Recommended Dose Research Articles

1198P - FPA150 (B7-H4 antibody) phase I update in advanced solid tumours: Monotherapy and in combination with pembrolizumab

1198P - FPA150 (B7-H4 antibody) phase I update in advanced solid tumours: Monotherapy and in combination with pembrolizumab

Safety, PK and preliminary efficacy of talazoparib in Japanese patients with advanced solid tumors; Phase 1 Study

Abstract Background Talazoparib is a potent, orally bioavailable, small molecule poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. The recommended dose (RD) of single-agent talazoparib in non-Japanese patients (pts) was determined as 1 mg/day [QD]. This ongoing Phase 1 study evaluated the safety, preliminary efficacy, and PK profile of single-agent talazoparib in Japanese pts with advanced solid tumors. Methods Primary endpoint was first-cycle dose limiting toxicity (DLT). The single dose and multiple-dose PK and anti-tumor activity were evaluated as secondary endpoints. Two dose levels (0.75 mg and 1 mg QD) of talazoparib were studied using modified 3 + 3 dose escalation scheme. Talazoparib was administered continuously with the cycle length of 28 days. Results A total of 9 pts (3 pts in 0.75 mg and 6 pts in 1 mg QD) with a variety of tumor types were enrolled. No DLT was reported in either dose levels. The most common treatment-related (TR) adverse events (AEs) were neutrophil count decreased, platelet count decreased and stomatitis (22.2%, 2 pts each). No grade 3 or more TRAEs were reported. Based on the preliminary PK analysis, the median time to reach maximum plasma concentration (Tmax) was ranging from 1.0 to 2.0 hours. Talazoparib was eliminated with terminal phase half-life ranging from 49 to 133 hours after single dose. The distributions of maximum plasma concentration (Cmax) and area under concentration-time curve (AUC) after single and multiple dose were within the range of those in non-Japanese pts. RD in Japanese pts was determined to be 1 mg QD. Conclusions No DLT was reported in Japanese pts who received up to 1 mg QD. Hematological toxicity was common AEs in Japanese pts as well as non-Japanese pts. RD in Japanese pts was determined as 1 mg QD. The PK profile in Japanese pts was comparable with that in non-Japanese pts. Now the study is expanding to evaluate the efficacy in Japanese pts with germline BRCA mutated advanced breast cancer.

456P - First-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumours

456P - First-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumours

P1.14-30 Phase I Study of Afatinib Plus Bevacizumab in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations

Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is one of the standard therapies for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. The first-generation EGFR-TKIs in combination with bevacizumab have been reported to improve progression-free survival (PFS). However, data on afatinib plus bevacizumab are limited. In this phase I study, we examined the safety and the efficacy of afatinib plus bevacizumab in patients with advanced non-squamous NSCLC harboring EGFR mutations. This study comprised two cohorts. In the dose-finding cohort, eligible patients received afatinib 20, 30, or 40 mg/day (days 1–21) plus bevacizumab 15 mg/kg (day 1) in 21-day cycles. This cohort was designed and conducted in a 3 + 3 manner. In the expansion cohort, the patients were treated with the recommended dose (RD) based on the findings in the dose-finding cohort, and we evaluated the preliminary efficacy of this combination therapy. The serum trough concentration of afatinib was assessed at the steady state. Sixteen patients were enrolled in this study (5 patients in the dose-finding cohort and 11 patients in the expansion cohort). No dose-limiting toxicities (DLTs) occurred with afatinib 30 mg/day. With afatinib 40 mg/day, 2 out of 2 patients had DLTs (grade 3 diarrhea) in cycle 1. From these results, afatinib 30 mg/day plus bevacizumab 15 mg/kg was decided as the RD. Additionally, 11 patients in the expansion cohort were treated with RD. Common treatment-emergent adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs and interstitial lung disease. The response rates and median PFS were 56% and 16.8 months in EGFR-TKI naïve patients, and 0% and 4.9 months in patients pretreated with EGFR-TKIs. The median serum concentration at the steady state was 13.7 ng/mL (range: 8.1–38.1 ng/mL) in the patients treated with the RD. Rebiopsy was conducted in eight patients after disease progression with afatinib plus bevacizumab, and three patients acquired an exon 20 T790M mutation. Afatinib 30 mg/day plus bevacizumab 15 mg/kg was well tolerated. Large-scale studies are warranted to evaluate the efficacy of this combination therapy.

