The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML

About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML patients. Monotherapy, while efficacious, shows short-lived responses, highlighting the need for combination therapies. Here we show that gilteritinib and CUDC-907, a dual inhibitor of PI3K and histone deacetylases, synergistically induce apoptosis in FLT3-ITD AML cell lines and primary patient samples and have striking in vivo efficacy. Upregulation of FLT3 and activation of ERK are mechanisms of resistance to gilteritinib, while activation of JAK2/STAT5 is a mechanism of resistance to CUDC-907. Gilteritinib and CUDC-907 reciprocally overcome these mechanisms of resistance. In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential.Subject terms: Acute myeloid leukaemia, Drug development     

Gilteritinib versus chemotherapy in Japanese patients with FLT3-mutated relapsed/refractory acute myeloid leukemia

Background

Until recently, no effective targeted therapies for FLT3-mutated (FLT3^mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3^mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P?<?0.001).

Methods

We evaluated the Japanese subgroup (n?=?48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC.

Results

Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade?≥?3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%).

Conclusion

Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.

     

Safety and tolerability of lurbinectedin (PM01183) in patients with acute myeloid leukemia and myelodysplastic syndrome

Trabectedin is an FDA‐approved DNA minor groove binder that has activity against translocation‐associated sarcomas. Lurbinectedin is a next‐generation minor groove binder with preclinical activity against myeloid leukemia cells. A dose‐finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Forty‐two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1‐hour intravenous infusion in a 3 + 3 study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8 or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients experienced dose‐limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary toxicity (n = 2), and renal failure (n = 2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and 2 patients a morphologic leukemia‐free state. Most (n = 30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease‐related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21‐23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single‐agent lurbinectedin was transiently leukemia suppressive for some patients.     

A Dose-finding Study of Metronomic Oral Vinorelbine in Combination With Oral Cyclophosphamide and Bevacizumab in Patients With Advanced Breast Cancer

BackgroundMetronomic chemotherapy can induce disease control in patients with metastatic breast cancer (MBC) and has better safety profiles than conventional chemotherapy. Evidence suggests that cytotoxics can be anti-angiogenic in pre-clinical models and may have synergistic effects when combined with anti-vascular endothelial growth factor therapies.Patients and MethodsPatients pretreated with ≥ 1 prior line of therapy for MBC received oral cyclophosphamide 50 mg daily in combination with oral vinorelbine at escalating doses of 20 mg (V20), 30 mg (V30), and 40 mg (V40) 3 times per week, and intravenous bevacizumab 15 mg/kg every 3 weeks. Patients with human epidermal growth factor receptor 2-positive disease were given the same regimen plus standard trastuzumab. Doses were escalated when 3 patients completed 3 treatment cycles of V20 and V30, without experiencing dose-limiting toxicities. The recommended dose was then tested in a further 6 patients. Circulating tumour cells and circulating endothelial cells (CEC) were measured in 30 mL of whole blood samples at baseline, after cycle 1, and at the disease progression.ResultsFifteen patients were recruited from June 2013 to October 2015. The median age was 61 years (range, 29-72 years); 80% had estrogen receptor-positive and 33% had human epidermal growth factor receptor 2-positive disease. At least 67% had visceral metastases, and 80% had received ≥ 2 lines of prior treatment. No dose-limiting toxicities were observed at the 3 dose-levels, making V40 the recommended dose. Overall 8 (53%) patients developed grade 2 adverse events (arthralgia, n = 3 [20%]; asthenia, n = 2 [13%]; diarrhea, n = 2 [13%]; leukopenia, n = 2 [13%]). Bevacizumab was associated with grade 3 hypertension (n = 3 [20%]). Stable disease as best response was observed in 11 (73.3%) patients. The clinical benefit rate was 66.6% (10/15 patients). The median time to progression was 6.9 months. At baseline, CECs were more commonly detectable than circulating tumor cells; however, no statistical correlation was found between CEC kinetics and response.ConclusionA metronomic vinorelbine dose of 40 mg combined with cyclophosphamide and bevacizumab is a promising treatment regimen in pretreated patients with MBC.     

