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PURPOSE: New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study. METHODS: Part 1 featured a 3 + 3 weight-based dose-escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator's decision, or death. RESULTS: The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed. CONCLUSIONS: Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016.
Sujet(s)
Anticorps monoclonaux humanisés/administration et posologie , Anticorps monoclonaux humanisés/pharmacocinétique , Inhibiteurs de points de contrôle immunitaires/administration et posologie , Inhibiteurs de points de contrôle immunitaires/pharmacocinétique , Tumeurs/traitement médicamenteux , Sujet âgé , Anticorps monoclonaux humanisés/effets indésirables , Anticorps monoclonaux humanisés/pharmacologie , Aire sous la courbe , Poids , Humains , Inhibiteurs de points de contrôle immunitaires/effets indésirables , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Mâle , Dose maximale tolérée , Adulte d'âge moyen , Tumeurs/anatomopathologie , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Résultat thérapeutiqueRÉSUMÉ
This document provides a short summary of the GARNET trial which was published in JAMA Oncology in October 2020. At the end of this document, there are links to websites where you can find more information about this study. The trial enrolled adult participants with advanced solid tumors. This report is restricted to patients with a particular type of endometrial cancer that has a deficient mismatch repair (dMMR) status. Patients received a trial treatment called dostarlimab (also known by the brand name Jemperli). In the US, dostarlimab is approved as a single therapy in adult patients with dMMR recurrent or advanced endometrial cancer that has progressed on or after platinum-based chemotherapy. In the EU, dostarlimab is approved as a single therapy in adult patients with recurrent or advanced dMMR/microsatellite instability-high (MSI-H) endometrial cancer that has progressed on or after treatment with a platinum-containing regimen. The GARNET trial looked at dostarlimab given intravenously to patients with dMMR endometrial cancer from 7 countries. The trial showed that dostarlimab was successful in shrinking the tumor in 42% of these patients. In general, the percentage of participants who experienced medical problems (referred to as side effects) was low and within expectations for this type of treatment. ClinicalTrials.gov NCT number: NCT02715284. To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF. Link to original article here.
Sujet(s)
Effets secondaires indésirables des médicaments , Tumeurs de l'endomètre , Adulte , Anticorps monoclonaux/effets indésirables , Réparation de mésappariement de l'ADN , Tumeurs de l'endomètre/traitement médicamenteux , Femelle , Humains , Instabilité des microsatellitesRÉSUMÉ
Inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the treatment landscape for patients with cancer. Clinical activity of anti-PD-(L)1 antibodies has resulted in increased median overall survival and durable responses in patients across selected tumor types. To date, 6 PD-1 and PD-L1, here collectively referred to as PD-(L)1, pathway inhibitors are approved by the US Food and Drug Administration for clinical use. The availability of multiple anti-PD-(L)1 antibodies provides treatment and dosing regimen choice for patients with cancer. Here, we describe the nonclinical characterization of dostarlimab (TSR-042), a humanized anti-PD-1 antibody, which binds with high affinity to human PD-1 and effectively inhibits its interaction with its ligands, PD-L1 and PD-L2. Dostarlimab enhanced effector T-cell functions, including cytokine production, in vitro. Since dostarlimab does not bind mouse PD-1, its single-agent antitumor activity was evaluated using humanized mouse models. In this model system, dostarlimab demonstrated antitumor activity as assessed by tumor growth inhibition, which was associated with increased infiltration of immune cells. Single-dose and 4-week repeat-dose toxicology studies in cynomolgus monkeys indicated that dostarlimab was well tolerated. In a clinical setting, based on data from the GARNET trial, dostarlimab (Jemperli) was approved for the treatment of adult patients with mismatch repair-deficient recurrent or advanced endometrial cancer that had progressed on or following prior treatment with a platinum-containing regimen. Taken together, these data demonstrate that dostarlimab is a potent anti-PD-1 receptor antagonist, with properties that support its continued clinical investigation in patients with cancer.
