Antibody-Chemotherapy Combo for Prostate Cancer

Recruiting at 2 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must be taking: Second generation anti-androgens

Must not be taking: Antiretrovirals, Investigational agents

Disqualifiers: Cardiac illness, Uncontrolled infection, 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: 24

Duration: Up to 2 years

7 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well pertuzumab, trastuzumab, hyaluronidase-zzxf and enzalutamide works in treating patients with castration-resistant prostate cancer that has spread from where it first started to other places in the body (metastatic). Pertuzumab and trastuzumab are monoclonal antibodies and forms of targeted therapy that attach to a receptor protein called human epidermal growth factor receptor-2 (HER2). HER2 is found on some cancer cells. When pertuzumab or trastuzumab attach to HER2, the signals that tell the cells to grow are blocked and the tumor cell may be marked for destruction by the body's immune system. Hyaluronidase is an endoglycosidase. It helps to keep pertuzumab and trastuzumab in the body longer, so that these medications will have a greater effect. Hyaluronidase also allows pertuzumab and trastuzumab to be given by injection under the skin and shortens their administration time compared to pertuzumab or trastuzumab alone. Chemotherapy drugs, such as enzalutamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pertuzumab, trastuzumab, hyaluronidase-zzxf and enzalutamide may kill more cancer cells.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot be on any other investigational agents for prostate cancer or drugs that interfere with the study drugs. It's best to consult with the trial team or your doctor for specific guidance.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that you cannot be on any other investigational agents or drugs that interfere with the study drugs. It's best to consult with the trial team or your doctor for specific guidance.

What data supports the idea that Antibody-Chemotherapy Combo for Prostate Cancer is an effective drug?

The available research shows that combining NLG207 with enzalutamide significantly reduced tumor size in preclinical models of prostate cancer. Specifically, in one study, this combination reduced average tumor volume by 93% after three weeks compared to a control group. Additionally, it decreased the rate of tumor growth by 51% compared to using enzalutamide alone. This suggests that the combination is more effective than enzalutamide by itself in these models. ^{1 2 3 4 5}

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

Research shows that Enzalutamide, when used with other treatments, can significantly reduce tumor size and slow tumor growth in prostate cancer models. It has also been proven to improve survival in men with metastatic, castration-resistant prostate cancer. ^{1 2 3 4 5}

What safety data is available for the antibody-chemotherapy combo treatment?

The safety data for the antibody-chemotherapy combo treatment, which includes pertuzumab, trastuzumab, and hyaluronidase-zzxf, is primarily derived from studies on HER2-positive breast cancer. The FeDeriCa study and FDA approval summary indicate that the subcutaneous formulation of these drugs is comparable in safety to their intravenous counterparts. Common adverse reactions include alopecia, nausea, diarrhea, anemia, and asthenia. Additional studies highlight that pertuzumab, when added to trastuzumab and chemotherapy, can increase the incidence of severe diarrhea, mucocutaneous disorders, and febrile neutropenia, although it does not increase cardiac toxicity in patients with low cardiovascular risk. These findings suggest that while the treatment is generally safe, it may have specific side effects that need to be managed. ^{6 7 8 9 10}

Is the antibody-chemotherapy combo generally safe for humans?

The combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf has been approved by the FDA for breast cancer treatment, with common side effects including hair loss, nausea, diarrhea, anemia, and weakness. It did not increase heart-related side effects in patients with low heart risk, but it did increase the risk of severe diarrhea and skin issues. ^{6 7 8 9 10}

Is the drug combination of Enzalutamide, Hyaluronidase-zzxf, Pertuzumab, and Trastuzumab promising for prostate cancer?

The combination of these drugs shows promise because using multiple drugs together can improve treatment effectiveness and safety. Pertuzumab is a targeted cancer drug that can help fight prostate cancer, and combining it with Enzalutamide, which is already used for prostate cancer, might make the treatment more effective. This approach can potentially lead to better outcomes for patients. ^{2 11 12 13 14}

What makes the antibody-chemotherapy combo for prostate cancer unique?

This treatment combines enzalutamide, a drug that blocks male hormones, with pertuzumab and trastuzumab, which are antibodies targeting specific proteins on cancer cells, potentially offering a novel approach by using a combination of mechanisms to tackle prostate cancer more effectively than single-agent therapies. ^{2 11 12 13 14}

Research Team

Jacob Orme

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

This trial is for adults with metastatic castration-resistant prostate cancer that has spread and are resistant to second-generation antiandrogens. Participants must be able to complete questionnaires, provide consent, have certain blood levels within normal ranges, and a good performance status. Pregnant or nursing individuals, those with severe diseases or infections, recent thromboembolic events, other active cancers (with exceptions), known drug sensitivities related to the study drugs, uncontrolled illnesses like heart failure or arrhythmias can't join.

