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Data from the EMBARK trial demonstrate the potential of enzalutamide monotherapy as an effective treatment for biochemically recurrent prostate cancer (BCR) without the side effects of testosterone-lowering therapy. Unfortunately, concerns about gynecomastia and how to manage this treatment-related toxicity have diminished enthusiasm. Existing data may offer an alternative scheduling strategy for enzalutamide monotherapy in BCR.
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What is most important to patients with BCR prostate cancer? Metastasis-free versus treatment-free survival.
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Recurrencia Local de Neoplasia , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/terapia , Antígeno Prostático Específico/sangre , Supervivencia sin Enfermedad , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológicoRESUMEN
PURPOSE: Sequential PET/CT studies oncology patients can undergo during their treatment follow-up course is limited by radiation dosage. We propose an artificial intelligence (AI) tool to produce attenuation-corrected PET (AC-PET) images from non-attenuation-corrected PET (NAC-PET) images to reduce need for low-dose CT scans. METHODS: A deep learning algorithm based on 2D Pix-2-Pix generative adversarial network (GAN) architecture was developed from paired AC-PET and NAC-PET images. 18F-DCFPyL PSMA PET-CT studies from 302 prostate cancer patients, split into training, validation, and testing cohorts (n = 183, 60, 59, respectively). Models were trained with two normalization strategies: Standard Uptake Value (SUV)-based and SUV-Nyul-based. Scan-level performance was evaluated by normalized mean square error (NMSE), mean absolute error (MAE), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR). Lesion-level analysis was performed in regions-of-interest prospectively from nuclear medicine physicians. SUV metrics were evaluated using intraclass correlation coefficient (ICC), repeatability coefficient (RC), and linear mixed-effects modeling. RESULTS: Median NMSE, MAE, SSIM, and PSNR were 13.26%, 3.59%, 0.891, and 26.82, respectively, in the independent test cohort. ICC for SUVmax and SUVmean were 0.88 and 0.89, which indicated a high correlation between original and AI-generated quantitative imaging markers. Lesion location, density (Hounsfield units), and lesion uptake were all shown to impact relative error in generated SUV metrics (all p < 0.05). CONCLUSION: The Pix-2-Pix GAN model for generating AC-PET demonstrates SUV metrics that highly correlate with original images. AI-generated PET images show clinical potential for reducing the need for CT scans for attenuation correction while preserving quantitative markers and image quality.
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Aprendizaje Profundo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Masculino , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Anciano , Persona de Mediana Edad , Glutamato Carboxipeptidasa II/metabolismo , Antígenos de Superficie/metabolismo , Procesamiento de Imagen Asistido por Computador/métodos , Algoritmos , Radiofármacos , Reproducibilidad de los ResultadosRESUMEN
PURPOSE OF REVIEW: Patients with biochemically recurrent prostate cancer (BCR) after unsuccessful curative therapies frequently have an indolent and asymptomatic disease course for years. There are no prospective data showing that treating BCR improves overall survival despite new imaging strategies and emerging therapeutic data. Managing BCR requires a unique perspective in oncology that balances toxicities and disease kinetics. RECENT FINDINGS: Prostate specific membrane antigen (PSMA) imaging is now widely available and can define subclinical disease in patients with BCR who otherwise have negative CT and bone scans, but limited data exists showing that treating PSMA-positive disease has long term impact. A phase 3 trial demonstrated that the androgen receptor pathway inhibitor enzalutamide either alone or with androgen deprivation therapy (ADT) was superior in delaying metastasis, relative to ADT alone. Survival benefits from this study remain unknown. SUMMARY: BCR is a heterogeneous population where overtreatment may present greater risk to patients than a disease course that is often indolent. Management of BCR should be individualized based on disease kinetics. Given the unique biology of BCR, future therapeutic research should emphasize an approach that alters disease trajectory without accompanying side effects and should explore options beyond ADT-based strategies.
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Antagonistas de Andrógenos , Neoplasias de la Próstata , Masculino , Humanos , Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/tratamiento farmacológico , Progresión de la Enfermedad , Antagonistas de Receptores Androgénicos , Tomografía de Emisión de PositronesRESUMEN
#PSMA is amazing new tech but is using it to expedite the call of disease progression helping #ProstateCancer patients?
