ZEN-3694 might also be effective. ^{1 2 3 4 5}

Is the combination of Testosterone, ZEN-3694, and Enzalutamide safe for humans?

Enzalutamide, used for prostate cancer, can cause side effects like severe low platelet count (thrombocytopenia) and seizures, especially in older patients. Some studies suggest that reducing the dose might help limit these side effects, but this could also reduce its effectiveness. ^{1 6 7 8 9}

What makes the combination of Testosterone, ZEN-3694, and Enzalutamide unique for prostate cancer treatment?

This treatment is unique because it combines Enzalutamide, a drug that targets the androgen receptor to treat prostate cancer, with Testosterone and ZEN-3694, potentially offering a novel approach by using multiple mechanisms to combat the disease. This combination could provide benefits over standard treatments by addressing different pathways involved in prostate cancer progression. ^{1 2 3 4 10}

Research Team

Samuel Denmeade, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

This trial is for men with prostate cancer that's resistant to castration and other treatments. Participants should have a certain level of PSA in their blood, be healthy enough for the study drugs, and not have brain metastases or uncontrolled illnesses.

Inclusion Criteria

Documented castrate level of serum testosterone (<50 ng/dl)

Screening PSA ≥ 1.0 ng/mL

I stopped taking second-gen AR inhibitors over 2 weeks ago.

Exclusion Criteria

Allergy to sesame seed oil or cottonseed oil

I need help with my daily activities due to my health condition.

I had major surgery less than 3 weeks ago or haven't fully recovered yet.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - BATZEN

Participants receive ZEN-3694 and high dose testosterone in 28-day cycles until disease progression

Variable, based on disease progression

Monthly visits for testosterone injections and monitoring

Treatment - ZENZA

Participants receive ZEN-3694 and Enzalutamide daily after progression on BATZEN

Variable, based on disease progression

Regular visits for monitoring and medication adjustment

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Enzalutamide
• Testosterone cypionate
• ZEN-3694

Trial Overview The COSMYC Trial is testing if combining testosterone (cypionate) with ZEN-3694 can shrink tumors when followed by enzalutamide plus ZEN-3694 in castration-resistant prostate cancer. It also examines if pre-dosing with testosterone enhances the effectiveness.

Participant Groups

Group I: ZENZA Experimental Treatment 3 Interventions

ZENZA cycles will begin once there is disease progression on bone and CT scans.ZEN-3694 dose will increase to 72 mg (one 48 mg and two 12 mg tablets) to be taken daily by mouth. Enzalutamide 160 mg (four 40 mg capsules) will be taken daily by mouth.

Group II: BATZEN Experimental Treatment 3 Interventions

ZEN-3694 48 mg (one 48 mg tablet) will be taken once per day by mouth each cycle (each cycle is 28 days). On the first day of each cycle, testosterone cypionate (400 mg) injection will be administered into the buttocks. The participant will continue with additional 28-day cycles of ZEN-3694 pills and testosterone injections until there is disease progression on bone and CT scans.

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Zenith Epigenetics

Industry Sponsor

Trials

10

Recruited

590+

Findings from Research

In a study of 95 patients with castration-resistant prostate cancer (CRPC), higher serum testosterone levels before starting enzalutamide treatment were associated with better quality of life (QoL) scores during treatment, as measured by the FACT-P questionnaire.

Patients with low testosterone levels experienced a significant decline in QoL after 12 weeks of enzalutamide treatment, suggesting that baseline testosterone levels could be a predictive marker for QoL changes in CRPC patients undergoing this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective study of the relationship between CRPC patient's quality of life after enzalutamide and serum testosterone levels measured via LC-MS/MS. Miyazawa, Y., Nakamura, T., Takezawa, Y., et al.[2023]

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]

Enzalutamide significantly improves overall survival in men with metastatic, castration-resistant prostate cancer (mCRPC), showing a 37% reduced risk of death compared to placebo, with median survival times of 18.4 months versus 13.6 months.

The results from the phase III AFFIRM trial support the continued targeting of the androgen receptor as an effective treatment strategy for prostate cancer, even after patients have developed resistance to castration therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide (formerly MDV3100) as a new therapeutic option for men with metastatic castration-resistant prostate cancer. Aragon-Ching, JB.[2021]

Enzalutamide combined with androgen deprivation therapy (ADT) significantly reduces the risk of death in men with non-metastatic castration-resistant prostate cancer (nmCRPC), regardless of age or region, based on a study involving 1401 participants with a median age of 74 years.

