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.
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.
12345What 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.
678910Is 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.
211121314Eligibility 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)
+16 more
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.
+5 more
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (HP, enzalutamide)Experimental Treatment8 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)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo Clinic in RochesterRochester, MN
Mayo Clinic in ArizonaScottsdale, AZ
Mayo Clinic in FloridaJacksonville, FL
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Who Is Running the Clinical Trial?
Mayo ClinicLead Sponsor
References
Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models. [2022]Effective treatments for patients with metastatic castration-resistant prostate cancer following disease progression on enzalutamide are currently an unmet clinical need. Simultaneous inhibition of the hypoxia-inducible factor (HIF)-1α and androgen receptor (AR) pathways has been previously shown to overcome enzalutamide resistance in vitro Combination treatment with NLG207, a nanoparticle-drug conjugate of camptothecin and inhibitor of HIF-1α, and enzalutamide was evaluated in preclinical prostate cancer models of enzalutamide resistance. The effect of NLG207 and enzalutamide on average tumor volume and tumor re-growth after 3 weeks of treatment was evaluated in vivo using the subcutaneous 22Rv1 xenograft and castrated subcutaneous VCaP xenograft models. Correlative assessments of antitumor activity were evaluated in vitro using cell proliferation and qPCR assays. NLG207 8 mg/kg alone and in combination with enzalutamide reduced average tumor volume by 93% after 3 weeks of treatment (P < 0.05) in comparison with vehicle control in the subcutaneous 22Rv1 xenograft model. Notably, the addition of NLG207 also enhanced the efficacy of enzalutamide alone in the castrated subcutaneous VCaP xenograft model, decreasing the median rate of tumor growth by 51% (P = 0.0001) in comparison with enzalutamide alone. In vitro assessments of cell proliferation and gene expression further demonstrated antitumor activity via AR-HIF-1α crosstalk inhibition. Combination treatment with NLG207 and enzalutamide was shown to be effective in preclinical prostate cancer models of enzalutamide resistance. Clinical investigation of this treatment combination is ongoing (NCT03531827).
Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. [2023]The addition of atezolizumab (anti-PD-L1) to enzalutamide (androgen receptor antagonist) did not prolong survival in metastatic prostate cancer.1 Efficacy with immunotherapies in prostate cancer will require additional studies to elucidate and target mechanisms of resistance within the prostate tumor microenvironment.
Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer. [2021]Enzalutamide (MDV3100) is a second-generation androgen receptor antagonist that improves survival in metastatic, castration-resistant prostate cancer (mCRPC). Alternatives include chemotherapy, radiation, immunotherapy and abiraterone.
Enzalutamide Bests Older NSAAs in mHSPC. [2021]According to results from ENZAMET, a global phase III trial, adding enzalutamide to standard treatment for men with metastatic hormone-sensitive prostate cancer is superior in prolonging survival compared with older nonsteroidal antiandrogen drugs.
Eyeing Enzalutamide for Hormone-Sensitive Prostate Cancer. [2020]In men with metastatic hormone-sensitive prostate cancer, the androgen-receptor inhibitor enzalutamide prolonged radiographic progression-free survival more than a placebo did when given with androgen-deprivation therapy.
Pertuzumab. Promising for some women with metastatic breast cancer, but more assessment needed. [2016]Adding trastuzumab to chemotherapy can prolong overall survival among women with metastatic or locally recurrent unresectable breast cancer that overexpresses HER-2 protein. Pertuzumab (Perjeta, Roche) is a monoclonal antibody that targets HER-2. It has a different binding site from that of trastuzumab, another anti-HER-2 antibody. Pertuzumab has been authorised in the European Union as an adjunct to the trastuzumab + docetaxel combination. A double-blind randomised placebo-controlled trial involving 808 carefully selected patients (including two men), followed for about 2.5 years, showed that the addition of pertuzumab to trastuzumab + docetaxel prolonged overall survival: it was estimated that the 3-year survival rate increased by 10% to 15%. Median progression-free survival was 6 months longer in the pertuzumab group. Addition of pertuzumab did not aggravate cardiac toxicity among patients with a low cardiovascular risk at baseline. In contrast, adding pertuzumab increased the incidence of potentially severe diarrhoea, mucocutaneous disorders (rash, dry skin, mucosal inflammation) and febrile neutropenia. In practice, these results are interesting but they must be confirmed in other comparative trials before recommending routine use of pertuzumab.
Pertuzumab protects the achilles' heel of trastuzumab--emtansine. [2018]Trastuzumab emtansine (T-DM1) represents a significant advancement in the treatment of HER2(+) breast cancers. Its clinical efficacy however will be limited by the development of therapeutic resistance. In this report, the HER3 ligand neuregulin is shown to mediate T-DM1 resistance, which was overcome by administration of pertuzumab, a steric inhibitor of HER2 dimerization.
