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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether bortezomib (Velcade) can reduce PSA levels in men with Metastatic Castration Resistant Prostate Cancer (mCRPC) that involves a PTEN gene deletion. Participants will receive bortezomib injections over several treatment cycles to determine if the drug can shrink their tumors. Eligible men have been diagnosed with mCRPC, have not undergone certain chemotherapy treatments, and have a confirmed PTEN deletion. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that bortezomib is likely to be safe for humans?

Research has shown that bortezomib is generally safe for cancer patients. In previous studies, it caused some side effects, but these were often mild or moderate. Common issues included a low blood platelet count, fever, and tiredness. Some patients experienced tingling or numbness, usually in the hands or feet, known as peripheral neuropathy.

Overall, the treatment is well-tolerated and shows promising results in fighting tumors. Some patients experienced a drop in their PSA levels, a marker used to track prostate cancer. This suggests that bortezomib not only has a manageable safety profile but may also be effective in treating certain types of cancer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Bortezomib is unique because it targets cancer cells in a different way than most prostate cancer treatments. While traditional treatments often focus on hormone therapy or chemotherapy, bortezomib works by inhibiting proteasomes, which are structures inside cells responsible for breaking down proteins. This disruption makes it harder for cancer cells to survive and multiply. Researchers are excited about bortezomib because it offers a novel approach that could be effective for patients who haven't responded well to existing therapies. Additionally, its subcutaneous delivery method might offer a more convenient and potentially less invasive option for patients.

What evidence suggests that bortezomib might be an effective treatment for prostate cancer?

Research suggests that bortezomib, which participants in this trial will receive, might be a promising treatment for prostate cancer, particularly when the PTEN gene is missing. This is significant because the absence of the PTEN gene is common in advanced prostate cancer, affecting up to 60% of cases. Studies have shown that bortezomib can slow tumor growth and block factors that help cancer spread. In some early studies, bortezomib reduced tumor growth by 60%. By targeting these specific pathways, bortezomib aims to shrink tumors and slow cancer progression. ^{1 3 6 7 8}

Who Is on the Research Team?

Umang Swami, MD, MS

Principal Investigator

University of Utah

Are You a Good Fit for This Trial?

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

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

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 (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]

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/15289299/

Bortezomib as a potential treatment for prostate cancer This trial included a large fraction of patients with androgen-independent prostate cancer. The maximum tolerated dose was reached at 1.6 mg/m(2) ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.4_suppl.TPS258

Borxpten: A phase II study of bortezomib (B) in patients (pts ... The tumor suppressor gene PTEN maps to chromosome region 10q23 and is deleted in 30% of primary and 60% of castration-resistant prostate cancer.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1164423/

Preclinical evaluation of the proteasome inhibitor bortezomib ... The first study concluded that bortezomib 1.0 mg/kg IV weekly for 4 weeks reduced tumor growth by 60% [13].

4. sciencedirect.com sciencedirect.com/science/article/pii/S002432052400715X

Bortezomib in cancer therapy: Mechanisms, side effects ... Bortezomib reduces pro-angiogenic factors like VEGF, inhibiting tumor growth and metastasis [43]. 2.1.3. Enhancing chemosensitivity. Bortezomib ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT00183937

NCT00183937 | Study of Bortezomib and Docetaxel for ... This study is for patients who have been treated with surgical removal of the testes or hormone therapy (Lupron or Zoladex) and whose prostate cancer has ...

6. aetna.com aetna.com/cpb/medical/data/600_699/0675.html

Bortezomib - Medical Clinical Policy Bulletins The more common toxicities were mild or moderate thrombocytopenia, fever and fatigue while peripheral neuropathy occurred in 3 patients and 1 patient developed ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06029998

Study Details | NCT06029998 | Bortezomib in Patients with ... The proportion of patients achieving PSA decline of ≥ 30% from baseline will be considered a response. To evaluate the antitumor activity of bortezomib in ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2820291/

Bortezomib-Mediated Inhibition of Steroid Receptor ... Bortezomib is generally safe in the preoperative setting. Antitumor activity was manifested by tumor cytopathic effect, drops in serum prostate-specific antigen ...