Phase‐1 study of abiraterone acetate in chemotherapy‐naïve Japanese patients with castration‐resistant prostate cancer

Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration‐resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase‐1, open‐label and dose‐escalation study. Chemotherapy‐naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28‐day treatment cycles. In the first cycle, AA monotherapy was given on days 1–7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut‐off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median t_max 2–3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose‐group experienced ≥50% prostate‐specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well‐tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov : NCT01186484.     

Safety and efficacy of first‐line dacomitinib in Japanese patients with advanced non‐small cell lung cancer

In a subgroup of Japanese patients in the ARCHER 1050 randomized phase 3 trial, we evaluated the efficacy and safety and determined the effects of dose modifications on adverse events (AE) and therapy management of first‐line oral dacomitinib 45 mg compared with oral gefitinib 250 mg, each once daily in 28‐d cycles, in patients with EGFR‐activating mutation–positive (EGFR‐positive; exon 19 deletion or exon 21 L858R substitution mutations) advanced non‐small cell lung cancer (NSCLC). The primary endpoint was progression‐free survival (PFS; RECIST, version 1.1, by blinded independent review). In 81 Japanese patients (40 dacomitinib, 41 gefitinib), PFS was longer with dacomitinib compared with gefitinib (hazard ratio [HR], 0.544 [95% confidence interval {CI}, 0.307‐0.961]; 2‐sided P = .0327; median 18.2 for dacomitinib [95% CI, 11.0‐31.3] mo, 9.3 [95% CI, 7.4‐14.7] mo for gefitinib). The most common Grade 3 AEs were dermatitis acneiform with dacomitinib (27.5%) and increased alanine aminotransferase with gefitinib (12.2%). A higher proportion of patients receiving dacomitinib (85.0%) compared with gefitinib (24.4%) had AEs leading to dose reduction. Incidence and severity of diarrhea, dermatitis acneiform, stomatitis and paronychia were generally reduced after dacomitinib dose reductions and dacomitinib treatment duration was generally longer in patients with a dose reduction in comparison with those without a dose reduction. Our results confirmed the efficacy and safety of first‐line dacomitinib in Japanese patients with EGFR‐positive advanced NSCLC.     

Pharmacokinetic study of bortezomib administered intravenously in Taiwanese patients with multiple myeloma

This phase 4, single‐arm, non‐randomized, open‐label, post approval commitment study evaluated the pharmacokinetics and safety of bortezomib in Taiwanese patients with multiple myeloma. Patients (≥20 years) with measurable secretory multiple myeloma (serum monoclonal IgG ≥10, IgA/IgE ≥5, IgD ≥0.5 g/L, IgM present [regardless of level], and urine M protein of ≥200 mg/24 h) received intravenous bortezomib 1.3 mg/m², twice weekly for 2 weeks, followed by a 10‐day resting phase (days 12 to 21). Pharmacokinetics and safety were assessed at pre‐specified time points. All enrolled patients (n = 18, men: 11; women: 7) completed the study. Mean (SD) C_max (maximum observed plasma concentration) on day 11 was 266 (77.5) ng/mL, approximately 60% higher compared with non‐Asian patients receiving a similar bortezomib regimen but with overlapping ranges. Because of the protracted terminal phase, half‐life (t_1/2), area under the plasma concentration‐time curve from time 0 to infinity (AUC_∞), volume of distribution (V_z), and systemic clearance were not assessable. All patients experienced treatment‐emergent adverse events (TEAEs); 78% were drug‐related. Most commonly reported TEAEs were thrombocytopenia (n = 11 [61%]), neutropenia (n = 9 [50%]), leukopenia (n = 6 [33%]), and diarrhoea (n = 6 [33%]); the most common serious adverse event was pneumonia (n = 2 [11%]). One patient had a dose reduction due to a TEAE of thrombocytopenia. Overall, bortezomib exposure (AUC) in Taiwanese patients (AUC_last [SD]: 230 [147] ng·h/mL) with twice weekly intravenous administration was comparable with non‐Asian population (AUC_last [SD]: 241 [82] ng·h/mL). Bortezomib treatment was associated with manageable toxicity profile and did not limit the continuity of therapy.     