704P - Results from phase I study of the oncolytic viral immunotherapy agent Canerpaturev (C-REV) in combination with gemcitabine plus nab-paclitaxel as first-line treatment of unresectable pancreatic cancer

704P - Results from phase I study of the oncolytic viral immunotherapy agent Canerpaturev (C-REV) in combination with gemcitabine plus nab-paclitaxel as first-line treatment of unresectable pancreatic cancer

A phase I dose-escalation trial of stereotactic body radiotherapy using 4 fractions for patients with localized prostate cancer

PurposeTo report results from our phase I dose-escalation study of stereotactic body radiotherapy (SBRT) using 4 fractions for patients with localized prostate cancer.Materials & methodsFraction sizes of 8 Gy, 8.5 Gy, and 9 Gy were defined as levels 1, 2, and 3. The prescribed dose was delivered to at least 95% of the planning target volume. Image-guided, intensity-modulated radiotherapy was delivered to all patients. Dose-limiting toxicity (DLT) was defined as acute toxicity of Grade 3 or higher. The maximum tolerated dose (MTD) was defined as the level at which ≥30% of patients showed DLT. The recommended dose (RD) was defined to be one dose level below the MTD. If no patients at level 3 showed DLT, level 3 was defined as the recommended dose (RD).ResultsNine patients were enrolled in each level. All patients were low or intermediate risk. Median durations of follow-up for patients at levels 1–3 were 48.9 months, 42.6 months, and 18.4 months, respectively. Protocol treatment was completed for all patients. No patient showed DLT at each dose level. Level 3 was therefore designated as the RD for the phase II study. Although most toxicities were Grade 1, genitourinary toxicity was common compared to gastrointestinal toxicity. Three-year biochemical control rate was 90.3%.ConclusionThe dose level of 36 Gy in 4 fractions with a 2-day break was tolerable and highly encouraging for SBRT of localized prostate cancer. The phase II trial to confirm the efficacy and toxicity of this treatment is now on going.Trial registrationUMIN, UMIN000010236. Registered 13 March 2013.

In Vitro Integration of Trichoderma Harzianum with Chemical Pesticides Pertain to different Classes

Mycoparasitic play a vital role in biological control and IPM. Trichoderma harzianum has the potential to control a large number of plant pathogenic fungi. Application Trichoderma harzianum in IPM require knowing the potential effect resulted from combination with chemical pesticides, so, the study test the mixabilities of common chemical pesticides with T. harzianum radial growth, sporulation and biomass production of the fungus at 0.1, 0.5 and 1 of recommended dose (RD) concentrations. Based on comparison between the tested insecticides on mycelial growth, T. harzianum showed profuse mycelial growth with etoxazole followed by teflubenzuron, while, profenofos caused complete inhibition. On the other hand, the tested fungicides showed that penconazole was the most toxic fungicide inhibited completely the mycelial growth with all tested concentrations, while, copper oxychloride+metalaxyl cause the same effect on the two higher concentrations. Finally, the tested herbicides showed that glyphosate isopropylammonium and bentazone inhibited completely the mycelial growth of T. harzianum at 1 RD, while, lower two concentrations caused a middle inhibition effect. The best sporulation results were obtained from etoxazole, bentazone, teflubenzuron and diniconazole, to surpass the control, while, the rest of the pesticides either significantly reduced or prevent sporulation completely. Based on mycelial dry weight, bentazone surpassed the control. The study recommends mixing T. harzianum with diniconazole, etoxazole, teflubenzuron and bentazone, respectively. Whereas, penconazole and profenofos are completely in compatible with T. harzianum but the rest of tested pesticides has antisporulant effect and mycelial growth inhibition was high and depend on exposure concentration.