Sujet(s)
Anticorps monoclonaux humanisés , Antinéoplasiques immunologiques , Tumeurs expérimentales , Récepteur-1 de mort cellulaire programmée , Animaux , Anticorps monoclonaux humanisés/composition chimique , Anticorps monoclonaux humanisés/immunologie , Anticorps monoclonaux humanisés/pharmacologie , Antinéoplasiques immunologiques/composition chimique , Antinéoplasiques immunologiques/immunologie , Antinéoplasiques immunologiques/pharmacologie , Cellules CHO , Cricetulus , Humains , Cellules Jurkat , Macaca fascicularis , Souris , Souris transgéniques , Tumeurs expérimentales/traitement médicamenteux , Tumeurs expérimentales/immunologie , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Récepteur-1 de mort cellulaire programmée/immunologie , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
IMPORTANCE: Deficient mismatch mutation repair mechanisms may sensitize endometrial cancers to anti-programmed death 1 (PD-1) therapies. Dostarlimab (TSR-042) is an investigational anti-PD-1 antibody that binds with high affinity to the PD-1 receptor. OBJECTIVE: To assess the antitumor activity and safety of dostarlimab for patients with deficient mismatch repair endometrial cancer. DESIGN, SETTING, AND PARTICIPANTS: This ongoing, open-label, single-group, multicenter study began part 1 on March 7, 2016, and began enrolling patients with deficient mismatch mutation repair endometrial cancer on May 8, 2017. Median follow-up was 11.2 months (range, 0.03 [ongoing] to 22.11 [ongoing] months; based on radiological assessments). Statistical analysis was performed July 8 to August 9, 2019. INTERVENTIONS: Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, treatment discontinuation, or withdrawal. MAIN OUTCOMES AND MEASURES: The primary end point was objective response rate and duration of response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: As of the data cutoff, 104 women (median age, 64.0 years [range, 38-80 years]) with deficient mismatch mutation repair endometrial cancers were enrolled and treated with dostarlimab. Of these, 71 had measurable disease at baseline and at 6 months or more of follow-up and were included in the analysis. There was a confirmed response in 30 patients (objective response rate, 42.3%; 95% CI, 30.6%-54.6%); 9 patients (12.7%) had a confirmed complete response, and 21 patients (29.6%) had a confirmed partial response. Responses were durable; the median duration of response was not reached (median follow-up was 11.2 months). The estimated likelihood of maintaining a response was 96.4% at 6 months and 76.8% at 12 months. Anemia (3 of 104 [2.9%]), colitis (2 of 104 [1.9%]), and diarrhea (2 of 104 [1.9%]) were the most common grade 3 or higher treatment-related adverse events. CONCLUSIONS AND RELEVANCE: In this nonrandomized trial, dostarlimab was associated with clinically meaningful and durable antitumor activity with an acceptable safety profile for patients with deficient mismatch mutation repair endometrial cancers after prior platinum-based chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02715284.
Sujet(s)
Anticorps monoclonaux humanisés , Réparation de mésappariement de l'ADN , Tumeurs de l'endomètre , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Anticorps monoclonaux humanisés/effets indésirables , Anticorps monoclonaux humanisés/usage thérapeutique , Tumeurs de l'endomètre/traitement médicamenteux , Tumeurs de l'endomètre/génétique , Femelle , Humains , Adulte d'âge moyen , Évaluation de la réponse des tumeurs solides aux traitements , Résultat thérapeutiqueRÉSUMÉ
Guanylyl cyclase C (GCC) is a cell-surface protein that is expressed by normal intestinal epithelial cells, more than 95% of metastatic colorectal cancers (mCRC), and the majority of gastric and pancreatic cancers. Due to strict apical localization, systemically delivered GCC-targeting agents should not reach GCC in normal intestinal tissue, while accessing antigen in tumor. We generated an investigational antibody-drug conjugate (TAK-264, formerly MLN0264) comprising a fully human anti-GCC monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable peptide linker. TAK-264 specifically bound, was internalized by, and killed GCC-expressing cells in vitro in an antigen-density-dependent manner. In GCC-expressing xenograft models with similar GCC expression levels/patterns observed in human mCRC samples, TAK-264 induced cell death, leading to tumor regressions and long-term tumor growth inhibition. TAK-264 antitumor activity was generally antigen-density-dependent, although some GCC-expressing tumors were refractory to TAK-264-targeted high local concentrations of payload. These data support further evaluation of TAK-264 in the treatment of GCC-expressing tumors.
