Histone deacetylase (HDAC) overexpression has been documented in various cancers and may be associated with worse outcomes. Data from early-phase studies of advanced non-small cell lung cancer ...(NSCLC) suggest encouraging antitumor activity with the combination of an HDAC inhibitor and either platinum-based chemotherapy or an EGFR inhibitor; however, toxicity is a limiting factor in the use of pan-HDAC inhibitors. Selective inhibition of HDAC6 may represent a potential therapeutic target and preclinical studies revealed immunomodulatory effects with HDAC6 inhibition, suggesting the potential for combination with immune checkpoint inhibitors. This phase Ib, multicenter, single-arm, open-label, dose-escalation study investigated the HDAC6 inhibitor ACY-241 (citarinostat) plus nivolumab in patients with previously treated advanced NSCLC who had not received a prior HDAC or immune checkpoint inhibitor.
The orally administered ACY-241 dose was escalated (180, 360, or 480 mg once daily). Nivolumab was administered at 240 mg (day 15 of cycle 1, then every 2 weeks thereafter). The primary endpoint was to determine the maximum tolerated dose (MTD) of ACY-241 plus nivolumab. Secondary endpoints included safety, tolerability, and preliminary antitumor activity. Pharmacodynamics was an exploratory endpoint.
A total of 18 patients were enrolled, with 17 patients treated. No dose-limiting toxicities (DLTs) occurred with ACY-241 at 180 or 360 mg; 2 DLTs occurred at 480 mg. The MTD of ACY-241 was 360 mg. The most common grade ≥ 3 treatment-emergent adverse events were dyspnea (n = 3; 18%) and pneumonia (n = 3; 18%). At the 180-mg dose, 1 complete response and 2 partial responses (PRs) were observed. At the 360-mg dose, 3 PRs were observed; 1 patient achieved stable disease (SD) and 1 experienced progressive disease (PD). At the 480-mg dose, no responses were observed; 1 patient achieved SD and 3 experienced PD. Acetylation analyses revealed transient increases in histone and tubulin acetylation levels following treatment. An increase in infiltrating total CD3
T cells was observed following treatment.
The study identified an MTD for ACY-241 plus nivolumab and the data suggest that the combination may be feasible in patients with advanced NSCLC. Responses were observed in patients with advanced NSCLC.
https://clinicaltrials.gov/ct2/show/NCT02635061 (identifier, NCT02635061).
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Background: Identification of new regimens for patients (pts) with relapse/refractory NSCLC is an ongoing need. HDAC inhibitor monotherapy has cytostatic activity in pts with ...NSCLC. The HDAC6 inhibitor ACY-241 has immunomodulatory activity and may synergize with immune checkpoint inhibitors (ICI). This phase Ib study investigated ACY-241 + nivo in metastatic NSCLC. Methods: Previously platinum-treated, ICI-naïve pts with advanced NSCLC and ECOG PS ≤ 1 were eligible. In 3 + 3 dose-escalation, pts received ACY-241 (180, 360, or 480 mg PO; d 1-28) + nivo 240 mg on d 15 of cycle 1 and d 1,15 subsequently in 28-d cycles. Primary outcomes: safety and RP2D. Secondary outcome: antitumor activity. Exploratory outcome: biomarker analyses; peripheral blood samples and tumor biopsies were collected pre- and on-treatment. Results: As of Jan 17, 2019, 18 pts were treated. Median age 66 y; 56% male, 78% PS 1, 93% stage IV, 28% PD-L1–negative, and 89% adenocarcinoma (11% squamous). No DLTs were observed at ACY-241 180 or 360 mg, and 2 DLTs were observed at 480 mg (gr 3 nausea lasting > 72 h despite medication; gr 5 cardiac arrest); 360 mg was declared RP2D. Common all-grade AEs: fatigue (22%), arthralgia (17%), and cough (17%); 1 gr 3 cerebrovascular accident (related to brain metastasis unrelated to study drug) and 1 additional gr 5 AE (myasthenia gravis, possibly related to ACY-241 and nivo) occurred. Of 13 response-evaluable pts, 8 had clinical benefit (1 CR, 3 PR 1 PD-L1–negative, 1 unconfirmed PR tumor shrinkage followed by new lesion, 3 SD); 5 had PD. At data cutoff, treatment was ongoing in 5 pts (12 – 30 cycles). Histone and tubulin acetylation levels were transiently increased after treatment. Circulating IL-2, IL-1β, MMP-9, and IL-10 levels increased, with undetectable TNF-α and IFN-γ modulation. Treatment-related changes in tumor-infiltrating T
reg
, MDSC, T
CM
, and macrophages varied between pts but revealed a trend of increased infiltrating cytotoxic T and NK cells. Conclusions: The ACY-241 + nivo combination is feasible and can be considered for further research as a potential NSCLC treatment option. Biomarker analyses may help identify an optimal population for the combination. Clinical trial information: NCT02635061.