A Phase I Study of Neoadjuvant Capecitabine, Oxaliplatin, and Irinotecan (XELOXIRI) in Patients with Locally Advanced Rectal Cancer

Objectives: The aim of this study was to determine the recommended dose (RD) of capecitabine combined with oxaliplatin and irinotecan (XELOXIRI) as a neoadjuvant chemotherapy in patients with locally advanced rectal cancer. Method: Patients received irinotecan and oxaliplatin (85 mg/m²) on day 1, and capecitabine (1,000 mg/m² orally twice daily) on days 1–7 of a biweekly schedule. Three dose levels, ranging from 100 to 150 mg/m², were explored for irinotecan in sequential cohorts of 6 patients. Dose-limiting toxicities (DLTs) were assessed in the first cycle to determine the RD. Results: Six patients were enrolled. The DLT was grade 3 febrile neutropenia, which was observed in 2 of the 6 patients at dose level 1. The RD of irinotecan was defined as 150 mg/m². Toxicity was manageable: the most common grade ≥3 toxicities were neutropenia (2 patients), anemia (1 patient), and anorexia (1 patient). Nodal downstaging (cN+ to ypN0) was detected in 2 patients and the T stage was downstaged in 3 patients. Conclusions: XELOXIRI is a feasible and active regimen for patients with locally advanced rectal cancer. Febrile neutropenia was the DLT, and the RD of irinotecan is 150 mg/m².

Effects of two common fungicides on the reproduction of Aporrectodea caliginosa in natural soil

The use of pesticides in agroecosystems can have negative effects on earthworms, which play key roles in soil functioning such as organic matter decomposition. The aim of this study was to assess the effects of two fungicides (Cuprafor micro®, composed of copper oxychloride, and Swing Gold®, composed of epoxiconazole (EPX) and dimoxystrobin (DMX)) on earthworm reproduction by exposing adults and cocoons. First, adult Aporrectodea caliginosa individuals were exposed for 28 days to 3.33, 10 and 30 times the recommended dose (RD) of Cuprafor micro® corresponding to 25.8, 77.5 and 232.5 mg kg−1 dry soil of copper, respectively, and 0.33, 1 and 3 times the RD of Swing Gold® (corresponding to 5.2 × 10−2 mg DMX kg−1 + 1.94 × 10−2 mg EPX kg−1, 1.55 × 10−1 mg DMX kg−1 + 5.81 × 10−2 mg EPX kg−1 and 4.62 × 10−1 mg DMX kg−1 + 1.74 × 10−1 mg EPX kg−1 respectively), in addition to a control soil with no fungicide treatment. Cocoon variables (production, weight, hatching success, hatching time) were monitored. Second, “naïve” cocoons produced by uncontaminated earthworms were exposed to soils contaminated by the same concentrations of the two fungicides, and we assessed hatching success and hatching time. In the first experiment, cocoon production was halved at the highest copper concentration (232.5 mg Cu kg−1 of dry soil) as compared to the control. Cocoons took 5 more days to hatch, and the hatching success decreased by 35% as compared to the control. In the Swing Gold® treatments, cocoon production was reduced by 63% at 3 times the RD, and the hatching success significantly decreased by 16% at the RD. In the second experiment, only the hatching success of cocoons was impacted by Swing Gold® at 3 times the RD (30% less hatching). It is concluded that the cocoon stock in the soil is crucial for the renewal of populations in the field. The most sensitive endpoint was the hatching success of the cocoons produced by exposed adults. This endpoint and the effects observed on the “naïve” cocoons could be taken into account in pesticide risk assessment.

Real-world short-term effectiveness of ustekinumab in 305 patients with Crohn's disease: results from the ENEIDA registry.

There are limited data of ustekinumab administered according to the doses recommended in the UNITI studies. To assess the real-world, short-term effectiveness of ustekinumab in refractory Crohn's disease (CD) METHODS: Multicentre study of CD patients starting ustekinumab after June 2017 at the recommend dose (260, 390 or 520mg based on weight ~6mg/kg IV week 0 and 90mg subcutaneously week 8). Values for Harvey-Bradshaw Index (HBI), C-reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 8 and 14. Demographic and clinical data, previous treatments, AEs and hospitalisations were documented. Possible predictors of clinical remission were examined. Three hundred and five patients were analysed (≥2 previous anti-TNFα therapies 64% and vedolizumab 29%). At baseline, 217 (72%) had an HBI >4 points. Of these, 101 (47%) and 126 (58%) achieved clinical remission at weeks 8 and 14, respectively. FC levels returned to normal (<250µg/g) in 46% and 54% of the patients at weeks 8 and 14 respectively. CRP returned to normal (<3mg/L) in the 35% and 41% of the patients at week 8 and 14 respectively. AEs were recorded in 38, and 40 patients were hospitalised. Intolerance to the most recent anti-TNF agent and fewer previous anti-TNF agents were associated with clinical remission at week 14. Endoscopic severity was associated with poor response. This is the first study to show the real-world effectiveness and safety of ustekinumab administered according to the recommended induction regimen in a cohort of highly refractory CD patients.