Y90‐Ibritumomab tiuxetan (Y90‐IT) and high‐dose melphalan as conditioning regimen before autologous stem cell transplantation for elderly patients with lymphoma in relapse or resistant to chemotherapy: a feasibility trial (SAKK 37/05)

Standard conditioning regimens for autologous stem cell transplantation (ASCT) are often not tolerated by elderly patients, on one hand. Single high‐dose melphalan, on the other hand, has been shown to be safe and active as a pretransplant preparative regimen in elderly patients. Y⁹⁰‐Ibritumomab tiuxetan (Y⁹⁰‐IT) is well tolerated and feasible in the transplantation setting. We therefore investigated the combination of high‐dose melphalan and Y⁹⁰‐IT as a conditioning regimen for patients ≥65 years of age. Patients with relapsed or resistant CD20‐positive lymphoma in remission after salvage chemotherapy could be enrolled. High‐dose therapy consisted of standard dose Y⁹⁰‐IT (0.4‐mCi/kg body weight) followed by melphalan at escalating doses (100, 140, 170 and 200 mg/m²) and ASCT. The primary objective was to identify the maximum tolerated dose; secondary end points were complete response (CR) rate 100 days after transplantation and toxicity. Twenty patients (median age 72 years) were included. No DLT occurred at any dose level. Thirteen patients completed the treatment, 11 were evaluable for response. Seven patients did not complete treatment because of mobilization failure (n = 3), progressive disease (n = 2), worsening of cardiac function (n = 1), and grade 3 dyspnea (n = 1). Seven patients achieved a CR/complete remission/unconfirmed (CRu) and 2 had stable disease. Five out of 7 responding patients were still alive more than 3 years after transplantation. The 2 patients with SD had a long‐term survival of 3 and 5 years, respectively. Nonhematological grade 3 or higher treatment related adverse events (AEs) were infection (n = 6), including 2 cases of febrile neutropenia, diarrhea (n = 3), mucositis, anorexia, viral hepatitis, hypokalemia, dehydration, and multiorgan failure (n = 1 for each). The combination of Y⁹⁰‐IT and high‐dose melphalan is feasible before ASCT for elderly patients, with promising activity and manageable toxicity.     

Independent prognostic impact of CD15 on complete remission achievement in patients with acute myeloid leukemia

The prognostic role of CD15 in acute myeloid leukemia (AML) has been tested in different studies with conflicting results. To address this issue, we retrospectively evaluated a cohort of 460 AML patients of all ages with the exclusion of acute promyelocytic leukemia (M/F 243/217, median age 50.6 years [range 0.9‐81.2]) intensively treated at our institute between January 1999 and December 2010. CD15 positivity was found in 171 of 406 evaluable patients (42.1%). Complete remission (CR) was achieved by 334 patients (72.6%), while 82 (17.8%) were resistant and 44 (9.6%) died during induction: the median CR duration was 15.5 months (range 0.6‐176.0), with 2‐year disease‐free survival rate of 45.1% (95% confidence interval 39.6‐50.6). The median overall survival was 14.4 months (range 0.3‐177.0), with 2‐year overall survival rate of 42.2% (95% confidence interval 37.5‐46.9). At univariate analysis for CR achievement, age < 60 years (P < .001), World Health Organization classification (P = .045), low‐risk karyotype (P < .001), no high‐risk karyotype (P = .006), positivity for AML‐ETO (P = .004)/CBFβ‐MYH11 (P = .003)/CD15 (P = .006)/CD11b (P = .013), negativity for FLT3‐ITD (P = .001), Hb > 8 g/dL (P = .020), and white blood cell < 50 × 10⁹/L (P = .034) had a favorable impact. At a multivariate logistic regression model, CD15 positivity (P = .002), age < 60 years (P = .008), white blood cell < 50 × 10⁹/L (P = .017), and low‐risk/no high‐risk karyotype (P = .026/P = .025) retained an independent prognostic role on CR achievement . The baseline assessment of CD15 positivity appears to have a role in the risk evaluation for CR achievement in AML patients undergoing intensive chemotherapy and should be assessed in prospective studies together with other clinical and biologic features already reported.     

