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PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

This randomized, open-label trial compared the efficacy and safety of adjuvantWe assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma toTwo hundred eighty-seven of 432 patients and 310 of 434 patients completedThe primary end point (independently assessed DFS) was not met despite favorable OS seen with

TPS3157 Background: Kidney associated antigen 1 (KAAG1) is highly and selectively expressed on tumor cell surface, such as ovarian, prostate, and triple negative breast cancers (TNBC), and is rapidly internalized and co-localized with a lysosomal marker, making an ideal candidate for an antibody-drug conjugate (ADC) target. ADCT-901 is an ADC composed of a humanized monoclonal antibody IgG1 against KAAG1, conjugated through a cathepsin-cleavable linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In mouse xenograft models of human-derived TNBC, ovarian, and renal cancers significant tumor reduction was observed after a single dose of ADCT-901, providing the rationale for clinical development of a PBD-based ADC to treat KAAG1 expressing tumors (Zammarchi et al, AACR 2019). This study aims to identify the recommended dose and schedule for expansion and to characterize safety and tolerability of ADCT-901 in patients (pts) with selected advanced solid tumors that generally express KAAG1. Methods: ADCT-901-101 is a phase 1, multicenter, 2-part, open-label study that will enroll ̃70 pts (NCT04972981). Part 1: pts will receive escalating doses of ADCT-901 guided by a 3+3 design (1st dose: 15 µg/kg every 3 weeks [Q3W]; highest dose: 290 µg/kg Q3W). Dose escalation will be evaluated by administering the lowest dose to first 3 pts, then increasing/decreasing the dose based on dose-limiting toxicity (DLT) experienced by pts. The dose and schedule of ADCT-901 identified in part 1 will be tested in part 2 to characterize safety, tolerability, and preliminary efficacy of ADCT-901. Primary endpoints include incidence of DLTs (part 1 only), frequency/severity of adverse events (AE) and serious AE, clinically significant changes in vitals, laboratory values, overall tolerability, and frequency of dose interruptions and reductions. Secondary endpoints include overall response rate, duration of response, progression-free and overall survival, pharmacokinetic parameters of ADCT-901 total antibody, PBD-conjugated antibody, unconjugated SG3199 in serum, and frequency of confirmed positive antidrug antibody responses. Exploratory endpoints include tumor modulation and potential pharmacodynamic changes. Key inclusion criteria: pathologic diagnosis of selected solid tumor (cholangiocarcinoma, renal cell carcinoma, ovarian/fallopian tube and prostate cancers, TNBC) locally advanced or metastatic at time of screening, pts refractory or intolerant to existing therapy, tissue biopsy or available tissue sample, ECOG of 0-2, and adequate organ function based on predefined laboratory parameters. Pts with symptomatic CNS metastases and clinically significant third space fluid accumulation will be excluded. The study opened for recruitment in September 2021; enrollment is ongoing. Funding: ADC Therapeutics; medical writing: CiTRUS Health Group. Clinical trial information: NCT04972981.

Background The phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study. Patients and methods Paediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m2 of nab-paclitaxel on days 1, 8 and 15 of each 28-day cycle. The primary end-point was the overall response rate (ORR; complete response [CR] + partial response [PR]). Secondary end-points included duration of response, disease control rate (DCR; CR + PR + stable disease [SD]), progression-free survival, 1-year overall survival, safety and pharmacokinetics. Results Forty-two patients were enrolled, 14 each with Ewing sarcoma, neuroblastoma and rhabdomyosarcoma. The ORRs were 0%, 0% and 7.1% (1 confirmed PR), respectively. The DCRs were 30.8% (4 SD), 7.1% (1 SD) and 7.1% (1 confirmed PR and 0 SD) in the Ewing sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively. The median progression-free survival was 13.0, 7.4 and 5.1 weeks, respectively, and the 1-year overall survival rates were 48%, 25% and 15%, respectively. The most common grade III/4IVadverse events were haematologic (neutropenia [50%] and anaemia [48%]), and grade III/IV peripheral neuropathy occurred in 2 patients (14%) in the rhabdomyosarcoma group. Pharmacokinetics analyses revealed that paclitaxel tissue distribution was both rapid and extensive. Conclusions In this phase II study, limited activity was observed; however, the safety of nab-paclitaxel in paediatric patients was confirmed. Trial registration NCT01962103 and EudraCT 2013-000144-26.

Background nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. Patients and methods Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Results Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m2 and grade 4 neutropenia >7 days at 270 mg/m2. The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1–2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m2. Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. Conclusions nab-Paclitaxel 240 mg/m2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. ClinicalTrials.gov NCT01962103. EudraCT 2013-000144-26.

9029 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 Treg, MDSC, TCM, 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.

2547Background: Citarinostat is an oral, selective histone deacetylase 6 inhibitor that inhibits growth of solid tumor cell lines and exhibits potent synergy with Pac in preclinical studies. We con...

En ce qui concerne Ia politique sur plantes genetiquement modifiees, l'Afrique est un terrain de luttes d'influence et de debats. Les enjeux sont a la fois economiques, politiques et ecologiques. Dans cet article, nous montrons que les biotechnologies vegetales sont l'une des techniques, a combiner avec d'autres, qui pourraient permettre d'assurer la securite alimentaire et sanitaire de l'Afrique, et que les risques qu'entraineront l'utilisation de cette technique doivent etre soigneusement analyses. Nous presenterons ensuite la position des differents pays africains vis-a-vis des conventions internationales (propriete intellectuelle, biosecurite et commerce) et nous caracteriserons leurs politiques nationales et de recherche vis-a-vis des OGM. (Resume d'auteur)