Phase I/II Clinical Trial of Weekly Intraperitoneal Paclitaxel (IP-PTX) with Monthly Intravenous Carboplatin (IV-CBDCA) for Minimal Residual Disease of Ovarian, Tubal, and Peritoneal Carcinoma

We conducted weekly intraperitoneal administration of paclitaxel (IP-PTX) with monthly intravenous administration of carboplatin (IV-CBDCA), as a prospective phase 1/2 setting. The purpose of this study was to assess the pharmacokinetics and to decide the recommended dose (RD) according to modified Fibonacci method. Patients aged 20-75 years old with histological confirmed mullerian cancers (epithelial ovarian cancer; EOC, fallopian tubal cancer; FTC, and primary peritoneal cancer; PPC) from stage IC to IV or the patients with recurrent disease with small residual disease (including retention of ascetic fluid, para-aortic nodes recurrence after optimal debulked after interval debulking surgery; IDS) were eligible. The protocol regimen consisted of IP-PTX on day1 (D1), 8, and 15, at a starting dose level 1(DL1) of 45 mg/m2, with 15 mg/ m2 incremental, and IV-CBDCA was fixed dose AUC 5.0 mg/mL.min on D1, monthly. The accrual period was from August 2000 until September 2005. As for result, twelve patients were enrolled. No dose limiting toxicity (DLT) was observed in DL1. In dose level 2 (DL2, 60 mg/m2), one grade 3 (G3) hypersensitive reaction to CBDCA was detected. Further 5 patients had been enrolled but additional DLT was not identified. The RD was decided as DL2, which was the same dose of RD in weekly IP-PTX reported by Francis et al. The serum AUCs of PTX in DL1 and DL2 were 1605 nM.min and 2365 nM.min, respectively. By serum CA125, five complete responses were observed out of 8 evaluable patients by Rustin’s criteria. In conclusion, the combination of weekly IP-PTX and monthly IV-CBDCA at AUC 5.0 mg/mL.min was feasible and the recommended dose of IP-PTX was 60 mg/m2. The therapy was moderate effective for optimal debulking mullerian carcinomas. From our pharmacokinetic results, as for the patients with extra-pelvic lesions, additional IV-PTX would be necessary like GOG 172 experimental arm.

Influence of boron fertilization on cauliflower productivity, nutrient uptake and soil nutrient status in an acid Alfisol in Northwestern Himalaya

ABSTRACTModern agriculture over the years has resulted in depletion of boron (B) from soil which has been emerged as a serious obstacle for sustainable agriculture. We studied the availability of B in soil and cauliflower (Brassica oleracea var. botrytis L.) productivity under different levels of B fertilization. A field experiment was conducted during 2013–2014 and 2014–2015, at experimental farm of Himachal Pradesh Agricultural University, Palampur on silt-clay loam soil (acid Alfisol) under mid hill wet temperate condition. Different levels of B for the study included 0, 0.75, 1.5, 2.5, 5, 10, 20 and 30 kg B ha−1 along with recommended dose (RD) of NPK and farmyard manure (FYM, 20 t ha−1). The application of B influenced biological yield significantly up to 5 kg ha−1. Highest curd yield in 2013–2014 (11.03 t ha−1) and 2014–2015 (12.93 t ha−1) was recorded in 1.5 and 0.75 kg ha−1 B along with NPK + FYM, respectively. At higher rates of boron i.e. 10, 20 and 30 kg ha−1, due to toxic effects, a reduction in curd yield was recorded in both years. Maximum mean uptake of N, P and K by leaves and curd was recorded with the application of boron at 1.5 kg ha−1, whereas mean B uptake was highest when boron was applied at 2.5 kg ha−1. The highest mean value (1.79 mg kg−1) of soil available boron was recorded with 30 kg B ha−1. Application of boron at 2.4 kg ha−1 was worked out as optimum dose for cauliflower.

