DFMO + Testosterone + Enzalutamide for Prostate Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Laura Sena, MD, PhD

Age: 18+

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must be taking: Androgen ablative therapy

Must not be taking: Anticoagulants

Disqualifiers: Opioid use, Uncontrolled infection, Seizure history, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial involves treating patients with advanced prostate cancer that hasn't responded to other treatments. The treatment plan includes taking DFMO, followed by a combination of DFMO and testosterone, and then switching to another medication. These drugs work together to stop cancer cells from growing by blocking important processes they need to survive.

Will I have to stop taking my current medications?

The trial requires that you stop taking abiraterone for at least 2 weeks before starting. If you're on prednisone, attempts should be made to reduce the dose, but you can continue on the lowest dose if needed. If you're on anticoagulation therapy with warfarin, rivaroxaban, or apixaban, you'll need to switch to enoxaparin before starting the trial.

What data supports the effectiveness of the drug combination DFMO + Testosterone + Enzalutamide for prostate cancer?

Enzalutamide has been shown to improve survival in patients with castration-resistant prostate cancer, as it effectively blocks signals that help cancer grow. Additionally, testosterone levels can influence the effectiveness of enzalutamide, suggesting that managing testosterone may enhance treatment outcomes. ^{1 2 3 4 5}

Is the combination of DFMO, Testosterone, and Enzalutamide safe for humans?

Enzalutamide, used for prostate cancer, has been associated with some side effects like severe low platelet count (thrombocytopenia) and skin reactions. These side effects highlight the importance of monitoring during treatment. ^{6 7 8 9 10}

What makes the DFMO + Testosterone + Enzalutamide drug unique for prostate cancer?

This treatment combines enzalutamide, a drug that blocks the effects of male hormones in prostate cancer, with testosterone and DFMO, which may help overcome resistance to enzalutamide and improve its effectiveness. This combination is unique because it targets multiple pathways involved in prostate cancer growth, potentially offering a new approach for patients who have developed resistance to standard treatments. ^{1 2 11 12 13}

Research Team

Laura Sena, MD, PhD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

Men over 18 with advanced prostate cancer that's resistant to castration and has spread, who have low testosterone levels and disease progression despite previous treatments. They must not be on certain blood thinners or have had major surgery recently, among other criteria.

Inclusion Criteria

I have tried to stop taking prednisone or am on the lowest dose I can manage.

My liver is working well.

My blood counts are within a healthy range.

Exclusion Criteria

Patients with indwelling Foley or suprapubic catheter for obstructive symptoms are eligible.

Patients allergic to sesame seed oil or cottonseed oil are excluded.

You have a serious hearing problem that affects your daily life and requires a hearing aid.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sequential treatment with DFMO, high dose testosterone, and enzalutamide over a 119-day cycle

17 weeks

Multiple visits for administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

13 months

Long-term follow-up

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

3 years after end of treatment

Treatment Details

Interventions

• Difluoromethylornithine (DFMO) (Other)
• Enzalutamide (Hormone Therapy)
• Testosterone (Hormone Therapy)

Trial Overview The trial tests a combination of DFMO (a drug) and high dose testosterone followed by enzalutamide (another drug) in men with metastatic castrate-resistant prostate cancer. It aims to see if this sequence improves outcomes compared to current treatments.

Participant Groups

Group I: Repeat Sequential DFMO and High dose Testosterone in Sequence with Enzalutamide Experimental Treatment 4 Interventions

Eligible patients will receive 7 days of DFMO (1000 mg PO bid) (days 1-7 of cycle), followed by 56 days of combined testosterone (testosterone cypionate 400 mg IM on day 8 and day 36) and DFMO (1000 mg PO bid) (days 8-63 of cycle), followed by 56 days of enzalutamide (160 mg PO daily) (days 64-119).

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Dr. William G. Nelson

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Director since 1992

MD, PhD

Dr. Elizabeth Jaffee

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Chief Medical Officer since 2023

MD

Panbela Therapeutics

Industry Sponsor

Trials

1

Recruited

50+

Prostate Cancer Foundation

Collaborator

Trials

52

Recruited

3,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Pete Hegseth

United States Department of Defense

Chief Executive Officer

Bachelor's degree in Political Science from Princeton University, JD from Harvard Law School

Lisa Hershman

United States Department of Defense

Chief Medical Officer since 2021

MD from Uniformed Services University of the Health Sciences

Findings from Research

In a phase III study involving men with progressive castration-resistant prostate cancer, enzalutamide significantly improved overall survival compared to placebo, with a median survival of 18.4 months versus 13.6 months.

Enzalutamide also showed benefits across all secondary endpoints, including a higher rate of prostate-specific antigen (PSA) decline and improved quality of life, although it was associated with common side effects like fatigue and diarrhea, and a rare incidence of seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel antiandrogen for patients with castrate-resistant prostate cancer. Hoffman-Censits, J., Kelly, WK.[2021]

Enzalutamide effectively inhibits androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) by blocking multiple steps, including androgen binding and nuclear translocation, without exhibiting AR agonistic activity, which is a significant advantage over bicalutamide.

In preclinical models, enzalutamide not only reduced tumor volume in CRPC xenografts but also induced apoptosis in prostate cancer cells, suggesting its potential as a powerful treatment option for patients with advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer. Guerrero, J., Alfaro, IE., Gómez, F., 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]

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 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]

Enzalutamide, a treatment for metastatic castration-resistant prostate cancer, was linked to a case of acute generalized exanthematous pustulosis (AGEP) in a 62-year-old male patient, indicating a potential skin-related side effect of this medication.

The patient's skin reaction occurred shortly after starting enzalutamide and resolved within four weeks, suggesting that the long half-life of enzalutamide (5.8 days) may contribute to the prolonged duration of symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide induced acute generalized exanthematous pustulosis. Alberto, C., Konstantinou, MP., Martinage, C., et al.[2020]

References

1. 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]

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

Clinical appraisal of abiraterone in the treatment of metastatic prostatic cancer: patient considerations, novel opportunities, and future directions. [2021]

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

A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy. [2017]

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

Enzalutamide: a novel antiandrogen for patients with castrate-resistant prostate cancer. [2021]

5. 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]

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

Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

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

8. 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]

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

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

10. Poland pubmed.ncbi.nlm.nih.gov

Enzalutamide induced acute generalized exanthematous pustulosis. [2020]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Molecular Mechanisms of Enzalutamide Resistance in Prostate Cancer. [2022]

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

The Effect of Time to Castration Resistance on Outcomes With Abiraterone and Enzalutamide in Metastatic Prostate Cancer. [2021]

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

Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. [2021]