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Neoplasias de la Próstata Resistentes a la Castración , Humanos , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Masculino , Estadificación de Neoplasias , Glutamato Carboxipeptidasa II/metabolismo , Antígenos de Superficie , Metástasis de la Neoplasia , Progresión de la Enfermedad , Antígeno Prostático Específico/sangreRESUMEN
RATIONALE AND OBJECTIVES: Efficiently detecting and characterizing metastatic bone lesions on staging CT is crucial for prostate cancer (PCa) care. However, it demands significant expert time and additional imaging such as PET/CT. We aimed to develop an ensemble of two automated deep learning AI models for 1) bone lesion detection and segmentation and 2) benign vs. metastatic lesion classification on staging CTs and to compare its performance with radiologists. MATERIALS AND METHODS: This retrospective study developed two AI models using 297 staging CT scans (81 metastatic) with 4601 benign and 1911 metastatic lesions in PCa patients. Metastases were validated by follow-up scans, bone biopsy, or PET/CT. Segmentation AI (3DAISeg) was developed using the lesion contours delineated by a radiologist. 3DAISeg performance was evaluated with the Dice similarity coefficient, and classification AI (3DAIClass) performance on AI and radiologist contours was assessed with F1-score and accuracy. Training/validation/testing data partitions of 70:15:15 were used. A multi-reader study was performed with two junior and two senior radiologists within a subset of the testing dataset (n = 36). RESULTS: In 45 unseen staging CT scans (12 metastatic PCa) with 669 benign and 364 metastatic lesions, 3DAISeg detected 73.1% of metastatic (266/364) and 72.4% of benign lesions (484/669). Each scan averaged 12 extra segmentations (range: 1-31). All metastatic scans had at least one detected metastatic lesion, achieving a 100% patient-level detection. The mean Dice score for 3DAISeg was 0.53 (median: 0.59, range: 0-0.87). The F1 for 3DAIClass was 94.8% (radiologist contours) and 92.4% (3DAISeg contours), with a median false positive of 0 (range: 0-3). Using radiologist contours, 3DAIClass had PPV and NPV rates comparable to junior and senior radiologists: PPV (semi-automated approach AI 40.0% vs. Juniors 32.0% vs. Seniors 50.0%) and NPV (AI 96.2% vs. Juniors 95.7% vs. Seniors 91.9%). When using 3DAISeg, 3DAIClass mimicked junior radiologists in PPV (pure-AI 20.0% vs. Juniors 32.0% vs. Seniors 50.0%) but surpassed seniors in NPV (pure-AI 93.8% vs. Juniors 95.7% vs. Seniors 91.9%). CONCLUSION: Our lesion detection and classification AI model performs on par with junior and senior radiologists in discerning benign and metastatic lesions on staging CTs obtained for PCa.
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Neoplasias Óseas , Aprendizaje Profundo , Estadificación de Neoplasias , Neoplasias de la Próstata , Tomografía Computarizada por Rayos X , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/secundario , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Anciano , Persona de Mediana Edad , Interpretación de Imagen Radiográfica Asistida por Computador/métodosRESUMEN
BACKGROUND: Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events. OBJECTIVE: To review the evidence on hematological toxicities, including anemia, thrombocytopenia, and neutropenia from PARPis in prostate cancer. STUDY METHODOLOGY: A systematic review and meta-analysis using the PRISMA guidelines was performed for phase II and III randomized controlled trials (RCTs) of PARPis in prostate cancer. PubMed, Embase, and Ovid All EBM reviews-Cochrane were queried from inception to 9 June 2023. The Mantel-Haenszel method was used to report risk ratios (RR) and 95% confidence intervals (CI) for all-grade and high-grade anemia, thrombocytopenia, and neutropenia toxicities. RESULTS: The systematic review retrieved eight phase II and III RCTs; specifically, eight were included in the anemia, five in the all-grade thrombocytopenia and neutropenia, and four in the high-grade thrombocytopenia and neutropenia outcomes. Compared to a placebo and/or other non-PARPi treatments, PARPi use was associated with an increased risk of all-grade anemia (RR, 3.37; 95% CI, 2.37-4.79; p < 0.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97-10.44; p = 0.0004), and neutropenia (RR, 3.11; 95% CI, 1.60-6.03; p = 0.0008). High-grade anemia (RR, 6.94; 95% CI, 4.06-11.86; p < 0.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80-10.88; p < 0.00001) were also associated with an increased risk, while high-grade neutropenia (RR, 3.63; 95% CI, 0.77-17.23; p = 0.10) showed no significant association. Subgroup stratification analyses showed differences in various all-grade and high-grade toxicities. CONCLUSION: PARPis were associated with an increased risk of hematological AEs. Future studies with more pooled RCTs will enhance this understanding and continue to inform patient-physician shared decision-making. Future studies may also have a role in improving the current management strategies for these AEs.
