ARX517 + Enzalutamide for Prostate Cancer

(ARX517 Trial)

Recruiting at8 trial locations

Age: 18+

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Ambrx, Inc.

Must be taking: LHRH agonists

Must not be taking: Chemotherapy, Apalutamide

Disqualifiers: CNS metastases, Invasive malignancy, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing ARX517, a new drug, in adults with advanced prostate cancer that doesn't respond to usual treatments. The study aims to see if the drug is safe and effective in stopping or slowing down cancer growth.

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

The trial requires stopping certain medications before enrollment, such as chemotherapy within 21 days and hormonal therapy (except LHRH analogs) within 7 days. However, you must continue LHRH therapy if you are already on it.

What data supports the effectiveness of the drug ARX517 + Enzalutamide for prostate cancer?

Enzalutamide is known to improve survival in men with metastatic, castration-resistant prostate cancer, and has shown a significant reduction in the risk of disease progression or death compared to placebo. However, resistance to enzalutamide can develop, and new treatments like ARX517 are being explored to address this issue. ^{1 2 3 4 5}

What safety data exists for ARX517 + Enzalutamide in humans?

There is no specific safety data available for ARX517, but enzalutamide, a drug often used with it, has been associated with some side effects like severe low platelet count (thrombocytopenia) and seizures in certain cases. Additionally, some adverse effects of enzalutamide have been reported more frequently in Japanese patients with prostate cancer. ^{3 4 6 7 8}

What makes the drug ARX517 + Enzalutamide unique for prostate cancer treatment?

ARX517 combined with Enzalutamide is unique because it targets prostate cancer that has become resistant to Enzalutamide, a common issue with current treatments. This combination may offer a new approach to overcoming resistance by potentially addressing androgen receptor mutations and variants that contribute to treatment failure. ^{1 2 3 4 6}

Research Team

Ambrx

Principal Investigator

Ambrx, Inc.

Eligibility Criteria

This trial is for adult men with metastatic castration-resistant prostate cancer who have had at least two FDA-approved treatments, including one targeting androgen receptors. They must be on hormone therapy with low testosterone levels and have adequate blood counts. Men with brain metastases needing steroids, significant heart rhythm issues, serious eye conditions, other recent cancers, or lung diseases can't join.

Inclusion Criteria

I am on hormone therapy for cancer and my testosterone is low.

My prostate cancer was confirmed through a tissue examination.

My cancer has spread to other parts of my body.

Exclusion Criteria

My heart's electrical cycle is longer than normal.

I have serious eye problems confirmed by an eye doctor.

I haven't had lung diseases like interstitial lung disease or pneumonitis in the last year.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ARX517 as monotherapy or in combination with androgen receptor pathway inhibitors, administered via intravenous infusion every 3 weeks

1.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and pharmacokinetic parameters

3 years

Treatment Details

Interventions

• ARX517 (Protein-Protein Interaction Inhibitor)

Trial Overview The study is testing ARX517 alone or combined with other drugs in men with advanced prostate cancer that resists standard hormonal treatment. It's an early-stage trial to see if these treatments are safe and how well patients tolerate them.

Participant Groups

Group I: ARX517+Apalutamide Experimental Treatment 2 Interventions

ARX517 and apalutamide

Group II: ARX517+AAP Experimental Treatment 3 Interventions

ARX517 and abiraterone acetate plus prednisone(AAP)

Group III: ARX517 Experimental Treatment 1 Intervention

ARX517 will be administered via intravenous (IV) infusion, with the initial treatment regimen by weight-based infusion at an interval of every 3 weeks. Other treatment regimen may be explored.

Who Is Running the Clinical Trial?

Ambrx, Inc.

Lead Sponsor

Trials

8

Recruited

860+

Johnson & Johnson

Industry Sponsor

Trials

116

Recruited

167,000+

Findings from Research

JJ-450 is a novel androgen receptor antagonist that effectively inhibits both wild-type and enzalutamide-resistant ARF876L mutant activity in prostate cancer cells, unlike enzalutamide which fails to inhibit the mutant.