Inclusion Criteria

Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with liver involvement)

I can take care of myself and am up and about more than half of my waking hours.

Willingness to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)

Exclusion Criteria

I have had a heart attack in the last 6 months or have heart failure needing ongoing treatment.

I have not had a blood clot in the last 60 days.

My mild nerve damage has been stable for 3 months after my last treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneously on day 1 of each cycle and enzalutamide orally once daily on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups every 3 months until progressive disease, then every 6 months thereafter.

Up to 2 years

Every 3 months, then every 6 months

Treatment Details

Interventions

• Enzalutamide
• Hyaluronidase-zzxf
• Pertuzumab
• Trastuzumab

Trial Overview The TraPPer Study is testing the combination of pertuzumab, trastuzumab (both monoclonal antibodies targeting HER2 on cancer cells), hyaluronidase-zzxf (to enhance the effect and administration of these antibodies), and enzalutamide (a chemotherapy drug). The goal is to see if this combo works better at killing prostate cancer cells that no longer respond to typical hormone treatments.

Participant Groups

Group I: Treatment (HP, enzalutamide) Experimental Treatment 8 Interventions

Patients receive pertuzumab, trastuzumab, and hyaluronidase-zzxf SC on day 1 of each cycle and enzalutamide PO QD on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, biopsy, CT, and MRI scans and collection of blood samples throughout the study.

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Findings from Research

In preclinical models of metastatic castration-resistant prostate cancer, the combination of NLG207 (a HIF-1α inhibitor) and enzalutamide significantly reduced tumor volume by 93% after 3 weeks, indicating strong efficacy against enzalutamide resistance.

The addition of NLG207 enhanced the effectiveness of enzalutamide, decreasing the median tumor growth rate by 51%, suggesting that targeting both HIF-1α and androgen receptor pathways could be a promising strategy for overcoming treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models. Schmidt, KT., Chau, CH., Strope, JD., et al.[2022]

Combining atezolizumab, an anti-PD-L1 immunotherapy, with enzalutamide, an androgen receptor antagonist, did not improve survival rates in patients with metastatic prostate cancer.

Further research is needed to understand the mechanisms of resistance to immunotherapy in the prostate tumor microenvironment, which may help improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. Siddiqui, BA., Subudhi, SK., Sharma, P.[2023]

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]

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 men with metastatic hormone-sensitive prostate cancer, enzalutamide, when combined with androgen-deprivation therapy, significantly prolonged radiographic progression-free survival compared to a placebo.

This finding highlights the efficacy of enzalutamide as an androgen-receptor inhibitor in improving outcomes for patients undergoing treatment for advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eyeing Enzalutamide for Hormone-Sensitive Prostate Cancer. [2020]

A study involving 808 patients with HER-2 positive breast cancer showed that adding pertuzumab to trastuzumab and docetaxel significantly improved overall survival, with a 3-year survival rate increase of 10% to 15%.

While pertuzumab did not worsen cardiac toxicity in patients with low cardiovascular risk, it was associated with increased side effects such as severe diarrhea and skin disorders, indicating the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab. Promising for some women with metastatic breast cancer, but more assessment needed. [2016]

Trastuzumab emtansine (T-DM1) is an effective treatment for HER2-positive breast cancers, but its effectiveness can be reduced due to the development of resistance.

The resistance to T-DM1 is mediated by the HER3 ligand neuregulin, but this can be countered by using pertuzumab, which inhibits HER2 dimerization, potentially restoring the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab protects the achilles' heel of trastuzumab--emtansine. Gwin, WR., Spector, NL.[2018]

The FeDeriCa study demonstrated that the subcutaneous formulation of pertuzumab and trastuzumab is non-inferior to the intravenous version in terms of serum drug levels, indicating it can effectively deliver the same therapeutic benefits in patients with HER2-positive early breast cancer.

Safety profiles were comparable between the subcutaneous and intravenous groups, with similar rates of serious adverse events, suggesting that the new formulation is a safe alternative for patients undergoing neoadjuvant treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Tan, AR., Im, SA., Mattar, A., et al.[2021]

The FDA approved Phesgo, a subcutaneous injection combining pertuzumab, trastuzumab, and hyaluronidase-zzxf, for treating HER2-positive early-stage and metastatic breast cancer, based on the FeDeriCa trial which showed that the subcutaneous formulation is pharmacokinetically comparable to the intravenous versions.