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Anticorps monoclonaux/immunologie , Immunoconjugués/pharmacologie , Oligopeptides/métabolisme , Récepteurs des entérotoxines/immunologie , Animaux , Anticorps monoclonaux/métabolisme , Anticorps monoclonaux humanisés , Technique de Western , Tumeurs colorectales/enzymologie , Tumeurs colorectales/anatomopathologie , Femelle , Cellules HEK293 , Humains , Muqueuse intestinale/enzymologie , Souris , Souris SCID , Récepteurs des entérotoxines/génétique , Récepteurs des entérotoxines/métabolisme , RT-PCR , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
BACKGROUND: Antibody-drug conjugates (ADCs) are an emerging technology consisting of an antibody, linker, and toxic agent, which have the potential to offer a targeted therapeutic approach. A novel target recently explored for the treatment of pancreatic cancer is guanylyl cyclase C (GCC). The objective of this study was to determine the anti-tumorigenic activity of TAK-264, an investigational ADC consisting of an antibody targeting GCC linked to a monomethyl auristatin E payload via a peptide linker. METHODS: The antiproliferative effects of TAK-264 assessed in a panel of eleven pancreatic cancer cell lines. Additionally, ten unique pancreatic ductal adenocarcinoma cancer patient-derived xenograft models were treated with TAK-264 and the efficacy was determined. Baseline levels of GCC were analyzed on PDX models and cell lines. Immunoblotting was performed to evaluate the effects of TAK-264 on downstream effectors. RESULTS: GCC protein expression was analyzed by immunoblotting in both normal and tumor tissue; marked increase in GCC expression was observed in tumor tissue. The in vitro experiments demonstrated a range of responses to TAK-264. Eight of the ten PDAC PDX models treated with TAK-264 demonstrated a statistically significant tumor growth inhibition. Immunoblotting demonstrated an increase in phosphorylated-HistoneH3 in both responsive and less responsive cell lines and PDAC PDX models treated with TAK-264. There was no correlation between baseline levels of GCC and response in either PDX or cell line models. CONCLUSION: TAK-264 has shown suppression activity in pancreatic cancer cell lines and in pancreatic PDX models. These findings support further investigation of ADC targeting GCC.
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PURPOSE: This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC). MATERIALS AND METHODS: Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264. RESULTS: Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade ≥ 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response. CONCLUSION: TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose.
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Anticorps monoclonaux/usage thérapeutique , Tumeurs gastro-intestinales/traitement médicamenteux , Récepteurs des entérotoxines/métabolisme , Sujet âgé , Anticorps monoclonaux/pharmacologie , Anticorps monoclonaux humanisés , Femelle , Tumeurs gastro-intestinales/génétique , Tumeurs gastro-intestinales/métabolisme , Humains , Mâle , Adulte d'âge moyenRÉSUMÉ
BACKGROUND: The transmembrane receptor guanylate cyclase-C (GCC) has been found to be expressed in colorectal cancers. However, limited data are available on GCC protein expression in non-colorectal gastrointestinal tumors and few studies have reported whether GCC protein expression was consistently preserved in synchronous primary and metastatic cancer tissues. METHODS: GCC protein status was assessed by immunohistochemistry in tumor specimens from individuals (n = 627) with gastrointestinal tumors, including esophageal (n = 130), gastric (n = 276), pancreatic (n = 136), and colorectal (n = 85) primary and metastatic tumors. Tissue specimens consisted of tissue microarrays containing esophageal, gastric, pancreatic tumors, and whole-slide tissue sections from colorectal cancer patients with matching primary and metastatic tumors. RESULT: Among the evaluated esophageal, gastric, and pancreatic tumors, the frequency of GCC positivity at the protein level ranged from 59% to 68%. GCC was consistently expressed in primary and matched/synchronous metastatic lesions of colorectal cancer tissues derived from the same patients. CONCLUSION: This observational study demonstrated the protein expression of GCC across various gastrointestinal malignancies. In all cancer histotypes, GCC protein localization was observed predominantly in the cytoplasm compared to the membrane region of tumor cells. Consistent immunohistochemistry detection of GCC protein expression in primary colorectal cancers and in their matched liver metastases suggests that the expression of GCC is maintained throughout the process of tumor progression and formation of metastatic disease.
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Tumeurs gastro-intestinales/enzymologie , Tumeurs gastro-intestinales/anatomopathologie , Récepteurs des entérotoxines/métabolisme , Adénocarcinome/enzymologie , Adénocarcinome/anatomopathologie , Humains , Métastase tumoraleRÉSUMÉ
BACKGROUND: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. METHODS: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n=62) or paclitaxel alone (n=60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. FINDINGS: TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p<0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n=53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n=32, 38%; HR 0.5; p=0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n=47, 39%) had a trend towards improved PFS (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; HR 0.618; p=0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. INTERPRETATION: These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted.