In laboratory tests, JJ-450 not only blocked the proliferation of prostate cancer cells expressing the ARF876L mutation but also prevented its nuclear translocation, suggesting it could be a promising treatment for castration-resistant prostate cancer that has become resistant to enzalutamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel androgen receptor antagonist JJ-450 inhibits enzalutamide-resistant mutant ARF876L nuclear import and function. Wu, Z., Wang, K., Yang, Z., et al.[2021]

Enzalutamide significantly improves overall survival and radiographic progression-free survival in men with metastatic, castration-resistant prostate cancer (mCRPC), as shown in two major randomized trials (AFFIRM and PREVAIL) involving patients who had previously undergone chemotherapy and those who were chemotherapy naive.

While enzalutamide is generally safe and effective, it can cause side effects like fatigue and has specific safety concerns, such as an increased risk of seizures and falls, particularly in older patients (≥ 75 years).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer. Graff, JN., Gordon, MJ., Beer, TM.[2021]

Enzalutamide-resistant prostate cancer (ENZ-R CRPC) cells show high levels of both full-length androgen receptor (ARFL) and its variant AR-V7, with ARFL being the primary driver of resistance, as evidenced by a 12-fold higher expression in ENZ-R-LNCaP cells compared to CRPC-LNCaP cells.

Targeting both ARFL and AR variants using antisense oligonucleotides effectively induced apoptosis, suppressed cell growth, and delayed tumor growth in various CRPC models, suggesting that combined AR targeting strategies could be a promising approach for treating AR-dependent CRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation 2.5 antisense oligonucleotides targeting the androgen receptor and its splice variants suppress enzalutamide-resistant prostate cancer cell growth. Yamamoto, Y., Loriot, Y., Beraldi, E., et al.[2022]

The PREVAIL Phase 3 trial demonstrated that enzalutamide significantly improves radiographic-progression free survival in men with castration-resistant prostate cancer (CRPC), with 65% of patients showing no progression compared to those on placebo.

Enzalutamide also provided a median overall survival benefit of 32.4 months versus 30.2 months for the placebo group, indicating its efficacy as a treatment option before chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide for treatment of CRPC: rationale for sequencing and potential clinical biomarker for resistance. Lochrin, SE., Figg, WD., Finn, SP.[2020]

In a study of 48 men with intermediate or high-risk localized prostate cancer, the combination therapy of enzalutamide, dutasteride, and leuprolide resulted in a pathologic complete response (pCR) rate of 4.3% and minimal residual disease (MRD) in 13.0% of patients, indicating some effectiveness in reducing cancer prior to surgery.

In contrast, the enzalutamide-only group showed no patients achieving pCR or MRD, and had a higher median residual cancer burden, suggesting that the combination therapy may be more effective in managing prostate cancer by better targeting androgen receptor activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Enzalutamide Prior to Prostatectomy. Montgomery, B., Tretiakova, MS., Joshua, AM., et al.[2021]

Enzalutamide (Enz) therapy can extend the lives of patients with castration-resistant prostate cancer (CRPC) by an average of 4.8 months, but many patients eventually develop resistance to this treatment.

The AR degradation enhancer ASC-J9(®) shows promise as a new therapy by effectively targeting and degrading the androgen receptor mutant AR-F876L, which is linked to Enz resistance, potentially improving outcomes for patients with CRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ASC-J9(®) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L. Wang, R., Lin, W., Lin, 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]

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]

References

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

A novel androgen receptor antagonist JJ-450 inhibits enzalutamide-resistant mutant ARF876L nuclear import and function. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer. [2021]

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

Generation 2.5 antisense oligonucleotides targeting the androgen receptor and its splice variants suppress enzalutamide-resistant prostate cancer cell growth. [2022]

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

Enzalutamide for treatment of CRPC: rationale for sequencing and potential clinical biomarker for resistance. [2020]

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

Neoadjuvant Enzalutamide Prior to Prostatectomy. [2021]

6. Ireland pubmed.ncbi.nlm.nih.gov

ASC-J9(®) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L. [2021]

7. 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]

8. 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]