Bortezomib for Prostate Cancer

(BORXPTEN Trial)

Overseen By Susan Sharry

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: University of Utah

Must be taking: Androgen deprivation therapy

Disqualifiers: Neuropathy, Recent surgery, Brain metastases, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

22 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to test the anti-tumor activity of bortezomib in participants with Metastatic Castration Resistant Prostate Cancer (mCRPC) with PTEN Deletion. The main question\[s\] it aims to answer is if the use of bortezomib will result in a decline in PSA for participants. Participants will receive a sub-cutaneous injection of bortezomib for up 8 cycles. Each cycle is about 21 days.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions a washout period (time without taking certain medications) for prohibited medications before starting the treatment. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug Bortezomib for prostate cancer?

Bortezomib, a drug known for treating multiple myeloma, has shown potential in prostate cancer by blocking certain pathways that help cancer cells survive, making them more likely to die. This suggests it might be effective against prostate cancer, although more research is needed to confirm this. ^{1 2 3 4 5}

How does the drug Bortezomib differ from other prostate cancer treatments?

Bortezomib is unique because it is a proteasome inhibitor, which means it works by blocking the action of proteasomes (cellular complexes that break down proteins) to slow the growth of cancer cells. Unlike traditional hormone therapies for prostate cancer, Bortezomib can be combined with hormone blockade to potentially enhance treatment effectiveness without significant additional side effects. ^{6 7 8 9 10}

Research Team

Umang Swami, MD, MS

Principal Investigator

University of Utah

Eligibility Criteria

Men over 18 with advanced prostate cancer resistant to hormone therapy and no prior mCRPC treatments can join. They must have a life expectancy over 3 months, treated or stable other cancers, good organ function, and agree to use contraception. Excluded are those with severe heart issues, active infections like TB or hepatitis B/C, recent major surgery or therapies, brain metastases, uncontrolled blood pressure or HIV.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

Absolute neutrophil count ≥ 1500/mm3

Sexually active fertile patients and their partners must agree to use medically accepted methods of contraception during the course of the study and for 4 months after the last dose of study treatment in accordance with section 5.4.3

Exclusion Criteria

You have experienced a strong allergic reaction in the past to the experimental drug or any of its ingredients.

Left ventricular ejection fraction < 50%

You are currently taking any experimental drugs for other research studies.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a sub-cutaneous injection of bortezomib for up to 8 cycles, each cycle lasting 21 days

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Treatment Details

Interventions

• Bortezomib

Trial Overview The trial tests bortezomib's effectiveness in reducing PSA levels in men with metastatic castration-resistant prostate cancer that has a specific genetic change (PTEN deletion). Participants will receive subcutaneous injections of bortezomib for up to eight cycles lasting about three weeks each.

Participant Groups

Group I: Bortezomib Experimental Treatment 1 Intervention

bortezomib starting at a dose of 1.3 mg per square meter of the body-surface area (BSA) subcutaneously on days 1, 4, 8, and 11 in a 21-day cycle.

Bortezomib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in United States as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Canada as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Japan as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Findings from Research

Bortezomib, a proteasome inhibitor, has demonstrated strong anti-cancer activity in cell cultures and animal models, enhancing the effectiveness of traditional chemotherapy and overcoming drug resistance.

In Phase II trials involving 254 patients with relapsed multiple myeloma, bortezomib showed promising response rates and manageable side effects, leading to further investigation in a Phase III trial against high-dose dexamethasone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical update: proteasome inhibitors in hematologic malignancies. Richardson, P.[2019]

Bortezomib is recommended for use in both newly diagnosed and relapsed/refractory multiple myeloma patients, whether they are eligible for autologous stem cell transplantation or not, based on a systematic review of evidence.

The guidelines also emphasize the importance of monitoring and managing potential toxicities associated with bortezomib treatment, such as the risk of herpes zoster reactivation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib in multiple myeloma: a practice guideline. Kouroukis, CT., Baldassarre, FG., Haynes, AE., et al.[2015]

Bortezomib (VELCADE) is a proteasome inhibitor that disrupts protein balance in cells, leading to cell death, particularly in cancer cells, and is effective in treating relapsed myeloma after prior treatments.

Phase III trials have shown that bortezomib significantly outperforms high-dose dexamethasone in efficacy for relapsed myeloma, and further studies are exploring its use in other cancers and treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib: proteasome inhibition as an effective anticancer therapy. Richardson, PG., Mitsiades, C.[2015]

Proteasome inhibition using Velcade significantly enhances the sensitivity of prostate cancer cells to apoptosis triggered by death ligands like Fas ligand and TRAIL, indicating a potential mechanism for its anticancer effects.