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BACKGROUND: The emergence of positron emission tomography (PET) in prostate cancer is impacting clinical practice, but little is known about PET imaging as a tool to determine treatment failure in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To evaluate PET imaging dynamics in mCRPC patients on enzalutamide with stable computed tomography (CT) and technetium-99m (Tc99) bone scans. DESIGN, SETTING, AND PARTICIPANTS: All patients were on treatment with enzalutamide for first-line mCRPC in a clinical trial at the National Cancer Institute (Bethesda, MD, USA). A volunteer sample had serial 18F-sodium fluoride (NaF) PET in parallel with CT and Tc99. Regions of interest (ROIs) on NaF were analyzed quantitatively for response. INTERVENTION: Patients were randomized to enzalutamide with/without a cancer immunotherapy, Prostvac. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A post hoc, descriptive analysis was performed comparing the changes seen on CT and Tc99 as per RECIST 1.1 with NaF PET scans including the use of a quantitative analysis. RESULTS AND LIMITATIONS: Eighteen mCRPC patients had 67 NaF scans. A total of 233 ROIs resolved after treatment, 52 (22%) of which eventually retuned while on therapy. In all, 394 new ROIs were seen, but 112(28%) resolved subsequently. Of 18 patients, 14 had new ROIs that ultimately resolved after appearing. Many patients experienced progression in a minority of lesions, and one patient with radiation intervention to oligoprogression had a remarkable response. This study is limited by its small number of patients and post hoc nature. CONCLUSIONS: These data highlight the dynamic nature of NaF PET in mCRPC patients treated with enzalutamide, where not all new findings were ultimately related to disease progression. This analysis also provides a potential strategy to identify and intervene in oligoprogression in prostate cancer. PATIENT SUMMARY: In this small analysis of patients with prostate cancer on enzalutamide, changes on 18F-sodium fluoride positron emission tomography (PET) imaging were not always associated with treatment failure. Caution may be indicated when using PET imaging to determine whether new therapy is needed.
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Antineoplásicos , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: Metastatic colorectal cancer (mCRC) is incurable, and median overall survival is less than 2½ years. Although monoclonal antibodies that block PD-1/PD-L1 interactions are active in microsatellite unstable/mismatch repair deficient tumors, a growing dataset shows that most patients with microsatellite stable/mismatch repair proficient tumors will not benefit from the blockade of PD-1/PD-L1 interactions. Here we present results from patients with mCRC (n = 22) treated with the anti-PD-L1 monoclonal antibody avelumab. METHODS: Patients received treatment on a phase I, open-label, dose-escalation trial via a consecutive parallel-group expansion in colorectal cancer. Patients aged 18 years and older with mCRC measurable by RECIST v1.1 who had received at least 1 line of systemic therapy for metastatic disease enrolled. Patients with prior immune checkpoint inhibitor treatment were excluded. Patients received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate. RESULTS: Twenty-two participants received treatment from July 2013 to August 2014. There were no objective responses and median progression-free survival was 2.1 months (95% CI: 1.4-5.5 months). There were 5 grade 3 treatment-related adverse events: GGT elevation (n = 2), PRESS (n = 1), lymphopenia (n = 1), and asymptomatic amylase/lipase elevation (n = 1). CONCLUSION: As demonstrated with other anti-PD-1/PD-L1 monoclonal antibodies, avelumab is not active in unselected patients with mCRC (ClinicalTrials.gov Identifier: NCT01772004).
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Anticuerpos Monoclonales Humanizados , Neoplasias Colorrectales , Humanos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias del Colon , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias del Recto , Criterios de Evaluación de Respuesta en Tumores SólidosRESUMEN
Androgen deprivation therapy (ADT) has been a mainstay of prostate cancer treatment for decades. Relugolix was FDA-approved in 2020 and is currently the only ADT option via an oral route. While the opportunity to use an oral medication for this indication has some advantages, a balanced discussion is required to understand in what clinical settings this agent truly has benefit over long-acting injectable formulations of ADT. Furthermore, patient preference, compliance, financial toxicity, and perhaps most importantly, pharmacologic characteristics must be considered.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/uso terapéutico , Pirimidinonas/uso terapéutico , Compuestos de Fenilurea/uso terapéuticoRESUMEN
BACKGROUND: Before 2018, there was no standard of care for non-metastatic (M0) castration resistant prostate cancer nmCRPC. Androgen receptor antagonists (ARAs) were commonly used sequentially nmCRPC. METHODS: This was a multicenter, randomized clinical trial comparing the ARA flutamide+/-PROSTVAC, a pox viral vaccine targeting PSA that includes T-cell co-stimulatory molecules. Eligible men had negative CT and Tc99 bone scans, and rising PSA on ADT. Previous treatment with ARA was a stratification factor. Patients were also evaluated for antigen-specific immune responses using intracellular cytokine staining. RESULTS: Thirty-three patients randomized to flutamide and 31 to flutamide+vaccine. The median age was 71.8 and 69.8 years, respectively. The median time to treatment failure after a median potential follow-up of 46.7 months was, 4.5 months (range 2-70) for flutamide alone vs. 6.9 months (2.5-40; P = .38) with flutamide+vaccine. Seven patients in each arm had a >50% PSA response. Antigen-specific responses were similar in both arms (58% of patients in flutamide alone and 56% in flutamide+vaccine). The treatments were well tolerated. The most common side effect > grade 2 was injection site reaction seen in 29/31 vaccine patients which were self-limiting. CONCLUSION: The combination of flutamide+PROSTVAC did not improve outcomes in men with nmCRPC compared with flutamide alone. (ClinicalTrials.gov Identifier: NCT00450463).