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Aurora kinase A/génétique , Azépines/administration et posologie , Marqueurs biologiques tumoraux/génétique , Tumeurs/traitement médicamenteux , Pyrimidines/administration et posologie , Adulte , Sujet âgé , Allèles , Azépines/effets indésirables , Survie sans rechute , Femelle , Humains , Mâle , Adulte d'âge moyen , Stadification tumorale , Tumeurs/génétique , Tumeurs/anatomopathologie , Paclitaxel/administration et posologie , Paclitaxel/effets indésirables , Polymorphisme de nucléotide simple , Inhibiteurs de protéines kinases/administration et posologie , Pyrimidines/effets indésirables , Résultat thérapeutiqueRÉSUMÉ
Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1-10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.
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Adénocarcinome/traitement médicamenteux , Anticorps monoclonaux/usage thérapeutique , Antinéoplasiques/usage thérapeutique , Immunoconjugués/usage thérapeutique , Tumeurs du pancréas/traitement médicamenteux , Adénocarcinome/métabolisme , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Anticorps monoclonaux humanisés , Femelle , Humains , Mâle , Adulte d'âge moyen , Tumeurs du pancréas/métabolisme , Récepteurs des entérotoxines/métabolisme , Tumeurs du pancréasRÉSUMÉ
BACKGROUND: One approach to identify patients who meet specific eligibility criteria for target-based clinical trials is to use patient and tumor registries to prescreen patient populations. OBJECTIVE: Here we demonstrate that the Total Cancer Care (TCC) Protocol, an ongoing, observational study, may provide a solution for rapidly identifying patients with CD30-positive tumors eligible for CD30-targeted therapies such as brentuximab vedotin. METHODS: The TCC patient gene expression profiling database was retrospectively screened for CD30 gene expression determined using HuRSTA-2a520709 Affymetrix arrays (GPL15048). Banked tumor tissue samples were used to determine CD30 protein expression by semiquantitative immunohistochemistry. Statistical comparisons of Z- and H-scores were performed using R statistical software (The R Foundation), and the predictive value, accuracy, sensitivity, and specificity of CD30 gene expression versus protein expression was estimated. RESULTS: As of March 2015, 120,887 patients have consented to the institutional review board-approved TCC Protocol. A total of 39,157 fresh frozen tumor specimens have been collected, from which over 14,000 samples have gene expression data available. CD30 RNA was expressed in a number of solid tumors; the highest median CD30 RNA expression was observed in primary tumors from lymph node, soft tissue (many sarcomas), lung, skin, and esophagus (median Z-scores 1.011, 0.399, 0.202, 0.152, and 1.011, respectively). High level CD30 gene expression significantly enriches for CD30-positive protein expression in breast, lung, skin, and ovarian cancer; accuracy ranged from 72% to 79%, sensitivity from 75% to 100%, specificity from 70% to 76%, positive predictive value from 20% to 40%, and negative predictive value from 95% to 100%. CONCLUSIONS: The TCC gene expression profiling database guided tissue selection that enriched for CD30 protein expression in a number of solid tumor types. Such an approach may improve screening efficiency for enrolling patients into biomarker-based clinical trials.
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Background The first-in-class antibody-drug conjugate TAK-264 (formerly MLN0264) consists of an antibody targeting guanylyl cyclase C (GCC) conjugated to monomethyl auristatin E (MMAE) via a peptide linker. This phase II study evaluated the efficacy and safety of TAK-264 in patients with adenocarcinoma of the stomach or gastroesophageal junction expressing GCC, who had progressed on ≥1 line of prior therapy. Methods This study used a two-stage design, with an interim analysis conducted after stage I to determine whether to continue to stage II or discontinue on the grounds of futility. Adult patients with gastric and gastroesophageal junction adenocarcinoma expressing low, intermediate, or high GCC levels received TAK-264 1.8 mg/kg as a 30-min intravenous infusion once every 21 days, for up to 1 year. The primary endpoint was objective response rate. Radiographic assessments of tumor burden were performed every 2 cycles (6 weeks). Results A total of 38 patients participated in the study. Patients received a median of 2 (range 1-14) cycles; 8 (21%) received at least 6 cycles. The most common adverse events were nausea (53%), fatigue (32%), and decreased appetite (29%). Grade ≥3 events including anemia, diarrhea, and neutropenia were seen in 14 (37%) patients. Systemic exposure to TAK-264 was maintained throughout each treatment cycle. Two patients (6%) with intermediate GCC expression had objective responses. Conclusions TAK-264 demonstrated a manageable safety profile in this patient population. The stage I interim analysis did not support continuation to stage II of the study.