The study found that Velcade increases the stability and activity of caspase-8, a key protein in the apoptosis pathway, which may explain how it enhances the apoptotic response in prostate cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proteasome inhibition blocks caspase-8 degradation and sensitizes prostate cancer cells to death receptor-mediated apoptosis. Thorpe, JA., Christian, PA., Schwarze, SR.[2015]

In a phase II study involving 12 patients with metastatic breast cancer, bortezomib (VELCADE) was well tolerated but did not show objective clinical responses, with only one patient achieving stable disease and the rest experiencing disease progression.

Despite its limited efficacy as a single agent, bortezomib demonstrated a significant reduction in plasma interleukin-6 levels and a mean inhibition of specific chymotryptic activity of 53.1%, suggesting potential for future combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Yang, CH., Gonzalez-Angulo, AM., Reuben, JM., et al.[2020]

Castration-resistant prostate cancer (CRPC) patients with bone metastases are at high risk for skeletal-related events (SREs), with nearly half experiencing complications like fractures or the need for surgery due to prolonged hormonal treatment.

While bone-targeted agents (BTAs) like zoledronic acid and denosumab prevent SREs, they do not improve overall survival; however, combining BTAs with newer therapies like abiraterone acetate and enzalutamide may enhance clinical outcomes and extend survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone Targeting Agents in Patients with Metastatic Prostate Cancer: State of the Art. Mollica, V., Rizzo, A., Rosellini, M., et al.[2021]

In a study of 91 patients with biochemical relapse after radical prostatectomy, 2 years of bicalutamide monotherapy resulted in a 2-year treatment failure-free survival rate of 74.6%, indicating some efficacy in delaying disease progression.

However, 26.4% of patients could not complete the treatment due to disease progression, and the study suggests that bicalutamide should not be the standard treatment for all patients, particularly those at high risk or with a quick return of PSA levels after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two years of bicalutamide monotherapy in patients with biochemical relapse after radical prostatectomy. Okubo, T., Mitsuzuka, K., Koie, T., et al.[2022]

Bortezomib (BZM) significantly slowed the rise of PSA levels in patients with early PSA recurrence after local therapy, indicating its efficacy as a treatment option.

The combination of BZM with hormone blockade showed promising results, with 11 out of 15 patients achieving complete responses and a median time to complete response of 42 days, while the major side effect was neurotoxicity, affecting some patients' treatment continuity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy of recurrent prostate cancer with the proteasome inhibitor bortezomib plus hormone blockade. Kraft, AS., Garrett-Mayer, E., Wahlquist, AE., et al.[2020]

Prostate cancer treatment varies by disease stage, with localized cases potentially curable through surgery, radiation, or hormonal therapy, but 30-50% may progress despite initial treatment.

Hormone refractory metastatic prostate cancer is challenging to treat and has a poor prognosis, highlighting the need for new therapies like immunotherapy, which has shown promise in other cancers and is being explored for prostate cancer through recent studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospects of immunotherapy for the treatment of prostate carcinoma--a review. Hillman, GG., Triest, JA., Cher, ML., et al.[2019]

Radiopharmaceuticals, particularly radium-223, have been shown to prolong survival in patients with bone metastatic castrate-resistant prostate cancer, making them a significant treatment option alongside traditional therapies.

The future of radiopharmaceuticals is promising, with ongoing development of agents that target tumors more effectively, including prostate-specific membrane antigen-targeted therapies, which may enhance treatment efficacy beyond current bone-seeking agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isotope Therapy for Castrate-Resistant Prostate Cancer: Unique Sequencing and Combinations. Sartor, O.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical update: proteasome inhibitors in hematologic malignancies. [2019]

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

Bortezomib in multiple myeloma: a practice guideline. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Bortezomib: proteasome inhibition as an effective anticancer therapy. [2015]

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

Proteasome inhibition blocks caspase-8 degradation and sensitizes prostate cancer cells to death receptor-mediated apoptosis. [2015]

5. England pubmed.ncbi.nlm.nih.gov

Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. [2020]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Bone Targeting Agents in Patients with Metastatic Prostate Cancer: State of the Art. [2021]

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

Two years of bicalutamide monotherapy in patients with biochemical relapse after radical prostatectomy. [2022]

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

Combination therapy of recurrent prostate cancer with the proteasome inhibitor bortezomib plus hormone blockade. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Prospects of immunotherapy for the treatment of prostate carcinoma--a review. [2019]

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

Isotope Therapy for Castrate-Resistant Prostate Cancer: Unique Sequencing and Combinations. [2022]