FOR46 + Enzalutamide for Prostate Cancer

Overseen By UCSF Genitourinary Medical Oncology

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Rahul Aggarwal

Must be taking: LHRH analogue

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Radiotherapy, Small cell cancer, Cardiac, Seizure, others

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

Compensation: Varies

Number of Visits: 91

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with metastatic castration-resistant prostate cancer, a type of cancer that continues to grow even with low testosterone levels. The study tests the effectiveness of the experimental drug FOR46 in combination with enzalutamide, a medication already used for this condition, to determine if this combination can slow or shrink the cancer. Suitable candidates for this trial have previously tried treatments like abiraterone and must have a specific type of prostate cancer that has spread despite these efforts. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop all current medications. However, you cannot take certain medications like strong CYP3A4 inhibitors within 7 days of starting the trial. If you're already taking enzalutamide, you can continue without a wash-out period. It's best to discuss your specific medications with the trial team.

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

Research has shown that FOR46 was safe in earlier studies, with a manageable safety profile. Patients generally tolerated the treatment well, experiencing few serious side effects. In one study, FOR46 showed early signs of effectiveness, with 48% of patients experiencing tumor shrinkage.

Enzalutamide, already approved for treating prostate cancer, has been shown to help patients live longer. In a large study, it reduced the risk of death by 33% compared to those who did not take it, indicating its general safety for patients.

Overall, both FOR46 and enzalutamide have demonstrated promising safety in earlier studies, making them reasonable options for participants in this trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of FOR46 and enzalutamide for prostate cancer because it introduces a potentially groundbreaking mechanism of action. While enzalutamide is a well-established androgen receptor inhibitor, FOR46 is a novel antibody-drug conjugate that targets a specific protein on cancer cells, potentially offering a more precise strike against the cancer. This combination could enhance the effectiveness of enzalutamide by directly attacking the cancer cells, making it a promising option for patients who may not respond to existing treatments alone. Additionally, the use of prophylactic Pegfilgrastim aims to manage potential side effects, ensuring patients can maintain their treatment regimen. This innovative approach could offer new hope for individuals battling prostate cancer.

What evidence suggests that the combination of FOR46 and enzalutamide could be effective for metastatic castration resistant prostate cancer?

This trial will evaluate the combination of FOR46 with enzalutamide for treating advanced prostate cancer. Research has shown that this combination may help treat prostate cancer that no longer responds to hormone therapy. Specifically, one study reported that 48% of patients experienced tumor shrinkage. Participants in this trial will initially receive enzalutamide alone, followed by the addition of FOR46. Enzalutamide alone extended life by nearly 5 months in men with advanced prostate cancer after chemotherapy. Long-term results also favor enzalutamide, showing it helps patients live longer without the cancer worsening compared to other treatments. These findings suggest that adding FOR46 could enhance enzalutamide's effectiveness, offering hope for those with this type of prostate cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Rahul Aggarwal, MD

Principal Investigator

University of San Francisco

Are You a Good Fit for This Trial?

Men with metastatic castration-resistant prostate cancer who've progressed after abiraterone treatment. They must not have had other systemic anti-cancer therapies recently, no prior CD46-targeting treatments, and should be in good physical condition (ECOG <=1). Adequate organ function is required, and they can't have brain metastases or certain heart conditions. Participants need to agree to use contraception.

Inclusion Criteria

My PSA level is 2 ng/mL or higher, or my cancer can be measured using specific criteria.

My blood tests show my organs are functioning well.

I agree to have a PET scan for research during my screening.

Exclusion Criteria

My prostate cancer has shown signs of small cell neuroendocrine characteristics.

I have a serious heart condition or recent heart attack or stroke.

I haven't taken any strong medication that affects liver enzymes in the last week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in Treatment

Participants receive enzalutamide monotherapy for 14 days before starting FOR46

2 weeks

1 visit (in-person)

Treatment

Participants receive FOR46 in combination with enzalutamide, with dose escalation to determine MTD

Up to 2 years

Regular visits as per protocol

Follow-up

Participants are monitored for overall survival every 90 days after treatment ends

Up to 2 years

Every 90 days (+/- 30 days)

What Are the Treatments Tested in This Trial?

Interventions

• Enzalutamide
• FOR46

Trial Overview The trial tests FOR46 combined with enzalutamide against prostate cancer that resists standard hormone therapy. FOR46 targets a protein called CD46 on cancer cells. The study aims to see if this combination improves response rates and how long patients benefit from the treatment.

How Is the Trial Designed?

Group I: Dose Expansion Experimental Treatment 3 Interventions

Participants will receive a lead-in treatment period of enzalutamide monotherapy for 14 days (day -14 to day -1), followed by addition of FOR46 on Cycle 1 Day 1, at the maximum tolerated dose (MTD) as determined in Phase 1b. If participants are on enzalutamide at the time of study entry, and remain on continuous dosing at 160 mg daily, the lead-in treatment period will not be required. Prophylactic Pegfilgrastim (G-CSF) 6mg, subcutaneously (SQ) will also be administered on Day 2 during all treatment cycles. Pegfilgrastim could be modified to a lower dose of 3 mg with treating investigator approval.

Group II: Does Escalation Experimental Treatment 4 Interventions

Approximately 3 dose levels of FOR46 will be evaluated. Participants will receive a lead-in treatment period of enzalutamide monotherapy for 14 days (day -14 to day -1), followed by addition of FOR46 on Cycle 1 Day 1. If participants are on enzalutamide at the time of study entry, and remain on continuous dosing at 160 mg daily, the lead-in treatment period will not be required. Prophylactic Pegfilgrastim (G-CSF) 6mg, subcutaneously (SQ) will also be administered on Day 2 during all treatment cycles. Pegfilgrastim could be modified to a lower dose of 3 mg with treating investigator approval.