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Adénocarcinome/traitement médicamenteux , Antinéoplasiques/usage thérapeutique , Tumeurs de l'oesophage/traitement médicamenteux , Immunoconjugués/usage thérapeutique , Récepteurs des entérotoxines/immunologie , Tumeurs de l'estomac/traitement médicamenteux , Adénocarcinome/métabolisme , Adénocarcinome/anatomopathologie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antinéoplasiques/effets indésirables , Antinéoplasiques/pharmacocinétique , Tumeurs de l'oesophage/métabolisme , Tumeurs de l'oesophage/anatomopathologie , Jonction oesogastrique/anatomopathologie , Femelle , Humains , Immunoconjugués/effets indésirables , Immunoconjugués/pharmacocinétique , Mâle , Adulte d'âge moyen , Récidive tumorale locale/traitement médicamenteux , Récidive tumorale locale/métabolisme , Récidive tumorale locale/anatomopathologie , Récepteurs des entérotoxines/métabolisme , Tumeurs de l'estomac/métabolisme , Tumeurs de l'estomac/anatomopathologie , Résultat thérapeutique , Charge tumorale/effets des médicaments et des substances chimiquesRÉSUMÉ
CONTEXT: - Excision repair cross-complementation 1 (ERCC1) is a key enzyme in nuclear excision repair pathway and has a critical role in helping remove DNA adducts caused by cross-linking agents, such as platinum-containing cancer chemotherapies and other DNA-damaging therapeutic modalities. ERCC1 expression, evaluated by techniques such as immunohistochemistry, has been associated with clinical response; ERCC1+ tumors are more resistant to cisplatin treatment than are ERCC1- tumors. Although several immunohistochemistry, anti-ERCC1 antibodies are available, the 8F1 clone, in particular, has been used in many studies. Recent evidence has suggested that the 8F1 antibody cross-reacts with at least one other protein, raising concerns about the specificity of this clone. OBJECTIVE: - To design an immunohistochemistry assay to detect ERCC1 levels that show dynamic range and consistent analytic performance. DESIGN: - Two different primary antibodies to ERCC1, clones 4F9 and D6G6, were evaluated on formalin-fixed, paraffin-embedded tissue. We then performed a fit-for-purpose assay validation with the 4F9 clone, which included sensitivity assessment across several solid tumor types and evaluation of analytic parameters, such as precision and reproducibility. RESULTS: - The 4F9 clone was consistently superior to the D6G6 clone in the optimization phase. A range of expression was seen in ovarian, head and neck, non-small cell lung, and esophageal cancer samples when tested with the 4F9 clone. The antibody showed acceptable reproducibility (31.02%) and precision (16.06%). CONCLUSIONS: - This assay can be used to assess ERCC1 levels during clinical studies of patient tumors from a variety of tumor types.
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Anticorps monoclonaux/métabolisme , Protéines de liaison à l'ADN/métabolisme , Endonucleases/métabolisme , Protéines tumorales/métabolisme , Tumeurs/métabolisme , Adénocarcinome/diagnostic , Adénocarcinome/métabolisme , Adénocarcinome/anatomopathologie , Spécificité des anticorps , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/métabolisme , Carcinomes/diagnostic , Carcinomes/métabolisme , Carcinomes/anatomopathologie , Carcinome pulmonaire non à petites cellules/diagnostic , Carcinome pulmonaire non à petites cellules/métabolisme , Carcinome pulmonaire non à petites cellules/anatomopathologie , Lignée cellulaire tumorale , Clones cellulaires , Études de cohortes , Protéines de liaison à l'ADN/antagonistes et inhibiteurs , Protéines de liaison à l'ADN/génétique , Endonucleases/antagonistes et inhibiteurs , Endonucleases/génétique , Femelle , Régulation de l'expression des gènes tumoraux , Tumeurs de la tête et du cou/diagnostic , Tumeurs de la tête et du cou/métabolisme , Tumeurs de la tête et du cou/anatomopathologie , Humains , Immunohistochimie , Tumeurs du poumon/diagnostic , Tumeurs du poumon/métabolisme , Tumeurs du poumon/anatomopathologie , Mâle , Protéines tumorales/antagonistes et inhibiteurs , Protéines tumorales/génétique , Tumeurs/diagnostic , Tumeurs/anatomopathologie , Tumeurs de l'ovaire/diagnostic , Tumeurs de l'ovaire/métabolisme , Tumeurs de l'ovaire/anatomopathologie , Reproductibilité des résultats , Sensibilité et spécificitéRÉSUMÉ
