Golimumab and Apalutamide for the Treatment of Castration-Resistant Prostate Cancer, TRAMP Study

Study Overview
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Brief Summary
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This phase II trial tests how well golimumab and apalutamide work in treating patients with castration resistant prostate cancer. Golimumab is in a class of medications called tumor necrosis factor (TNF) inhibitors. It works by blocking the action of TNF, a substance in the body that causes inflammation. Apalutamide is in a class of medications called androgen receptor inhibitors. It works by blocking the effects of androgen (a male reproductive hormone) to stop the growth and spread of cancer cells. Giving golimumab and apalutamide may work better in treating patients with castration-resistant prostate cancer.

Detailed Description
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OUTLINE: Patients receive golimumab subcutaneously (SC) every 4 weeks for 6 doses and apalutamide orally (PO) daily. Treatment with apalutaminde continues in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy at baseline and during cycle 4. Patients also undergo computed tomography (CT) scans or magnetic resonance imaging (MRI), prostate-specific membrane antigen (PSMA) positron emission tomography (PET), and collection of blood samples at baseline, during cycle 4, and at end of treatment. After completion of study treatment, patients are followed every 3 months.

Official Title
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TRAMP: Tumor Necrosis Factor- α Blockade and AR Inhibition in Men With CRPC

Conditions
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Castration-Resistant Prostate Carcinoma, Prostate Adenocarcinoma

Intervention / Treatment
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* Drug: Apalutamide
* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Drug: Golimumab
* Procedure: Magnetic Resonance Imaging
* Procedure: PSMA PET Scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of histologically diagnosed prostatic adenocarcinoma Participants must have evidence of castration resistant prostate cancer as evidenced by a confirmed rising prostate specific antigen (PSA) or radiographic progression (per Prostate Cancer Working Group 3 [PCWG3] or Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1) and a castrate serum testosterone level (i.e., =< 50 ng/dL) Participants must have been treated with at least 6 months of novel hormonal therapy (NHT) in the hormone-sensitive setting including but not limited to either abiraterone, enzalutamide, darolutamide, or apalutamide. (Biosimilar or generic agents may be allowed at the discretion of the principal investigator [PI]) Participants demonstrate disease progression with two successive PSA rises above the nadir on the last prior therapy or most recent time interval, separated by >= 1 week, with the last determination having a value of >= 2 ng/mL, or evidence of radiographic disease progression on NHT prior to enrollment Participants may have received prior chemotherapy in the hormone-sensitive setting so long as >= 6 months prior to enrollment. (Prior chemotherapy in the CRPC setting is not allowed) Participants must be >= 18 years of age prior to signing informed consent Eastern Cooperative Oncology Group (ECOG) performance status score =< 2 Hemoglobin >= 9.0 g/dL, independent of transfusion and/or growth factors within 3 months prior to randomization Platelet count >= 100,000 x 10^9/uL independent of transfusion and/or growth factors within 3 months prior to randomization Absolute neutrophil count >= 1.5 x 10^3/mL Serum albumin >= 3.0 g/dL Serum creatinine =< 1.5 mg/dL Serum potassium >= 3.5 mmol/L Serum total bilirubin < 1.5 x upper limit of normal (ULN) (Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject may be eligible) Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase =< 1.5 x ULN Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug. Must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug Medications known to lower the seizure threshold (see list under prohibited meds) must be discontinued or substituted at least 4 weeks prior to study entry Have no signs or symptoms suggestive of active tuberculosis (TB) upon medical history and/or physical examination Have had no known recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation Within 8 weeks before the first administration of study intervention, have a negative QuantiFERON-TB test result Have a chest radiograph (both posterior-anterior and lateral views, or per country regulations where applicable), taken within 12 weeks before the first administration of study intervention and read by a radiologist or qualified pulmonologist, with no evidence of current, active TB or old, inactive TB. A chest computed tomography scan is also acceptable if already available or obtained outside of the study protocol Participants must sign an informed consent form (ICF) indicating that they understand the purpose of, and procedures required for, the study and are willing to participate in the study Exclusion Criteria: Subjects who have had chemotherapy in the CRPC setting Subjects who have received > 6 weeks of NHT in CRPC setting Subjects may not be receiving other investigational agents within 14 days prior to enrollment Subjects with predominant small cell or neuroendocrine variant prostate cancer on most recent standard of care biopsy Symptomatic central nervous system (CNS) metastases. Treated CNS metastases will be allowed if these are stable for at least 8 weeks prior to enrollment Hepatitis B infection (acute and chronic) as defined according to the American Society of Clinical Oncology guidelines. In the event the infection status is unclear, quantitative levels are necessary to determine the infection status. Hepatitis C (anti-hepatitis C virus [HCV] antibody positive or HCV-ribonucleic acid [RNA] quantitation positive) or known to have a history of hepatitis C. If positive, further testing of quantitative levels to rule out positivity is required Has impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions Major surgery within 2 weeks of the first dose, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration (Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate) Co-administration of other TNF-alpha inhibitors or disease-modifying anti-rheumatic drugs (DMARDS) for the treatment of rheumatoid arthritis or other rheumatologic condition. (Note: prior exposure to TNF-alpha inhibitors is allowed for non-rheumatologic disease (e.g., SARS-CoV-2) if washout period > 5 half-lives prior to study enrollment) Uncontrolled or concurrent illness including within the past 6 months, but not limited to, ongoing or active infection, history or ongoing chronic or recurrent infectious diseases, or any immune deficiency syndromes, severe or unstable angina, myocardial infarction, congestive heart failure (asymptomatic or symptomatic), uncontrolled hypertension, clinically significant arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias or New York Heart Association Class II to IV heart disease, or psychiatric illness/social situations that would limit compliance with study requirements Any other issue that would impair the ability of the subject to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments History of active or latent TB prior to screening or evidence of active or latent TB during screening History or ongoing chronic or recurrent infectious diseases, or any immune deficiency syndromes Concomitant diagnosis or history of congestive heart failure (CHF), including medically controlled asymptomatic CHF Has unstable cardiovascular disease, defined as a recent clinical deterioration (eg, unstable angina, rapid atrial fibrillation, or transient ischemic attack) in the last 3 months prior to screening or a cardiac hospitalization within the last 3 months prior to screening History of a demyelinating disorder such as multiple sclerosis or optic neuritis Lupus or Lupus-like syndrome Hypersensitivity to any biologics or known allergies or clinically significant reactions to murine, chimeric, or human proteins, monoclonal antibodies (mAbs), or antibody fragments Have a transplanted organ (with the exception of a corneal transplant performed > 3 months prior to first administration of study drug) Currently has a malignancy or a history of malignancy within 5 years before screening (with the exception of prostate cancer or a nonmelanoma skin cancer that has been adequately treated with no evidence of recurrence for at least 3 months prior to the administration of the first study intervention Has a history of lymphoproliferative disease, including lymphoma; a history of monoclonal gammopathy of undetermined significance; or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy or splenomegaly Has or has had a herpes zoster infection within 2 months before screening Have had a serious infection (e.g., hepatitis, pneumonia, or pyelonephritis), have been hospitalized for an infection, or have been treated with parenteral antibiotics for an infection within 2 months prior to first administration of study drug. Less serious infections (e.g., acute upper respiratory tract infection, simple urinary tract infection) need not be considered exclusionary at the discretion of the investigator Immune deficiency syndrome (e.g., severe combined immunodeficiency syndrome [SCIDS], T cell deficiency syndromes, B cell deficiency syndromes, and chronic granulomatous disease) Are known to be infected with HIV (HIV antibody positive) Have had a Bacille Calmette-Guerin (BCG) vaccination within 12 months of screening Note: Patients must agree not to receive a Bacillus Calmette-Guerin (BCG) vaccination during the study, and within 16 weeks after the last administration of study intervention Has ever had a nontuberculous mycobacterial infection or opportunistic infection (eg, cytomegalovirus, pneumocystis jirovecii, aspergillosis) Has a history of active granulomatous infection, including histoplasmosis, or coccidioidomycosis, before screening Have signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, vascular, GI, rheumatologic, neurologic, psychiatric, or cerebral diseases Suicidal ideation Has a history of an infected joint prosthesis or has ever received antibiotics for a suspected infection of a joint prosthesis, if that prosthesis has not been removed or replaced Known allergies, hypersensitivity, or intolerance to apalutamide or its excipients Uncontrolled hypertension Gastrointestinal disorder affecting absorption Any condition that in the opinion of the investigator, would preclude participation in this study Seizure or known condition that may pre-dispose to seizure (e.g., prior stroke within 1 year to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign central nervous system (CNS) or meningeal disease which may require treatment with surgery or radiation therapy) History of seizure or any condition that in the opinion of the investigator may predispose to seizure or treatment with drugs known to lower the seizure threshold within 4 weeks prior to starting treatment with apalutamide

