DFMO + Testosterone + Enzalutamide for Prostate Cancer

Overseen By Kathy Schultz, RN

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: Anticoagulants

Disqualifiers: Opioid use, Uncontrolled infection, Seizure history, 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

Duration: 17 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for prostate cancer that has spread and does not respond to standard hormone therapy. Researchers aim to determine if using DFMO (Difluoromethylornithine), testosterone, and enzalutamide in sequence can improve health outcomes for patients without prostate cancer pain. The trial seeks men whose prostate cancer has progressed despite previous treatments like abiraterone and who are not experiencing cancer-related pain. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important advancements in prostate cancer care.

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.

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

Research shows that each treatment being tested has some safety data in humans. Here's a simpler breakdown:

For difluoromethylornithine (DFMO), studies have examined its safety and tolerability. One study combined DFMO with another drug and found it generally well-tolerated, though specific safety data for DFMO alone isn't highlighted.

Regarding testosterone, many studies on testosterone replacement therapy, even in men with prostate issues, have not shown a significant increase in prostate cancer risk or progression. This suggests testosterone is relatively safe to use.

Enzalutamide, a drug used for prostate cancer, has undergone extensive study. Research has shown it can be safe and effective, though there might be some risk of heart-related issues. Overall, it has a good safety profile for many patients.

In short, each treatment in this study has some evidence of being safe in humans, though the combination in this trial is still being studied. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this prostate cancer treatment because it combines DFMO, testosterone, and enzalutamide in a unique way. Unlike standard treatments that typically focus on hormone deprivation, this approach uses high-dose testosterone therapy to potentially disrupt cancer growth, alongside enzalutamide, which blocks testosterone's effects. DFMO is an added twist, targeting a different biochemical pathway to inhibit cancer cell growth. This combination aims to attack the cancer from multiple angles, offering hope for more effective management of prostate cancer.

What evidence suggests that this trial's treatments could be effective for prostate cancer?

In this trial, participants will receive a combination of treatments to address prostate cancer from different angles. Research has shown that enzalutamide can slow the progression of metastatic castration-resistant prostate cancer (mCRPC). Studies indicate that difluoromethylornithine (DFMO) reduces prostate growth by lowering certain chemicals in the body. Additionally, high-dose testosterone may disrupt cancer cells that have adapted to low testosterone levels. This combination of treatments aims to enhance effectiveness. ^{1 2 6 7 8}

Who Is on the Research Team?

Laura Sena, MD, PhD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Difluoromethylornithine (DFMO)
• Enzalutamide
• Testosterone

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.

How Is the Trial Designed?

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).

Difluoromethylornithine (DFMO) is already approved in United States for the following indications:

Approved in United States as IWILFIN for:

• High-risk neuroblastoma

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

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+

Published Research Related to This Trial

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]

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 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]

In a study involving 39 patients with localized prostate cancer, neoadjuvant treatment with degarelix alone resulted in significantly higher levels of intratumoral dihydrotestosterone (DHT) compared to combinations of degarelix with bicalutamide or LHRH agonist with bicalutamide, suggesting a unique mechanism of action for degarelix.

Patients receiving degarelix had lower serum follicle-stimulating hormone (FSH) levels after 12 weeks compared to those on LHRH agonist, indicating potential advantages in hormonal regulation during treatment.

NCBI (Pubmed)

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. Sayyid, RK., Evans, A., Hersey, K., et al.[2017]

Enzalutamide, a novel anti-androgen for prostate cancer, initially shows improved clinical activity, but resistance develops over time due to various molecular mechanisms, including alterations in androgen receptors and overexpression of oncogenes.

Specific mutations, such as the AR F876L variant, and glucocorticoid receptor overexpression have been linked to enzalutamide resistance, highlighting the complexity of treatment challenges in advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

Abiraterone acetate, an irreversible CYP17 inhibitor, significantly improves overall survival in men with docetaxel-refractory castration-resistant prostate cancer (CRPC), extending median survival by 3.9 months compared to placebo.

The FDA approved abiraterone for CRPC treatment in 2011, and its indication was later expanded to all CRPC cases, highlighting the importance of targeting androgen synthesis and the androgen receptor axis in prostate cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

In a study of 80 patients with metastatic castration-resistant prostate cancer, a shorter time to castration resistance during primary androgen deprivation therapy (ADT) was linked to poorer progression-free survival (PFS) and overall survival after starting treatment with abiraterone or enzalutamide.

Despite the association, the time to castration resistance was not an independent predictor of survival or prostate-specific antigen (PSA) response when analyzed with other factors, suggesting that while it may indicate initial treatment outcomes, it does not determine the effectiveness of subsequent AR-targeting therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Time to Castration Resistance on Outcomes With Abiraterone and Enzalutamide in Metastatic Prostate Cancer. Hung, J., Taylor, AR., Divine, GW., 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]

In a phase 3 trial involving 1125 men with metastatic, hormone-sensitive prostate cancer, adding enzalutamide to testosterone suppression significantly improved overall survival, with a 3-year survival rate of 80% compared to 72% in the standard-care group.

While enzalutamide showed better progression-free survival and overall survival, it was associated with a higher incidence of adverse effects, including fatigue and seizures, particularly in patients also receiving early docetaxel.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. Davis, ID., Martin, AJ., Stockler, MR., et al.[2021]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06059118

NCT06059118 | Difluoromethylornithine and High Dose ... Difluoromethylornithine and High Dose Testosterone With Enzalutamide in Metastatic Castration-Resistant Prostate Cancer ... outcomes. Detailed Description.

2. withpower.com withpower.com/trial/phase-2-prostatic-neoplasms-8-2023-f9c48

DFMO + Testosterone + Enzalutamide for Prostate Cancer What data supports the effectiveness of the drug combination DFMO + Testosterone + Enzalutamide for prostate cancer? Enzalutamide has been shown to improve ...

3. urotoday.com urotoday.com/library-resources/mcrpc-treatment/154413-bipolar-androgen-therapy-rationale-candidate-patients-and-latest-evidence-for-mcrpc-patients.html

Bipolar Androgen Therapy: Rationale, Candidate Patients ... Prostate cancer cells adapt to chronic low testosterone conditions by upregulating androgen receptor activity through overexpression, gene amplification ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06059118?intr=DEPO-TESTOSTERONE&aggFilters=studyType:int&viewType=Table&rank=8

NCT06059118 | Difluoromethylornithine and High Dose ... A phase of research used to describe exploratory trials conducted before traditional phase 1 trials to investigate how or whether a drug affects the body. They ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2515594/

The Effect of Difluoromethylornithine on Decreasing ... In this randomized placebo-controlled trial, DFMO induced a decrease of prostate putrescine levels and rate of prostate growth.

6. esmoopen.com esmoopen.com/article/S2059-7029(25)01445-0/fulltext

Phase I dose-escalation trial of AMXT 1501 dicaprate plus ... The primary objective of this study was to determine the safety and tolerability of oral AMXT 1501 in combination with DFMO in patients with ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2059702925014450

Phase I dose-escalation trial of AMXT 1501 dicaprate plus ... AMXT 1501 plus DFMO produced an almost complete blockade of tumor growth, with a durable effect after treatment ceased. Evidence from this model suggested that ...

8. academic.oup.com academic.oup.com/jnci/article/93/1/57/2906107

α-Difluoromethylornithine and Polyamine Levels in the Human ... Also, investigators (7–10) have demonstrated marked polyamine suppression by DFMO in rodent prostates and prostate cell lines. Mohan et al. (2) measured ODC ...