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Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Masculino , Humanos , Flutamida/uso terapéutico , Flutamida/efectos adversos , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Antagonistas de Andrógenos/uso terapéutico , CastraciónRESUMEN
INTRODUCTION: Prostate cancer treatment has rapidly evolved in the past few years. Androgen deprivation therapy has been the backbone of treatment for locally advanced and metastatic prostate cancer, but incremental benefits in survival have been shown by adding androgen-receptor pathway inhibitors (ARPI) across various spectrums of disease state. In addition, docetaxel chemotherapy remains the first-line chemotherapy regimen available with survival benefits shown with triplet therapy in those who are chemotherapy eligible. However, disease progression remains inevitable and novel agents such as radioligand therapy with lutetium have shown improvement in survival. AREAS COVERED: This review discusses the pivotal trials that led to the U.S. FDA approval of agents utilized in metastatic prostate cancer and explores the use of novel agents including prostate-specific membrane antigen-targeting agents, radioligands, cell-based therapy, chimeric antigen receptor T-cell, BiTE, and antibody drug conjugates. EXPERT OPINION: Treatment landscape for metastatic castrate-resistant prostate cancer (mCRPC) has evolved beyond additional agents with ARPI and/or docetaxel, including other treatments with sipuleucel-T, radium, cabazitaxel, PARP inhibitors, and lutetium, which have specific indications and roles in sequencing. Novel therapies remain critically needed after progression from lutetium.
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Antagonistas de Andrógenos , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Docetaxel , Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Andrógenos/uso terapéutico , Lutecio/uso terapéuticoRESUMEN
The risks of development of colorectal and endometrial cancers in individuals with Lynch syndrome (LS) are well known and have been widely studied. In recent years, the potential association of other malignancies, including prostate cancer, with LS has been considered. Decision-making regarding screening for prostate cancer in the generalized population can be complicated; accounting for the possibility of a higher risk of cancer conferred by a potential genetic predisposition confounds the creation of salient guidelines even further. Although tissue-agnostic treatment approvals have been granted to several immune checkpoint inhibitors (ICIs) for their use in the treatment of subsets of patients whose tumors exhibit high levels of microsatellite instability or high tumor mutational burden, a paucity of data exists regarding the use of ICIs in the first line treatment of patients with locally advanced prostate cancer harboring these features. A significant reduction in tumor volume in response to the combination of immune checkpoint inhibition and androgen deprivation therapy is described in this report of a male with Muir-Torre syndrome who was found to have locally advanced adenocarcinoma of the prostate. While anecdotal, the anti-tumor activity of this combination of therapy is notable and calls attention to the importance of considering further investigation of the use of immune checkpoint blockade as a primary therapeutic option in patients with localized prostate cancer.