Production and Economics of Hybrid Tomato (Solanum lycopersicum) under Drip Fertigation

A field study was conducted at experimental farm of Interfaculty Department of Irrigation Water Management, Post Graduate Institute, M.P.K.V., Rahuri, Maharashtra, India during Rabi season of 2014-15. The experiment was laid out in randomized block design with eight treatments and three replications. The treatments consisted of four levels of fertilizer application as 100%, 75%, 75% with foliar sprays and 50% recommended dose (RD) under drip fertigation (DF) and compared with conventional irrigation and conventional fertilizer application. The significantly higher yield (52.62 t ha-1) of tomato was obtained in DF with 100% RD and it was at par with DF with 75% RD + 3 foliar sprays, DF with 100% RD, N and K drip, P through soil and DF with 75% RD. The drip method had lowest water use (458.4 mm) as compared with 878.6 mm in surface irrigation method. The treatment consisting DF with 100% RD provided net seasonal income (Rs. 3,93,311 ha-1), net extra income over control (Rs.1,52,056 ha-1). The maximum B:C ratio (3.96) was observed in DI with 100% RD, N and K drip, P through soil followed by DF with 100% RD. The fertigation with 75% RD in 18 weekly splits as per schedule is the best treatment for improved growth, yield and water productivity of tomato (var. Abhinav) cultivated in silty clay loam soils of Western Maharashtra.

Nutrient Use and Yield of Banana as influenced by Fertigation

A field experiment was conducted during 2010-2011 in medium deep clay soils at the Research Farm of Mahatma Phule Krishi Vidyapeeth, Rahuri, Maharashtra to find out the effect of drip fertigation on yield and nutrient use efficiency of banana (cv. Grand naine). The treatments comprised of 100, 80 and 60 % recommended dose (RD) of fertilizer applied through drip in two schedules (Schedule A-equal, Schedule B crop growth stage), drip irrigation with only N through drip, drip with conventional fertilizers through soil and surface irrigation as control. The drip irrigation increased banana yield by 59.6 per cent and saved fertilizer to the tune of 40 per cent .The treatment comprising of 100 % RD of fertigation (schedule B) had maximum banana yield (81.84 t ha-1) over surface irrigation (51.26 t ha-1), however, it was at par with 100 % RD of fertigation in uniform 16 splits and 80 % RD of fertigation. Application of water soluble fertilizers through drip resulted in highest nutrient availability than control. In general, 100 % RD had the highest nutrient availability than 80 % and 40 % RD of fertilizer. The nutrient availability was more in treatment in which fertilizers were applied as per growth stages (schedule B) than equal splits (schedule A). The uptake of nutrients was higher in fertigated treatments than other treatments

PS1344 PHASE 1/2 STUDY OF DSP‐7888 IN PATIENTS WITH HIGHER‐RISK (HR) MYELODYSPLASTIC SYNDROMES (MDS) AFTER FAILURE OF AZACITIDINE (AZA) THERAPY