We report population pharmacokinetic, pharmacodynamic, and pharmacokinetic-safety analyses to support phase II/III dose/regimen selection of alisertib, a selective Aurora A kinase (AAK) inhibitor. Phase I studies in adult cancer patients evaluated dosing on Days 1-7 in 21-day cycles or Days 1-21 in 35-day cycles, with corresponding maximum tolerated doses of 50 mg twice daily (BID) and 50 mg QD, respectively. Population pharmacokinetic analyses supported dose- and time-linear pharmacokinetics without identification of clinically meaningful covariates. Exposure-related increases in skin mitotic index and decreases in chromosomal alignment/spindle bipolarity in tumor mitotic cells confirmed AAK inhibition. Exposures in the 7-day schedule at or near 50 mg BID are expected to result in tumor AAK inhibition based on pharmacodynamic assessment in patient tumors. Exposure-safety analyses of data from patients receiving doses of 5-200 mg/day in the 7-day schedule support a low (â¼7%) predicted incidence of dose-limiting toxicity at 50 mg BID. Taken together, these analyses support a pharmacologically active and acceptably tolerated dose range of alisertib for future clinical development.
Sujet(s)
Antinéoplasiques/administration et posologie , Antinéoplasiques/pharmacocinétique , Aurora kinase A/antagonistes et inhibiteurs , Azépines/administration et posologie , Azépines/pharmacocinétique , Calcul des posologies , Inhibiteurs de protéines kinases/administration et posologie , Inhibiteurs de protéines kinases/pharmacocinétique , Pyrimidines/administration et posologie , Pyrimidines/pharmacocinétique , Administration par voie orale , Antinéoplasiques/effets indésirables , Aurora kinase A/métabolisme , Azépines/effets indésirables , Essais cliniques de phase I comme sujet , Essais cliniques de phase II comme sujet , Relation dose-effet des médicaments , Humains , Dose maximale tolérée , Modèles biologiques , Inhibiteurs de protéines kinases/effets indésirables , Pyrimidines/effets indésirablesRÉSUMÉ
PURPOSE: Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas. PATIENTS AND METHODS: Patients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles. RESULTS: We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event-related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response. CONCLUSION: The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.
Sujet(s)
Antinéoplasiques/usage thérapeutique , Aurora kinase A/antagonistes et inhibiteurs , Azépines/usage thérapeutique , Lymphome de Burkitt/traitement médicamenteux , Lymphome folliculaire/traitement médicamenteux , Lymphome B diffus à grandes cellules/traitement médicamenteux , Lymphome à cellules du manteau/traitement médicamenteux , Lymphome T/traitement médicamenteux , Inhibiteurs de protéines kinases/usage thérapeutique , Pyrimidines/usage thérapeutique , Adulte , Sujet âgé , Antinéoplasiques/administration et posologie , Antinéoplasiques/effets indésirables , Antinéoplasiques/pharmacocinétique , Azépines/administration et posologie , Azépines/effets indésirables , Azépines/pharmacocinétique , Lymphome de Burkitt/enzymologie , Calendrier d'administration des médicaments , Femelle , Humains , Lymphome folliculaire/enzymologie , Lymphome B diffus à grandes cellules/enzymologie , Lymphome à cellules du manteau/enzymologie , Lymphome T/enzymologie , Mâle , Adulte d'âge moyen , Thérapie moléculaire ciblée/méthodes , Inhibiteurs de protéines kinases/administration et posologie , Inhibiteurs de protéines kinases/effets indésirables , Inhibiteurs de protéines kinases/pharmacocinétique , Pyrimidines/administration et posologie , Pyrimidines/effets indésirables , Pyrimidines/pharmacocinétique , Récidive , Résultat thérapeutiqueRÉSUMÉ
PURPOSE: Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies. METHODS: Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25-90 mg for 14 or 21 consecutive days plus 14 or 7 days' rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days' rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30-50 mg twice-daily (BID) for 7 days plus 14 days' rest in 21-day cycles. RESULTS: Fifty-eight patients were enrolled (PIC n = 28, ECT n = 30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease. CONCLUSION: The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma.