Treatment options are limited for recurrent nasopharyngeal carcinoma (NPC). We report results from a phase II study of CC-486 (oral azacitidine) in advanced NPC.
Patients with locally advanced or ...metastatic NPC and 1–2 prior treatment regimens received CC-486 300 mg daily on days 1–14 of 21-day cycles until disease progression or unacceptable toxicity. The first 6 patients of Asian-Pacific Islander (API) ethnicity received a reduced dose of 200 mg to preserve safety and tolerability; if well tolerated, subsequent API patients received CC-486 300 mg. The study could advance to stage 2 if > 4 patients achieved a response. Co-primary end-points were overall response rate (ORR) and progression-free survival (independent review). Key secondary end-points were overall survival and safety.
Owing to faster-than-anticipated enrolment, 36 patients, including 13 of API ethnicity, were enrolled; the median age was 54.0 years. Most patients were male (81%) and had an Eastern Cooperative Oncology Group performance status ≤ 1 (97%). Among 25 efficacy-evaluable patients, the ORR was 12%; the median progression-free and overall survival were 4.7 and 18.0 months, respectively. The most common grade III/IV treatment-emergent adverse events were neutropenia (33%) and febrile neutropenia (11%). Twenty-one posttreatment deaths, primarily due to progressive disease or disease complications, and 1 on-treatment death (epistaxis, unrelated to study drug) occurred. The study did not advance to stage 2.
CC-486 did not show sufficient clinical activity to support further development as monotherapy in this patient population. The safety profile of CC-486 in NPC was consistent with that in other solid tumours.
•Treatment options are limited for advanced nasopharyngeal carcinoma (NPC).•Patients with advanced NPC and ≤2 prior regimens received CC-486 (oral azacitidine).•Overall response rate was 12%, and median progression-free survival was 4.7 months.•CC-486 showed insufficient activity to support further development in advanced NPC.•The safety profile of CC-486 in NPC was consistent with that in other solid tumours.
Abstract
Background: TNMBC has an aggressive clinical course and poor prognosis. In phase II trials, nab-P–based therapy has demonstrated efficacy and tolerability as first-line therapy, in patients ...with MBC. The international triple-negative Albumin-bound paclitaxel combination treatment study (tnAcity) will evaluate 2 nab-P regimens (with either Gem or Carbo) and compare the selected regimen with Gem/Carbo as first-line treatment for TNMBC.