Background:Although azacitidine (AZA) is the standard frontline therapy for higher‐risk (HR) myelodysplastic syndromes (MDS), approximately 40% of patients fail to respond and almost all responders eventually relapse. The prognosis for patients after AZA failure is poor with no approved therapeutic options and a median overall survival (OS) of approximately 6 months from treatment failure (Prebet T, et al. J Clin Oncol. 2011;29:3322–7.). Wilms’ tumor 1 (WT1) is constantly expressed in the leukemic cells of acute leukemia and MDS, and it is considered a prominent therapeutic target for MDS. DSP‐7888 is a WT1‐based cancer vaccine containing peptides that induce WT1‐reactive cytotoxic T lymphocytes and helper T cells. A partial peptide of DSP‐7888, WT4869 showed preliminary clinical activity in HR‐MDS (Ueda Y, et al. Cancer Sci. 2017;108:2445–53.). We hypothesized that DSP‐7888 could have significant clinical activity in HR‐MDS.Aims:This uncontrolled, open‐label, multicenter Phase 1/2 clinical trial was designed to determine the recommended dose (RD) of DSP‐7888 and evaluate its safety and clinical activity, including OS, in patients with HR‐MDS after AZA treatment failure (NCT02436252).Methods:The RD of DSP‐7888 was determined in Phase 1 using a 3+3 design that included two dose levels (3.5 and 10.5 mg/body). Eligible patients had HR‐ or lower‐risk MDS but not chronic myelomonocytic leukemia or refractory anemia with excess blasts in transformation. To evaluate clinical activity, the Phase 2 trial included 42 patients with MDS who showed no response to AZA treatment (including eligible patients from Phase 1). Patients were administered DSP‐7888 in solution intradermally with the RD—100 μL at six sites for 10.5 mg. Study drug was given every 2 weeks for 6 months and then every 2 to 4 weeks until no clinical benefit was seen. The primary endpoint was OS. Written informed consent was obtained from all patients.Results:Overall 47 patients received DSP‐7888 in Phase 1 (n = 12) and Phase 2 (n = 35). No dose‐limiting toxicities (DLT) were observed for 3.5 mg or 10.5 mg in the DLT evaluation period (first 2 cycles of DSP‐7888 in Phase 1). RD was determined to be 10.5 mg.The safety population included all patients who received the study drug (N = 47). The most common adverse events (AEs) were injection site reactions (ISR) in 91.5% (n = 43) of all patients; 27.9% were grade 1, 37.2% grade 2, 34.9% grade 3, and no grade 4. Other than ISR, AEs related to study drug seen in &gt;5% included pyrexia (10.6%) and febrile neutropenia (8.5%).The Phase 2 clinical activity analysis was performed on patients with HR‐MDS (N = 42) and included those from Phase 1 who met the criteria (n = 7); 76.2% were male and median age was 74.0 years (range: 63–93). The median OS was 8.5 months (90% CI: 6.8–11.1). The disease control rate was 19.5% with a median duration of response of 2.7 months. (The disease control rate included patients who had achieved a complete response [CR], partial response, marrow CR, or stable disease.) Hematologic improvement was seen in 9.8% of patients. The median time to transformation to acute myeloid leukemia or death was 5.7 months (90% CI: 3.6–7.1).Of the 42 patients, 37 were evaluable for WT1 reactive immune response and the results are shown in the Table.Summary/Conclusion:DSP‐7888 was tolerable and showed signs of clinical activity in patients with HR‐MDS; those who had a positive immune response showed a significantly longer OS than those who were negative. Identifying the optimal population for treatment with DSP‐7888 is important for further investigations.image

Full enrollment results from an extended phase I, multicenter, open label study of marizomib (MRZ) with temozolomide (TMZ) and radiotherapy (RT) in newly diagnosed glioblastoma (GBM).

2021 Background: Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for GBM. MRZ, an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma activity was combined with standard TMZ/RT → TMZ in newly diagnosed GBM (NCT02903069), to determine the recommended dose (RD). The primary endpoint of this expanded phase 1 trial was toxicity, with secondary endpoint of OS. Methods: Patients were enrolled in separate cohorts (TMZ/RT+MRZ→TMZ+MRZ, N=15; TMZ/RT→TMZ+MRZ, N=18) in dose-escalation (3+3 design), followed by dose-expansion (N=20) with TMZ/RT+MRZ at RD → TMZ+MRZ at RD. A separate cohort received TMZ/RT→TMZ+MRZ at RD with Tumor Treating Fields (Optune, N=13). MRZ was infused IV (10 min at 0.55, 0.7, 0.8, and 1.0 mg/m2) on Days 1, 8, 15, 29, 36 (42-day TMZ/RT+MRZ cycle) and Days 1, 8, 15 (28-day TMZ+MRZ cycle). Results: 66 patients treated; median age 58 years, 68% male, 50% receiving corticosteroid at baseline, 52% unmethylated MGMT. Dose-limiting toxicities (DLTs) in dose-escalation cohorts: 1 (fatigue) at 0.7 mg/m2 MRZ, 5 (ataxia/diarrhea; ataxia/confusion; myocardial infarction, delirium/ataxia; ataxia/fatigue) in 1.0 mg/m2 cohorts. MRZ demonstrated a steep dose-response with treatment-emergent adverse events (TEAEs)/DLTs predominately CNS AEs (Grade ≥3 TEAEs in 12 of 12 patients at 1.0 mg/m2 vs 22 of 41 patients at ≤0.8 mg/m2); the RD for MRZ was determined to be 0.8 mg/m2. Most common TEAEs (all grades): fatigue, nausea (both 70%), hallucination (54%), vomiting (53%), headache (47%), confusional state (33%), ataxia, constipation, muscular weakness (all 29%). Conclusions: CNS TEAEs were short-lasting, reversible and ameliorated by early dose reductions (29% patients dose-reduced), allowing patients to remain on treatment. For patients receiving MRZ with TMZ/RT→TMZ (N=35), the median OS was 14.8 months (17 deaths, median follow-up 14.3 months), and 7 patients remain active (Cycles 11-23). The MRZ RD + TMZ/Optune combination was tolerated, with 4 of 13 patients treated on this arm remaining active. An international Phase 3 trial (EORTC 1709-BTG/CCTG CE.8, NCT03345095) is ongoing. Clinical trial information: NCT02903069.