The study demonstrated that the subcutaneous treatment had similar efficacy to intravenous treatments, with common side effects including alopecia, nausea, and diarrhea, supporting its use across all approved indications for breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf Injection for Subcutaneous Use in Patients with HER2-positive Breast Cancer. Gao, JJ., Osgood, CL., Gong, Y., et al.[2022]

A Phase I study involving 24 healthy volunteers found that intravenous administration of rHuPH20 (up to 30,000 U) was well tolerated, with no serious adverse events reported, indicating a favorable safety profile.

The pharmacokinetics showed that rHuPH20 was rapidly cleared from the plasma, with plasma hyaluronan concentrations increasing in a dose-dependent manner and returning to baseline within one week, suggesting effective metabolism and clearance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Hyaluronidase PH20 Administered Intravenously in Healthy Volunteers. Printz, MA., Dychter, SS., DeNoia, EP., et al.[2022]

In a phase II study involving 42 patients with castration-resistant prostate cancer (CRPC) who had progressed after chemotherapy, pertuzumab was well tolerated, with diarrhea being the most common side effect (61% of patients).

Although no patients achieved complete or partial responses, five out of 30 patients with assessable efficacy had stable disease for at least 23 weeks, and retrospective analysis indicated that pertuzumab treatment may have prolonged survival compared to historical controls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of single-agent pertuzumab (rhuMAb 2C4), a human epidermal growth factor receptor dimerization inhibitor, in castration-resistant prostate cancer after progression from taxane-based therapy. Agus, DB., Sweeney, CJ., Morris, MJ., et al.[2016]

The combination of enzalutamide (ENZ) and prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) significantly inhibited tumor growth in advanced castration-resistant prostate cancer (CRPC) models, showing better efficacy than either treatment alone.

In a preclinical study with patient-derived xenografts, the PSMA ADC+ENZ combination not only reduced tumor size but also resulted in the most pronounced survival benefits, with no deaths observed in the combination group, suggesting a promising new treatment strategy for CRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of PSMA ADC to enzalutamide therapy significantly improves survival in in vivo model of castration resistant prostate cancer. DiPippo, VA., Nguyen, HM., Brown, LG., et al.[2021]

In three cases of metastatic castration-resistant prostate cancer (mCRPC), patients showed significant responses to anti-PD-1 immunotherapy after being treated with bipolar androgen therapy (BAT) and enzalutamide, suggesting a potential strategy for enhancing immunotherapy effectiveness.

Two of the patients had inactivating mutations in HR DNA repair genes (BRCA2, ATM), indicating that specific genetic profiles may influence the success of immune checkpoint blockade in prostate cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer. Markowski, MC., Shenderov, E., Eisenberger, MA., et al.[2021]

Tasquinimod, an orally administered drug, has shown strong anti-cancer effects in both laboratory and animal studies, making it a promising option for treating advanced prostate cancer.

Early phase clinical trials indicate that tasquinimod is well-tolerated by patients and is associated with prolonged progression-free survival, although further results from ongoing Phase III trials are still awaited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of tasquinimod in the treatment of advanced prostate cancer. Williamson, SC., Hartley, AE., Heer, R.[2022]

References

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

Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models. [2022]

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

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. [2023]

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

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

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

Enzalutamide Bests Older NSAAs in mHSPC. [2021]

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

Eyeing Enzalutamide for Hormone-Sensitive Prostate Cancer. [2020]

6. France pubmed.ncbi.nlm.nih.gov

Pertuzumab. Promising for some women with metastatic breast cancer, but more assessment needed. [2016]

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

Pertuzumab protects the achilles' heel of trastuzumab--emtansine. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. [2021]

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

FDA Approval Summary: Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf Injection for Subcutaneous Use in Patients with HER2-positive Breast Cancer. [2022]

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

A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Hyaluronidase PH20 Administered Intravenously in Healthy Volunteers. [2022]

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

Efficacy and safety of single-agent pertuzumab (rhuMAb 2C4), a human epidermal growth factor receptor dimerization inhibitor, in castration-resistant prostate cancer after progression from taxane-based therapy. [2016]

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

Addition of PSMA ADC to enzalutamide therapy significantly improves survival in in vivo model of castration resistant prostate cancer. [2021]

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

Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer. [2021]

14. New Zealand pubmed.ncbi.nlm.nih.gov

A review of tasquinimod in the treatment of advanced prostate cancer. [2022]