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (golimumab, apalutamide)<br>Patients receive golimumab SC every 4 weeks for 6 doses and apalutamide PO daily. Treatment with apalutaminde continues in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy at baseline and during cycle 4. Patients also undergo CT scans or MRI, PSMA PET, and collection of blood samples at baseline, during cycle 4, and at end of treatment. | Drug: Apalutamide<br>* Given PO<br>* Other names: JNJ-56021927;Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Drug: Golimumab<br>* Given SC<br>* Other names: Immunoglobulin G1, Anti-(Human Tumor Necrosis Factor Alpha) (Human Monoclonal CNTO 148 Gamma-1-Chain), Disulfide with Human Monoclonal CNTO 148 Kappa-Chain, Dimer;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Procedure: PSMA PET Scan<br>* Undergo PSMA PET<br>* Other names: PSMA-Positron emission tomography;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate specific antigen (PSA)50 response rate | Defined by at least a 50% decline in PSA from baseline, in subjects with castrate resistant prostate cancer after combination treatment with TNF-alpha blockade (golimumab) and AR antagonism (apalutamide). | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Will determine objective response rate of measurable or evaluable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria for soft tissue metastases and Prostate Cancer Working Group 3 criteria for bone metastases. | Up to 4 years | 
| Radiographic progression free survival (PFS) | The sample mean and standard errors of the time to radiographic progression after the treatment will be summarized, and the post-treatment radiographic response rate together with its 95% confidence interval will be reported. | Up to 4 years | 
| PSA PFS | The interval between enrollment and the date of documented PSA progression. Progression will be declared if patient has documented to have a testosterone less than 50 ng/dL. In cases where a testosterone level has not been obtained and patient has not had an orchiectomy, progressive disease will be deemed if patient had a documented rise in PSA on luteinizing hormone-releasing hormone analogue therapy. Progression free survival curves will be generated using Kaplan-Meier methodology. | Up to 4 years | 
| PSA Doubling Time | The rate of PSA doubling will be calculated from nadir to confirmed PSA progression after 2 subsequent rises 1 week apart using standard calculators | Up to 4 years | 
| Time to subsequent antineoplastic therapy | The interval between enrollment and the date of documented initiation of next therapy. | Up to 4 years | 
| Incidence of adverse events | Assess the incidence and severity of adverse events according to the National Cancer Institute - Common Terminology Criteria for Adverse Events version 5.0. | Up to 30 days after final receipt of golimumab administration |