Oprozomib,pomalidomide, and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

IntroductionThis phase Ib study evaluated oprozomib, an oral proteasome inhibitor, plus pomalidomide-dexamethasone in relapsed/refractory multiple myeloma (RRMM).Patients and MethodsPatients received oprozomib once-daily on days 1 to 5 and 15 to 19 (5/14 schedule; 150 mg/day starting dose) or on 2 consecutive days weekly (2/7 schedule; 210 mg/day starting dose) of 28-day cycles, pomalidomide on days 1 to 21 (4 mg/day starting dose), and dexamethasone 20 mg on 2 consecutive days weekly. A 3 + 3 dose-escalation schema was used to determine the maximum tolerated dose.ResultsThirty-one patients were treated (5/14, n = 4; 2/7, n = 27). Oprozomib maximum tolerated dose was not defined. The 2/7 schedule (oprozomib 210 mg/day, pomalidomide 4 mg/day) was selected for dose expansion based on overall safety (n = 17). In this group, the most common adverse events (AEs) were gastrointestinal (diarrhea [88.2%], nausea [58.8%], and vomiting [58.8%]); grade ≥ 3 gastrointestinal AEs were uncommon. The most common grade ≥ 3 AEs were hematologic (anemia [47.1%], neutropenia [35.3%], and thrombocytopenia [29.4%]). One dose-limiting toxicity (gastric hemorrhage) occurred; 3 patients discontinued owing to AEs. The overall response rate was 70.6%.ConclusionSafety and pharmacokinetic profiles were concerns with the oprozomib formulation used in this study and need to be improved. Oprozomib-pomalidomide-dexamethasone (2/7 schedule) had encouraging efficacy, supporting an ongoing phase Ib study evaluating new oprozomib formulations for this combination in relapsed/refractory multiple myeloma.     

Invasive Mold Infections in FLT3-Mutated Acute Myeloid Leukemia

BackgroundThe incidence and risk factors for invasive mold infections (IMI) in acute myeloid leukemia (AML) patients carrying FLT3 mutations have not been addressed.Patients and MethodsThis retrospective cohort included FLT3-mutated AML patients (2008-2018). Primary outcome was IMI incidence within 6 months after first induction or salvage therapy.ResultsWe included 108 patients receiving fluconazole or micafungin prophylaxis. IMI incidence after induction and salvage therapy was 4.8% and 14.8%, respectively, and did not differ between patients receiving 3+7 regimen or 3+7 plus midostaurin (4.3% vs 4.5%). In a bivariate analysis, age (odds ratio, 1.11; P = .027) and FLT3 ITD mutation (odds ratio, 0.05; P = .023) were independently associated with IMI after induction chemotherapy. Gilteritinib was more frequently prescribed in patients with relapsed/refractory disease who developed IMI (50% vs 27.3%, P = .563).ConclusionFLT3 ITD mutation may be a preventive factor for IMI. Neither midostaurin nor salvage gilteritinib significantly increased the risk of IMI in this population.     

Limited Utility of Surveillance Imaging for Detecting Disease Relapse in Patients With Non-Hodgkin Lymphoma in First Complete Remission