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]A subcutaneous formulation of pertuzumab and trastuzumab with recombinant human hyaluronidase in one ready-to-use, fixed-dose combination vial (pertuzumab, trastuzumab, and hyaluronidase-zzxf) was approved by the US Food and Drug Administration (FDA) on June 29, 2020. We report the primary analysis of the FeDeriCa study, which was designed to assess the pharmacokinetics, efficacy, and safety of the fixed-dose subcutaneous formulation compared to intravenous pertuzumab plus trastuzumab in patients with HER2-positive early breast cancer in the neoadjuvant-adjuvant setting.
FDA Approval Summary: Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf Injection for Subcutaneous Use in Patients with HER2-positive Breast Cancer. [2022]On June 29, 2020, the FDA approved pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo) for the treatment of patients with HER2-positive early-stage and metastatic breast cancer. Patients should be selected for therapy based on an FDA-approved companion diagnostic test. Approval was primarily based on the FeDeriCa trial, a randomized, open-label, multicenter comparability study of pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection compared with intravenous pertuzumab and intravenous trastuzumab administered in the neoadjuvant and adjuvant settings with chemotherapy for the treatment of patients with early breast cancer. The pharmacokinetic endpoints were, first, to demonstrate that the exposure of subcutaneous pertuzumab was not inferior to that of intravenous pertuzumab, and then to demonstrate that the exposure of subcutaneous trastuzumab was not inferior to that of intravenous trastuzumab. The primary endpoints were met with the observed lower limit of the two-sided 90% confidence intervals above the prespecified noninferiority margins. The most common adverse reactions were alopecia, nausea, diarrhea, anemia, and asthenia. The totality of the evidence demonstrated comparability of the subcutaneous product to intravenous, allowing for extrapolation and approval of all breast cancer indications for which intravenous trastuzumab and pertuzumab are approved.
A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Hyaluronidase PH20 Administered Intravenously in Healthy Volunteers. [2022]Recombinant human hyaluronidase PH20 (rHuPH20) is used in subcutaneous formulations (eg, RITUXAN HYCELA [rituximab and hyaluronidase human], HERCEPTIN HYLECTA [trastuzumab and hyaluronidase-oysk], PHESGO [pertuzumab/trastuzumab/hyaluronidase-zzxf], and Darzalex FASPRO [daratumumab and hyaluronidase-fihj]) to increase the dispersion and absorption of coadministered therapeutics. Although unlikely, subcutaneous products that include rHuPH20 could be mistaken for the intravenous formulation of the corresponding drugs (eg, RITUXAN [rituximab], HERCEPTIN [trastuzumab], and DARZALEX [daratumumab]). To understand the potential effects of inadvertent intravenous injection of rHuPH20, we investigated the safety profile, pharmacokinetics (PK), and pharmacodynamics (PD) of rHuPH20 administered intravenously.
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]Pertuzumab represents a new class of targeted anticancer agents, human epidermal growth factor receptor (HER) dimerization inhibitors. The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent pertuzumab in castration-resistant prostate cancer (CRPC) patients who had experienced progression after prior chemotherapy.
Addition of PSMA ADC to enzalutamide therapy significantly improves survival in in vivo model of castration resistant prostate cancer. [2021]Despite multiple new therapies available to patients with advanced castration-resistant prostate cancer (CRPC), the overall survival benefit still remains relatively short. Therefore, it is important to investigate additional treatment options that could achieve greater efficacy. Because of tumor heterogeneity and the development of resistance to treatment with single agents, combination therapies using existing drugs with new agents can potentially broaden individual therapeutic windows and achieve improved efficacy and safety profiles. The objective of the current studies was to evaluate the efficacy of combination of enzalutamide (ENZ) with prostate specific membrane antigen antibody drug conjugate (PSMA ADC) to inhibit CRPC patient-derived xenografts (PDX) in a preclinical setting.
Extreme responses to immune checkpoint blockade following bipolar androgen therapy and enzalutamide in patients with metastatic castration resistant prostate cancer. [2021]Immune checkpoint inhibition has been shown to have limited efficacy in patients with metastatic prostate cancer. Prostate cancers that harbor certain homologous recombination (HR) DNA repair gene mutations, inactivating CDK12 mutations or have underlying mismatch repair deficiency may be effectively treated with immunotherapy. Combination therapy may improve clinical response rates to immune checkpoint blockade. We observed profound prostate-specific antigen (PSA) and/or objective responses to immune checkpoint blockade following prior treatment with bipolar androgen therapy (BAT) and enzalutamide.
A review of tasquinimod in the treatment of advanced prostate cancer. [2022]Castration resistant prostate cancer remains a major clinical burden and novel therapeutic options are urgently required to improve survival. Tasquinimod is an orally administered quinoline-3-carboxamide with potent antiangiogenic and antitumorigenic action that has shown promise in the treatment of advanced prostate cancers. This review explores both preclinical and clinical findings to date. In summary, tasquinimod has been shown to demonstrate a potent in vitro and in vivo anticancer action and completed early phase clinical trials have demonstrated good drug tolerance and prolonged progression-free survival. Although Phase III clinical trials are on-going, the findings to date highlight the promise of this drug in the treatment of advanced prostate cancer.