Sujet(s)
Antinéoplasiques/administration et posologie , Azépines/administration et posologie , Leucémie chronique lymphocytaire à cellules B/traitement médicamenteux , Lymphome malin non hodgkinien/traitement médicamenteux , Myélome multiple/traitement médicamenteux , Inhibiteurs de protéines kinases/administration et posologie , Pyrimidines/administration et posologie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antinéoplasiques/effets indésirables , Antinéoplasiques/pharmacocinétique , Aurora kinase A/antagonistes et inhibiteurs , Aurora kinase A/génétique , Aurora kinase A/métabolisme , Azépines/effets indésirables , Azépines/pharmacocinétique , Femelle , Humains , Leucémie chronique lymphocytaire à cellules B/génétique , Leucémie chronique lymphocytaire à cellules B/métabolisme , Lymphome malin non hodgkinien/génétique , Lymphome malin non hodgkinien/métabolisme , Mâle , Dose maximale tolérée , Adulte d'âge moyen , Myélome multiple/génétique , Myélome multiple/métabolisme , Récidive tumorale locale/traitement médicamenteux , Récidive tumorale locale/génétique , Récidive tumorale locale/métabolisme , Inhibiteurs de protéines kinases/effets indésirables , Inhibiteurs de protéines kinases/pharmacocinétique , Pyrimidines/effets indésirables , Pyrimidines/pharmacocinétiqueRÉSUMÉ
Variations within proteasome ß (PSMB) genes, which encode the ß subunits of the 20S proteasome, may affect proteasome function, assembly, and/or binding of proteasome inhibitors. To investigate the potential association between PSMB gene variants and treatment-emergent resistance to bortezomib and/or long-term outcomes, in the present study, PSMB gene sequence variation was characterized in tumor DNA samples from patients who participated in the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib versus high-dose dexamethasone for treatment of relapsed multiple myeloma. Twelve new PSMB variants were identified. No associations were found between PSMB single nucleotide polymorphism genotype frequency and clinical response to bortezomib or dexamethasone treatment or between PSMB single nucleotide polymorphism allelic frequency and pooled overall survival or time to progression. Although specific PSMB5 variants have been identified previously in preclinical models of bortezomib resistance, these variants were not detected in patient tumor samples collected after clinical relapse from bortezomib, which suggests that alternative mechanisms underlie bortezomib insensitivity.
Sujet(s)
Acides boroniques/usage thérapeutique , Dexaméthasone/usage thérapeutique , Myélome multiple/traitement médicamenteux , Myélome multiple/génétique , Proteasome endopeptidase complex/génétique , Pyrazines/usage thérapeutique , Antinéoplasiques/usage thérapeutique , Bortézomib , Cysteine endopeptidases , Résistance aux médicaments antinéoplasiques/génétique , Fréquence d'allèle , Génotype , Humains , Myélome multiple/anatomopathologie , Polymorphisme de nucléotide simple , Sous-unités de protéines/génétique , Récidive , Analyse de séquence d'ADN , Analyse de survie , Résultat thérapeutiqueRÉSUMÉ
OBJECTIVES: Aurora A kinase (AAK), a key mitotic regulator, is implicated in the pathogenesis of several tumors, including ovarian cancer. This single-arm phase II study assessed single-agent efficacy and safety of the investigational AAK inhibitor MLN8237 (alisertib), in patients with platinum-refractory or -resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS: Adult women with malignant, platinum-treated disease received MLN8237 50mg orally twice daily for 7 days plus 14 days' rest (21-day cycles). The primary endpoint was combined objective tumor response rate per Response Evaluation Criteria in Solid Tumors (RECIST) and/or CA-125 criteria. Secondary endpoints included response duration, clinical benefit rate, progression-free survival (PFS), time-to-progression (TTP), and safety. RESULTS: Thirty-one patients with epithelial ovarian (n=25), primary peritoneal (n=5), and fallopian tube carcinomas (n=1) were enrolled. Responses of 6.9-11.1 month duration were observed in 3 (10%) patients with platinum-resistant ovarian cancer. Sixteen (52%) patients achieved stable disease with a mean duration of response of 2.86 months and which was durable for ≥3 months in 6 (19%). Median PFS and TTP were 1.9 months. Most common drug-related grade≥3 adverse events were neutropenia (42%), leukopenia (23%), stomatitis, and thrombocytopenia (each 19%); 6% reported febrile neutropenia. CONCLUSIONS: These data suggest that MLN8237 has modest single-agent antitumor activity and may produce responses and durable disease control in some patients with platinum-resistant ovarian cancer. MLN8237 is currently undergoing evaluation in a phase I/II trial with paclitaxel in recurrent ovarian cancer.