Trial design: All patients must have pathologically confirmed TNBC (TN defined as < 1% estrogen receptor and progesterone receptor expression by immunohistochemistry (IHC) and 0 - 1+ human epidermal growth factor receptor 2 expression by IHC or confirmed negative by fluorescence in situ hybridization) with measurable metastatic disease. Eligibility criteria include no prior cytotoxic therapy for MBC, prior adjuvant or neoadjuvant anthracycline use unless not indicated by physician or other appropriate regimens were administered, and no history or current evidence of brain metastasis. Prior neoadjuvant or adjuvant chemotherapy must have been completed ≥ 6 months before randomization (≥ 12 months if using taxane-, Gem-, or platinum-containing regimen). Patients will be enrolled internationally in North America, Europe, Latin America, and Australia. In the phase II portion, 240 patients will be randomized to receive nab-P 125 mg/m2 plus Gem 1000 mg/m2 (arm A), nab-P 125 mg/m2 plus Carbo area under the curve (AUC) 2 (arm B), or the control regimen of Gem 1000 mg/m2 plus Carbo AUC 2 (arm C), all given intravenously on days 1 and 8 of a 21-day cycle. The phase II portion will identify the nab-P combination to be evaluated in the phase III portion based on efficacy and safety (Table 1). In the phase III portion, 550 patients will receive the selected nab-P regimen (A or B) or Gem/Carbo. The primary endpoint of the phase III portion is progression-free survival (PFS) by independent radiological assessment; secondary endpoints include overall response rate (ORR), overall survival (OS), disease control rate, duration of response, and safety (Table 1). Monotherapy is allowed in the event of hypersensitivity or toxicity to 1 of the treatment components. The trial design provides ≈ 90% power to detect a hazard ratio of 0.70 for PFS with a 2-sided 5% significant level. Current enrollment is 52 patients. Clinical trial NCT01881230.
Trial Design
ParameterPhase IIPhase IIINn = 240n = 550Randomization1:1:11:1StratificationDisease-free interval (DFI): ≤ 1 y vs > 1 yDFI: ≤ 1 y vs > 1 y Prior neo/adjuvant taxane (yes vs no)Key EndpointsPrimaryPFS by investigator assessmentPFS by independent assessment SecondaryORR by investigator assessmentORR Percentage of patients to initiate cycle 6OS OSPFS by investigator assessment SafetyDisease control rate Duration of response Safety ExploratoryTime to second-line therapy or deathTime to second-line therapy or death Circulating tumor cellsQuality of life Tumor biomarkersHealthcare resource utilization Tumor biomarkers
Citation Format: Denise A Yardley, Robert E Coleman, Pierfranco Conte, Joyce O'Shaughnessy, Javier Cortes, Stefan Glück, Adam Brufsky, Jean-Marc A Nabholtz, Li Li, JulieAnn Miller, Debora Barton, Nadia Harbeck, on bahalf of the tnAcity Investigators. tnAcity: A phase II/III trial of nab-paclitaxel (nab-P) plus either gemcitabine (Gem) or carboplatin (Carbo) vs Gem/Carbo as first-line treatment for patients with triple-negative metastatic breast cancer (TNMBC) abstract. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-2-01.
People often use strategic self-presentation to portray themselves in a favorable light. The current research used an online dating procedure to examine how perception of a potential romantic ...partner’s interest and liking influences one’s use of strategic self-presentation. During the study, participants were led to believe that they would meet a potential dating partner, when in reality the potential partner situation was achieved through a cover story. To measure participants’ use of strategic self-presentation, the study used changes between participant self-ratings prior to a manipulation and self-ratings one week later after the experimental manipulation at a second session. These self-ratings involved two trait variables (positive traits and negative traits, based on four specific traits) and one interest variable (based on two specific interests), which were endorsed in the fictitious partner profile. I manipulated two independent variables: (1) how much the potential partner allegedly liked the participant (low, moderate, high liking), and (2) whether the potential partner allegedly would see the participant’s ratings of their traits and interests (private versus public responses). It was expected that, among participants whose responses were allegedly shown to their partner (public response condition), participants would be more likely to change their self-ratings if they believed the partner moderately liked them (moderate perceived liking), compared to if they believed the partner liked them a lot or a little (high, low perceived liking, respectively). The results failed to support this hypothesis. Exploratory analyses for several different moderators are discussed.
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