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?

Rahul Aggarwal

Lead Sponsor

Trials

13

Recruited

550+

FibroGen

Industry Sponsor

Trials

60

Recruited

15,400+

Thane Wettig

FibroGen

Chief Executive Officer since 2023

Bachelor's degree in Mechanical Engineering from Case Western Reserve University, MBA from Duke University

Dr. Mark Eisner

FibroGen

Chief Medical Officer since 2020

MD from Harvard Medical School

Fortis Therapeutics, Inc.

Industry Sponsor

Trials

4

Recruited

160+

Published Research Related to This Trial

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 phase III trial involving patients with metastatic, castration-resistant prostate cancer (mCRPC) who had progressed after docetaxel treatment, enzalutamide significantly improved overall survival, with a median survival of 18.4 months compared to 13.6 months for placebo, indicating a 37% reduction in mortality risk.

Enzalutamide was generally well tolerated, with most side effects being mild to moderate, although there is a small, dose-dependent risk of seizures; it also improved quality of life and pain management for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide: a review of its use in metastatic, castration-resistant prostate cancer. Sanford, M.[2021]

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 study of 67 men with hormone-naive prostate cancer, 92.5% experienced an 80% or greater decline in prostate-specific antigen (PSA) levels after 25 weeks of treatment with enzalutamide, indicating strong efficacy in disease suppression.

Enzalutamide was generally well tolerated, with most side effects being mild to moderate, although some patients experienced grade 3 adverse events like pneumonia and hypertension, which were not deemed treatment-related.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Commentary on: "Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study." Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, Iversen P, Braeckman J, Heracek J, Baskin-Bey E, Ouatas T, Perabo F, Phung D, Hirmand M, Smith MR. Institut de Recherche Clinique, Université Catholique de Louvain, Brussels, Belgium. Electronic address: [e-mail]. Aarhus University Hospital, Aarhus, Denmark. Herlev Hospital, Herlev, Denmark. AZ Groeninge Kortrijk, Kortrijk, Belgium. UZ Leuven, Leuven, Belgium. Klinik und Poliklinik für Urologie, RWTH University Aachen, Aachen, Germany. Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. UZ Brussel, Brussels, Belgium. Univerzita Karlova v Praze, Prague, Czech Republic. Astellas Pharma Global Development, Leiden, Netherlands. Astellas Pharma Global Development, Northbrook, IL, USA. Medivation Inc, San Francisco, CA, USA. Massachusetts General Hospital Cancer Center, Boston, MA, USA: Lancet Oncol. 2014 May;15(6):592-600; doi: 10.1016/S1470-2045(14)70129-9. [Epub 2014 Apr 14]. Trump, D.[2018]

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]

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 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]

In a phase 3 trial involving 1401 men with nonmetastatic, castration-resistant prostate cancer, enzalutamide significantly improved median overall survival to 67.0 months compared to 56.3 months for placebo, indicating a 27% lower risk of death.

The safety profile of enzalutamide was consistent with previous studies, with a similar rate of serious adverse events compared to placebo, primarily involving fatigue and musculoskeletal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. Sternberg, CN., Fizazi, K., Saad, F., et al.[2021]

Enzalutamide is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC), approved for use both after chemotherapy and before chemotherapy, significantly improving patient survival.

The STRIVE Phase II clinical trial demonstrated that enzalutamide outperforms bicalutamide in patients with nonmetastatic and mCRPC who have not responded to androgen deprivation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of enzalutamide on the treatment of prostate cancer. Nadal, R., Bellmunt, J.[2021]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05011188

Study Details | NCT05011188 | FOR46 in Combination ... This is a Phase 1b/2 study evaluating FOR46 in combination with enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC)

2. onclive.com onclive.com/view/for46-shows-early-antitumor-activity-in-metastatic-castration-resistant-prostate-cancer

FOR46 Shows Early Antitumor Activity in Metastatic ... Additionally, among 21 evaluable patients, tumor regression was observed in 48% of patients. A total of 4 patients achieved confirmed partial ...

3. withpower.com withpower.com/trial/phase-2-prostatic-neoplasms-9-2021-d5b14

FOR46 + Enzalutamide for Prostate Cancer Another study showed that enzalutamide improved survival in men with advanced prostate cancer by nearly 5 months after chemotherapy. These findings suggest that ...

4. 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) ...

5. curetoday.com curetoday.com/view/adc-fg-3246-may-show-promise-in-advanced-prostate-cancer

ADC FG-3246 May Show Promise in Advanced Prostate ... “We observed a median radiographic progression-free survival [the time from treatment until new lesions are seen on scans] of 8.7 months in ...

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

Improved Survival with Enzalutamide in Biochemically ... The 8-year overall survival with monotherapy was 73.1% (95% CI, 67.6 to 77.9), which did not differ significantly from that with leuprolide ...

7. 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 ...

8. 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 ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12504157/

Comparative effectiveness and safety of enzalutamide ... Enzalutamide use was associated with superior overall survival (hazard ratio 0.88, 95% confidence interval [CI] 0.82–0.96) compared with ...

10. xtandi.com xtandi.com/clinical-trials

Clinical Trial Results | XTANDI® (enzalutamide) Men taking XTANDI had a 61% lower chance of their cancer progressing compared with men not taking XTANDI during the study. Progression was seen in 89 men (15.5 ...