IntroductionSurveillance imaging with computed tomography (CT) or positron emission tomography with CT (PET/CT) is commonly used in practice in patients with non-Hodgkin lymphoma (NHL) who are in remission after front-line therapies. We aimed to determine the utility of routine imaging for detecting first relapse in patients with NHL in complete remission (CR) after first-line therapies.Patients and MethodsWe retrospectively analyzed patients with NHL who achieved CR after first-line therapies and then subsequently had disease relapse. We evaluated whether the relapse was detected solely by surveillance CT or PET/CT or by patient-reported symptoms or physical examination findings, or both. Subgroup analysis was performed on baseline histologic type (indolent vs. aggressive NHL). Data were also collected to determine the cost of surveillance PET/CT and the number of additional diagnostic imaging procedures, invasive procedures, and iatrogenic complications directly resulting from an abnormality detected on a surveillance scan.ResultsOne hundred sixty-three patients with first relapse of NHL between January 1, 2000 and December 31, 2010 were included. The majority of the relapses were detected by patient-reported symptoms or physical examination, or both, as opposed to surveillance imaging (77.9% [n = 127] vs. 22.1% [n = 36]; P < .0001). There was no overall survival difference between the 2 groups (P = .66). Patient-reported symptoms led to the detection of the majority of relapses in aggressive (85.7% [n = 72] vs. 14.3% [n = 12]; P < .0001) as well as indolent NHL (69.6% [n = 55] vs. 30.4% [n = 24]; P = .0007). Surveillance PET/CT contributed to more than 75% of follow-up health care costs in the first 2 years of monitoring for relapse. The surveillance imaging group had 1 reported case of iatrogenic pneumothorax.ConclusionOur retrospective analysis suggests that there is a limited role for surveillance imaging by CT or PET/CT in detecting first relapse in NHL. There was no difference in survival outcomes between the 2 groups in our study.     

Clinical activity of ASP8273 in Asian patients with non‐small‐cell lung cancer with EGFR activating and T790M mutations

Epidermal growth factor receptor (EGFR)‐activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non‐small‐cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once‐daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose‐escalation/dose‐expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged ≥20 years) with NSCLC previously treated with ≥1 EGFR TKI received escalating ASP8273 doses (25‐600 mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M‐positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simon's two‐stage design (threshold response = 30%, expected response = 50%, α = 0.05, β = 0.1). Overall, 121 (n = 45 [33W/12M] phase I, n = 76 [48W/28M]) phase 2) patients received ≥1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400 mg, respectively. As 27 of the 63 patients treated with ASP8273 300 mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n = 32/76; 95% confidence interval, 30.9‐54.0). Median duration of progression‐free survival was 8.1 months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment‐related adverse event in phase II was diarrhea (57%, n = 43/76). ASP8273 300 mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR‐activating and T790M mutations.     

Prospective evaluation of the tolerability and efficacy of niraparib dosing based on baseline body weight and platelet count: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial

Background

The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer.

Methods

In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose.

Results

Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46–0.76] vs. ISD HR, 0.69 [95% CI, 0.48–0.98]) and the homologous recombination–deficient (FSD HR, 0.44 [95% CI, 0.30–0.64] vs. ISD HR, 0.39 [95% CI, 0.22–0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD.

Conclusions

In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.     

Phase I dose‐escalation trial of Sym004, an anti‐EGFR antibody mixture,in Japanese patients with advanced solid tumors

Sym004 is a 1:1 mixture of two antibodies targeting non‐overlapping epitopes of the epidermal growth factor receptor that antagonizes ligand binding and induces receptor downregulation. In preclinical models, it has superior antitumor activity to cetuximab and panitumumab. Japanese adults aged ≥20 years with an Eastern Cooperative Oncology Group status of 0/1 and life expectancy ≥3 months were eligible. Patients in Part A (dose escalation) had refractory or recurrent late‐stage solid tumors and received Sym004 6 mg/kg/wk (n = 3), 9 mg/kg loading/6 mg/kg/wk (n = 6), 12 mg/kg/wk (n = 6), or 18 mg/kg biweekly (n = 6). Patients in expansion Part B (n = 30) had esophageal squamous cell carcinoma and received Sym004 at the dose recommended from Part A. Fifty‐one patients received Sym004. No dose‐limiting toxicities were observed in Part A. A dose of 12 mg/kg/wk was selected for Part B. All patients in Part B experienced treatment‐related adverse events, most commonly dermatitis acneiform (76.7%). Eighteen grade ≥3 treatment‐related adverse events and five serious adverse events occurred (cardiac arrest, lung infection, interstitial lung disease, toxic skin eruption, blood creatinine increase). Two patients had treatment‐related adverse events resulting in death (cardiac arrest and blood creatinine increase). Five patients in Part B had a best overall response of partial response, 12 stable diseases and 12 disease progression (1 not evaluable). The objective response rate was 16.7% (95% CI: 5.6%‐34.7%). Sym004 therapy was well tolerated with no dose‐limiting toxicities at any dose studied. Evidence of antitumor activity was seen in patients with esophageal squamous cell carcinoma. ClinicalTrials.gov Identifier: NCT01955473.     