Belvarafenib, a novel pan-RAF inhibitor, in solid tumor patients harboring BRAF, KRAS, or NRAS mutations: Phase I study.

3000 Background: Belvarafenib (HM95573/GDC-5573) is an oral type II pan-RAF kinase inhibitor which demonstrates selective anti-tumor activity in several non-clinical cancer models and in cancer patients with RAS- or RAF- mutation. Here we present overall safety and efficacy findings of two phase 1 studies, consisting of dose escalation and dose expansion stages. Methods: Patients with advanced solid cancers harboring documented RAS- or RAF- mutation were enrolled. In the dose escalation study, patients were treated with Belvarafenib at a starting dose of 50 mg once daily (QD) to 800 mg BID to assess safety and tolerability and identify the recommended dose (RD). Dose escalation was guided based on pharmacokinetic data and used a traditional 3+3 design. The dose expansion study was comprised of 6 cohorts (according to the type of tumor and RAS- or RAF gene mutation) and patients received the RD of Belvarafenib. The primary objective was to explore anti-tumor activity (per RECIST 1.1) and pharmacodynamic effects. Results: The dose escalation study included 72 patients in 9 dose cohorts (cut-off date of 18 Jan 2017). Dose dependent increase in exposures observed up to 650 mg BID. The most common treatment-emergent adverse events that occurred in more than 20% of patients were rash, dermatitis acneiform and pyrexia. A total of 4 DLTs (different kinds of rashes) were reported and included 2 DLTs at the 800 mg BID level. Therefore, 650 mg BID was considered the MTD and 450 mg BID was identified as the RD for Belvarafenib. There were 7 partial responses (3 confirmed PRs) from 200 mg QD to 800 mg BID in NRAS-mutant melanoma, BRAF-mutant melanoma, KRAS-mutant sarcoma, and BRAF-mutant GIST. Four of nine patients with NRAS-mutant melanoma had a PR (ORR 44%). The dose expansion study included 63 patients in 5 indication-specific and basket cohorts administered with 450 mg BID Belvarafenib (cut-off date of 6 Oct 2018). No new safety signal was detected. There were two PRs each in patients with NRAS-mutant melanoma (2/9), BRAF-mutant melanoma (2/6) and BRAF-mutant CRC (2/7), respectively. Conclusions: Belvarafenib was well tolerated and exhibited anti-tumor activity in patients with advanced solid tumors harboring RAS or RAF mutations. Belvarafenib is being further investigated in combination with the MEK inhibitor cobimetinib. Clinical trial information: NCT02405065, NCT03118817.

Efficacy of organomineral fertilizers derived from biosolid or filter cake on early maize development

In the current world scenario of agriculture it is necessary to find technologies to reach high productivity that are effective in providing soil conditioning improvement for the plants. Thus, this study analyzed the efficacy of organomineral fertilizers formulated with different organic matter sources on growth factors of maize. The experiment was done in a greenhouse at Campus Umuarama, Federal University of Uberlândia-MG, in a randomized block design, as a 2 x 5 + 2 factorial, containing two sources of organic matter, biosolid and filter cake, five doses of P2O5 recommendation for the crop and two additional treatments: mineral fertilization (100% of P2O5 of the recommended dose) and a control (no fertilizer), with four replications. Plant height, stalk diameter, and chlorophyll a and b were determined at 35 days after sowing (DAS); plant height, stalk diameter, shoot and root fresh and dry matter were determined at 65 DAS. The organomineral sources with biosolid and filter cake yielded greater height and diameter at 35 DAS than those of mineral fertilization. Regardless of the fertilizer organic matter source, stalk diameter at 35 DAS presented linear increase with increasing doses of the fertilizer sources. The use of fertilizer based on biosolid resulted in greater shoot fresh matter than the filter cake source, regardless of dose applied. In general, greater results were obtained for root fresh and dry matter at the greater fertilizer doses in comparison with the mineral fertilization. Organomineral fertilizers can be a viable alternative for partial or total substitution of mineral fertilization, since similar or better results were found for maize growth characteristics.