The safety profile of enzalutamide was consistent across different age groups and regions, with treatment-emergent adverse events being more common in the placebo group, indicating that enzalutamide is a safe option for older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consistent survival benefit of enzalutamide plus androgen deprivation therapy in men with nonmetastatic castration-resistant prostate cancer: PROSPER subgroup analysis by age and region. De Giorgi, U., Hussain, M., Shore, N., et al.[2022]

In a study of 72 patients with metastatic castration-resistant prostate cancer (mCRPC), low serum testosterone levels during and before enzalutamide treatment were linked to significantly shorter progression-free survival (PFS) and failure-free survival (FFS), indicating that testosterone levels could serve as a predictive biomarker for treatment outcomes.

Patients with low testosterone levels (<0.217 nmol/L) during treatment had a median PFS of only 7.4 months compared to 20.8 months for those with higher levels, suggesting that monitoring testosterone could help identify patients at risk of treatment failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictive value of low testosterone concentrations during and prior to enzalutamide treatment in metastatic castration-resistant prostate cancer. van Winden, LJ., Lanfermeijer, M., Dezentje, V., et al.[2023]

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]

Enzalutamide demonstrated significant efficacy in managing non-metastatic castration-resistant prostate cancer, with a median prostate-specific antigen-progression-free survival of 35.0 months in a study of 66 Japanese patients.

The treatment showed a high prostate-specific antigen response rate of 88.9%, with most patients experiencing manageable adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide in patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical treatment in Japan (Japanese research for patients with non-metastatic castration-resistant prostate cancer-enzalutamide: JCASTRE-zero)-a prospective single-arm interventional study. Sugimoto, M., Kato, T., Tohi, Y., et al.[2022]

In a study of 14 Japanese patients with castration-resistant prostate cancer (CRPC), enzalutamide (ENZ) demonstrated a high efficacy, with 92% of patients achieving a significant reduction in prostate-specific antigen (PSA) levels of 50% or more from baseline.

The safety profile of ENZ was favorable, with only mild adverse events occurring in more than 20% of patients, indicating that even reduced doses of ENZ (80 or 120 mg/day) are effective and safe for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Enzalutamide in a Real-World Cohort of Japanese Patients With Castration-resistant Prostate Cancer. Hori, A., Sahashi, H., Sano, S., et al.[2021]

Enzalutamide (Enz) was evaluated in a retrospective study of 47 men with heavily pretreated metastasized castration-resistant prostate cancer (mCRPC), showing a 23% response rate with significant PSA declines, indicating its potential efficacy even in later treatment lines.

The treatment was generally well tolerated, with common side effects like fatigue and nausea, and resulted in a median overall survival of 40.1 weeks and a median progression-free survival of 12.1 weeks, suggesting it can be a viable option for patients who have exhausted other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide as a Fourth- or Fifth-Line Treatment Option for Metastatic Castration-Resistant Prostate Cancer. Badrising, SK., van der Noort, V., Hamberg, P., et al.[2021]

References

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

A prospective study of the relationship between CRPC patient's quality of life after enzalutamide and serum testosterone levels measured via LC-MS/MS. [2023]

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

Enzalutamide Bests Older NSAAs in mHSPC. [2021]

3. China pubmed.ncbi.nlm.nih.gov

Enzalutamide (formerly MDV3100) as a new therapeutic option for men with metastatic castration-resistant prostate cancer. [2021]

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

Consistent survival benefit of enzalutamide plus androgen deprivation therapy in men with nonmetastatic castration-resistant prostate cancer: PROSPER subgroup analysis by age and region. [2022]

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

Predictive value of low testosterone concentrations during and prior to enzalutamide treatment in metastatic castration-resistant prostate cancer. [2023]

6. 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]

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

Enzalutamide in patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical treatment in Japan (Japanese research for patients with non-metastatic castration-resistant prostate cancer-enzalutamide: JCASTRE-zero)-a prospective single-arm interventional study. [2022]

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

Low-Dose Enzalutamide in Late-Elderly Patients (≥ 75 Years Old) Presenting With Metastatic Castration-Resistant Prostate Cancer. [2021]

9. Greece pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Enzalutamide in a Real-World Cohort of Japanese Patients With Castration-resistant Prostate Cancer. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Enzalutamide as a Fourth- or Fifth-Line Treatment Option for Metastatic Castration-Resistant Prostate Cancer. [2021]