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BACKGROUND: This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR). METHODS: For dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT). The primary endpoint was safety. RESULTS: Ninety-one patients were treated in dose escalation (mCRPC=38) and expansion (BCR=35, mCRPC=18). Overall, treatment-related and immune-related adverse events occurred in 64 (70.3%) and 39 (42.9%) patients, with fatigue (40.7%), influenza-like illness (30.8%), diarrhea (23.1%), and immune-related thyroid dysfunction (19.8%) and rash (15.4%), as the most common. In patients with mCRPC, the objective response rate (ORR, 95% CI) was 5.6% (1.2% to 15.4%) and the median radiographic progression-free survival (rPFS) was 5.6 (3.5 to not estimable) months for all; the ORR was 16.7% (3.6% to 41.4%) and 6-month rPFS rate was 45.5% (24.9% to 64.1%) for those who received RP2D with measurable disease (n=18). 7.4% of patients with mCRPC achieved a ≥50% decline in baseline PSA (PSA-50), with a median duration of 4.6 (1.2-45.2) months. In patients with BCR, 9 (25.7%) achieved PSA-50; the median duration of PSA response was 3.9 (1.9-4.2) and 10.1 (6.9-28.8) months for Cohorts 5B-BCR and 1B-BCR. Overall, antigen specific T-cell response was 88.0% to PSMA, 84.0% to PSA, and 80.0% to PSCA. CONCLUSIONS: PrCa VBIR overall demonstrated safety signals similar to other ICI combination trials; significant side effects were seen in some patients with BCR. It stimulated antigen-specific immunity across all cohorts and resulted in modest antitumor activity in patients with BCR without using ADT. TRIAL REGISTRATION NUMBER: NCT02616185.
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Neoplasias de la Próstata Resistentes a la Castración , Vacunas , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Docetaxel/uso terapéutico , Antígeno Prostático Específico , Antagonistas de Andrógenos/uso terapéutico , Inmunoterapia , Hormonas/uso terapéuticoRESUMEN
Therapeutic cancer vaccines including sipuleucel- T , a prostatic acid phosphatase (PAP) targeted vaccine that improves survival in metastatic castration-resistant prostate cancer (mCRPC), can produce immune responses that translate to clinical benefit. The effects of sequential checkpoint inhibitors after therapeutic vaccine on immune responses are unknown. Avelumab is an anti-programmed death ligand-1 monoclonal antibody evaluated in patients with mCRPC in the JAVELIN solid tumor phase 1 trial expansion cohort, enriched for patients with a previous therapeutic prostate cancer-targeted vaccine. mCRPC patients received intravenous avelumab 10 mg/kg every 2 weeks with imaging every 6 weeks. Peripheral blood T-cell responses to PAP and to PA2024, the peptide containing PAP utilized by the vaccine, were evaluated pre and posttreatment. Eighteen patients enrolled, and previous treatments included abiraterone or enzalutamide in 14 (78%), therapeutic cancer vaccine in 14 (78%), and chemotherapy in 4 (22%). Avelumab had a manageable safety profile. There were no sustained prostate specific antigen decreases. Of 17 patients evaluable for best overall response by RECISTv1.1, 12 had stable disease (SD) and 5 had progressive disease. Seven patients had SD for >24 weeks posttreatment. Fourteen patients had previously received therapeutic cancer vaccines. Eleven (79%) had SD as the best overall response. Of these 14 patients, 9 had previously received sipuleucel T . Analysis of antigen-specific T-cell responses pre and postavelumab treatment did not demonstrate changes in interferon-γ production or proliferation in response to PAP or PA2024. This unplanned analysis does not support the use of sequential therapeutic cancer vaccine therapy followed by programmed death ligand-1 inhibition in mCRPC.
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Vacunas contra el Cáncer , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
BACKGROUND: NHS-IL12 is a first-in-class, recombinant fusion protein composed of the human monoclonal antibody NHS76 (binds exposed DNA/histones at sites of intratumoral necrosis) fused to 2 IL-12 heterodimers. The maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NHS-IL12 monotherapy given subcutaneously (SC) every 4 weeks was previously reported. The study was expanded to include a high-exposure cohort with NHS-IL12 SC every 2 weeks (q2w). METHODS: This single-arm, phase I trial evaluated NHS-IL12 12 µg/kg SC q2w or 16.8µg/kg SC q2w in patients with metastatic solid tumors. The primary endpoint was safety. RESULTS: Using a 3+3 design, 13 patients with advanced cancer were enrolled and 12 were dose-limiting toxicity (DLT) evaluable. There was 1 DLT (Grade 3 aspartate transaminase/alanine transaminase [AST/ALT] elevation). Other grade 3 toxicities included: flu-like symptoms 1/13 (8%), decreased absolute lymphocyte count (ALC) 1/13 (8%), decreased white blood cell count (WBC) 1/13 (8%), but most adverse events reported were low grade and self-limiting grade. Fifty percent of evaluable patients (6/12) experienced stable disease (SD) with 42% (5/12) developing progressive disease (PD) at the first restaging. CONCLUSION: Biweekly NHS-IL12 was well tolerated in this small phase I study. Additional studies incorporating NHS-IL12 with other immunomodulating agents are underway. (ClinicalTrials.gov Identifier: NCT01417546).