Sujet(s)
Azépines/usage thérapeutique , Tumeurs de la trompe de Fallope/traitement médicamenteux , Tumeurs de l'ovaire/traitement médicamenteux , Tumeurs du péritoine/traitement médicamenteux , Pyrimidines/usage thérapeutique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Aurora kinases , Azépines/effets indésirables , Survie sans rechute , Tumeurs de la trompe de Fallope/enzymologie , Tumeurs de la trompe de Fallope/anatomopathologie , Femelle , Humains , Adulte d'âge moyen , Tumeurs de l'ovaire/enzymologie , Tumeurs de l'ovaire/anatomopathologie , Tumeurs du péritoine/enzymologie , Tumeurs du péritoine/anatomopathologie , Inhibiteurs de protéines kinases/usage thérapeutique , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Pyrimidines/effets indésirablesRÉSUMÉ
Pharmacodynamic assays are important aspects for understanding molecularly targeted anticancer agents to investigate the relationship between drug concentration (pharmacokinetics) and drug "effect" or biological activity. As new drug entities are developed that affect DNA cell cycle, a pharmacodynamic assay which measures cell cycle perturbation would be a valuable clinical trial tool. During recent years, flow cytometry has established itself as a useful method to determine the relative nuclear DNA content and percentage of cycling cells of biological specimens. However to date, the analytical validation of cytometry based assays is limited and there is no suitable guidance for method validation of flow cytometry based cell cycle assays. Here we report the validation of a flow cytometry based cell cycle G(2)/M delay assay for use in evaluating the effect of investigational drug MLN8237, a small molecule inhibitor of a mitotic kinase Aurora A, for clinical trial use. The assay method was validated by examining assay robustness, repeatability, reproducibility, precision, and determining the cutoff for a true drug effect based on biostatistical analysis models. Experimental results show that the intra-assay repeatability was less than 20% with an intra-donor variability of less than 40%. The robustness of the assay was less than 30%. Since this is an ex-vivo stimulation assay, variability parameters were expected to be higher. Based on biostatistical modeling, an absolute change in %G(2)M of 5.2% (95% CI) was needed in order to detect a true drug effect. Overall, the assay demonstrated acceptable variability to warrant further in vivo testing.
Sujet(s)
Azépines/pharmacologie , Division cellulaire/effets des médicaments et des substances chimiques , Cytométrie en flux/normes , Phase G2/effets des médicaments et des substances chimiques , Inhibiteurs de protéines kinases/pharmacologie , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Pyrimidines/pharmacologie , Anthraquinones/composition chimique , Aurora kinases , Relation dose-effet des médicaments , Cytométrie en flux/méthodes , Humains , Cinétique , Agranulocytes/cytologie , Agranulocytes/effets des médicaments et des substances chimiques , Protein-Serine-Threonine Kinases/métabolisme , Reproductibilité des résultatsRÉSUMÉ
PURPOSE: Aurora A kinase is critical in assembly and function of the mitotic spindle. It is overexpressed in various tumor types and implicated in oncogenesis and tumor progression. This trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054, a selective small-molecule inhibitor of Aurora A kinase. METHODS: In this first-in-human, dose-escalation study, MLN8054 was given orally for 7, 14, or 21 days followed by a 14-day treatment-free period. Escalating cohorts of 3-6 patients with advanced solid tumors were treated until DLT was seen in ≥2 patients in a cohort. Serial blood samples were collected for pharmacokinetics and skin biopsies were collected for pharmacodynamics. RESULTS: Sixty-one patients received 5, 10, 20, 30, or 40 mg once daily for 7 days; 25, 35, 45, or 55 mg/day in four divided doses (QID) for 7 days; or 55, 60, 70, or 80 mg/day plus methylphenidate or modafinil with daytime doses (QID/M) for 7-21 days. DLTs of reversible grade 3 benzodiazepine-like effects defined the estimated MTD of 60 mg QID/M for 14 days. MLN8054 was absorbed rapidly, exposure was dose proportional, and terminal half-life was 30-40 h. Three patients had stable disease for >6 cycles. CONCLUSIONS: MLN8054 dosing for up to 14 days of a 28-day cycle was feasible. Reversible somnolence was dose limiting and prevented achievement of plasma concentrations predicted necessary for target modulation. A recommended dose for investigation in phase 2 trials was not established. A second-generation Aurora A kinase inhibitor is in development.