Phase 1b study of chemoprevention with green tea polyphenon E (PPE) and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (Erlotinib) in patients (pts) with advanced premalignant (AP) lesions of the head and neck.

6049 Background: Based on the strong synergistic effects between green tea polyphenon E (PPE) and EGFR-TKI in our preclinical studies (Int J Cancer, 2008; Cancer Prev Res, 2009; JCO, 2009), we conducted a phase 1b study with PPE and erlotinib combination for APL (mild-, moderate-, severe-dysplasia or carcinoma in situ [CIS]) of the oral cavity and larynx from 2/2011 to 11/2017 at Emory Winship Cancer Institute. Methods: All pts were enrolled after signing the IRB approved Informed Consent Form. Tissue biopsy before and at 6-months (6-M) treatment was mandatory, and cytobrushed samples of the APL and normal buccal mucosa at 3-, 6-, and 12-M were obtained for biomarker studies. Treatment included fixed dose of PPE (200 mg, P.O.,TID) and dose escalation of erlotinib P.O., (50mg [level 1], 75mg [level 2] and 100mg [level 3]) for 6-M. The primary endpoint was safety and toxicity, and secondary endpoints were evaluation of pathologic responses, cancer free survival (CFS) and biomarker modulation. Results: Out of 27 enrolled pts, 6 control subjects for biomarker studies, 2 ineligible, and 19 were treated with PPE and erlotinib for 6-M. Clinical characteristics of treated patients included median age, 63 yrs. (range,33-78); 9 M/10 F; 10 former or current smokers/9 never smokers; 15 severe dysplasia or CIS, 2 moderate dysplasia, 2 mild dysplasia; 13 had surgical resection; 17 oral cavity primary; and 2 at larynx. 3 pts were treated at dose level 1, 4 at level 2, and 12 at level 3. Toxicity (G0 or G1 excluded) were: skin rash (1 G3, 1 G2), pruritus/dry skin (1 G2), fatigue (1 G2), diarrhea (1 G2), epistaxis (1 G2), and hypertension (2 G3, 1 G2). Skin rash (associated with erlotinib) may be DLT and MTD has not been reached. The recommend doses for phase 2 or 3 studies will be PPE 200mg TID plus erlotinib 100mg QD. 17 pts were assessed for pathologic responses at 6-M: pCR 7/17 (41%), pPR 2/17 (12%), pSD 5/17 (29%) and pPD (3/17 (18%). The median follow up was 32 months. Median CFS has not been reached. 16 pts are alive at the time of data analyses and 1 pt died (by noncancerous reason). Biomarker studies are ongoing for tissues and/or cytobrushed samples. Conclusions: The treatment of the combination of green tea PPE plus erlotinib for 6-M was well tolerated in pts with APL of the head and neck, and showed significant pathologic response rates (pCR and pPR, 53%). This combination therefore deserves further investigation for efficacy testing. Clinical trial information: NCT01116336.

The first-in-human study of the pan-PIM kinase inhibitor PIM447 in patients with relapsed and/or refractory multiple myeloma.

PIM447, a novel pan-PIM inhibitor, has shown preclinical activity in multiple myeloma (MM). In the multicenter, open-label, first-in-human study, patients with relapsed and/or refractory MM were enrolled to determine the maximum-tolerated dose (MTD) or recommended dose (RD), safety, pharmacokinetics, and preliminary anti-myeloma activity of PIM447. PIM447 was administered in escalating oral doses of 70-700 mg once daily (q.d.) for 28-day continuous cycles. Seventy-nine patients with a median of four prior therapies were enrolled. Seventy-seven patients (97.5%) had an adverse event (AE) suspected as treatment related, with treatment-related grade 3/4 AEs being mostly hematologic. Eleven dose-limiting toxicities occurred, and an MTD of 500 mg q.d. and an RD of 300 mg q.d. were established. The main reason for discontinuation was disease progression in 54 patients (68.4%). In the entire study population, a disease control rate of 72.2%, a clinical benefit rate of 25.3%, and an overall response rate of 8.9% were observed per modified International Myeloma Working Group criteria. Median progression-free survival at the RD was 10.9 months. PIM447 was well tolerated and demonstrated single-agent antitumor activity in relapsed/refractory MM patients, providing proof of principle for Pim (Proviral Insertions of Moloney Murine leukemia virus) kinase inhibition as a novel therapeutic approach in MM.