Comparison of serum concentrations between different dosing strategies of posaconazole delayed‐release tablet at a large academic medical centre

It is unclear if the prophylaxis dose of 300 mg/day is sufficient for achieving serum concentrations targeting the treatment of invasive fungal infections. To evaluate differences between PCZ serum concentrations in patients receiving the DRT vs the OS and in patients receiving higher doses than 300 mg/day of the DRT, a retrospective review was conducted on inpatients who received PCZ for either treatment or prophylaxis. Baseline demographics including comorbid conditions, indication and dose of therapy were collected. Serum trough concentrations were collected at steady state. Fifty‐seven patients received PCZ during the study period. A total of 35 levels were collected (DRT n = 18, OS n = 17). Patients receiving the DRT had levels >0.7 mcg/mL 100% of the time compared to 58.8% in those receiving the OS. No significant difference was seen in serum concentrations at 300 mg/day (n = 14) vs 400 mg/day (n = 8) of the DRT (1.55 mcg/mL (1.08‐2.50) vs 2.5 mcg/mL (1.85‐2.70), P = .19). The DRT leads to more consistent levels in the therapeutic range than the OS. Standard dosing of 300 mg/day with DRT achieves adequate concentrations for prophylaxis and treatment of IFIs, although further data are needed to determine optimal serum concentrations for treatment.     

Phase II Study of Eribulin Mesylate Administered Biweekly in Patients With Human Epidermal Growth Factor Receptor-2–negative Metastatic Breast Cancer

BackgroundPatients with human epidermal growth factor receptor-2–negative metastatic breast cancer (MBC), whose disease progressed on prior chemotherapy, have a poor prognosis. Eribulin, a microtubule dynamics inhibitor, extends overall survival in previously treated MBC. The most common adverse event associated with eribulin is neutropenia, which may result in dose interruptions or reductions. A modified biweekly dosing schedule of eribulin was assessed for efficacy as well as improvements in hematologic toxicity.Patients and MethodsIn this open-label, single-arm, multicenter, phase II study, previously treated (2-5 chemotherapy regimens for metastatic disease) patients with human epidermal growth factor receptor-2–negative MBC received intravenous eribulin 1.4 mg/m² over 2 to 5 minutes on days 1 and 15 of each 28-day cycle. The primary study endpoints were objective response rate (ORR; complete response [CR] + partial responses [PR]) and disease control rate (DCR; CR + PR + stable disease [SD]).ResultsAmong 58 treated patients, the ORR was 12% (95% confidence interval [CI], 5%-24%), DCR (CR, n = 1; PR, n = 6; SD, n = 30) was 65%, and the median progression-free survival was 3.6 months (95% CI, 2.9-4.1 months). Grade 3 or 4 neutropenia was 31%; 50% of all patients, and 78% of patients with neutropenia (all grades), received hematopoietic growth-factor support.ConclusionThe efficacy and safety results obtained with a biweekly eribulin schedule in this phase II trial appear similar to those associated with the approved eribulin schedule (1.4 mg/m² on days 1 and 8 of a 21-day cycle) reported in the EMBRACE study.     

Phase I Study Assessing the Safety and Tolerability of Barasertib (AZD1152) With Low-Dose Cytosine Arabinoside in Elderly Patients With AML

IntroductionBarasertib is the pro-drug of barasertib-hydroxy-quinazoline pyrazole anilide, a selective Aurora B kinase inhibitor that has demonstrated preliminary anti-AML activity in the clinical setting.Patients and MethodsThis Phase I dose-escalation study evaluated the safety and tolerability of barasertib, combined with LDAC, in patients aged 60 years or older with de novo or secondary AML. Barasertib (7-day continuous intravenous infusion) plus LDAC 20 mg (subcutaneous injection twice daily for 10 days) was administered in 28-day cycles. The MTD was defined as the highest dose at which ≤ 1 patient within a cohort of 6 experienced a dose-limiting toxicity (DLT) (clinically significant adverse event [AE] or laboratory abnormality considered related to barasertib). The MTD cohort was expanded to 12 patients.ResultsTwenty-two patients (median age, 71 years) received ≥ 1 treatment cycle (n = 6, 800 mg; n = 13, 1000 mg; n = 3, 1200 mg). DLTs were reported in 2 patients (both, National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 stomatitis/mucositis; 1200 mg cohort). The most common AEs were infection (73%), febrile neutropenia (59%), nausea (50%), and diarrhea (46%). Barasertib plus LDAC resulted in an overall response rate (International Working Group criteria) of 45% (n = 10/22; according to investigator opinion).ConclusionThe MTD of 1000 mg barasertib in combination with LDAC in older patients with AML was associated with acceptable tolerability and preliminary anti-AML activity.     

Troxacitabine, a novel dioxolane nucleoside analog, has activity in patients with advanced leukemia.

PURPOSE: To investigate the toxicity profile, activity, and pharmacokinetics of a novel L-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was given as an intravenous infusion over 30 minutes daily for 5 days. The starting dose was 0.72 mg/m(2)/d (3.6 mg/m(2)/course). Courses were given every 3 to 4 weeks according to toxicity and antileukemic efficacy. The dose was escalated by 50% until grade 2 toxicity was observed, and then by 30% to 35% until the dose-limiting toxicity (DLT) was defined. RESULTS: Forty-two patients (AML: 31 patients; MDS: six patients [five MDS + one CMML]; ALL: four patients; CML-BP: one patient) were treated. Median age was 61 years (range, 23 to 79 years), and 29 patients were males. Stomatitis and hand-foot syndrome were the DLTs. The MTD was defined as 8 mg/m(2)/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m(2). Approximately 69% of troxacitabine was excreted as unchanged drug in the urine. Marrow hypoplasia occurred between days 14 and 28 in 73% of AML patients. Three complete remissions and one partial remission were observed in 30 assessable AML patients. One MDS patient achieved a hematologic improvement. A patient with CML-BP achieved a return to chronic phase disease. CONCLUSION: Troxacitabine has a unique metabolic and pharmacokinetic profile and significant antileukemic activity. DLTs were stomatitis and hand-foot syndrome. Troxacitabine merits further study in hematologic malignancies.     

Efficacy and Safety of Niraparib as Maintenance Treatment in Patients With Extensive-Stage SCLC After First-Line Chemotherapy: A Randomized,Double-Blind,Phase 3 Study

IntroductionZL-2306-005 is a randomized, double-blind, multicenter phase 3 study evaluating the efficacy and safety of niraparib, a poly(adenosine diphosphate-ribose) polymerase inhibitor, as first-line maintenance therapy in Chinese patients with platinum-responsive, extensive-stage SCLC (ES-SCLC).MethodsPatients with complete response (CR) or partial response (PR) to standardized, platinum-based first-line chemotherapy were randomized 2:1 to receive niraparib or placebo (300 mg [baseline body weight ≥ 77 kg, platelet count ≥ 150,000/μL] or 200 mg) once daily until progression or unacceptable toxicity. Primary end points were progression-free survival (PFS) (blinded independent central review) and overall survival (sample size planned: 591 patients). Secondary end points included investigator-evaluated PFS and safety.ResultsZL-2306-005 was terminated early owing to ES-SCLC treatment landscape changes (data cutoff: March 20, 2020). During July 2018–February 2020, a total of 185 of 272 patients screened were randomized (niraparib: n = 125 [CR = 1, PR = 124]; placebo: n = 60 [CR = 1, PR = 59]). Median (95% confidence interval [CI]) PFS (blinded independent central review) was 1.54 months (1.41–2.69, niraparib) and 1.36 months (1.31–1.48, placebo); hazard ratio (HR) = 0.66 (95% CI: 0.46–0.95, p = 0.0242). Median overall survival was 9.92 months (9.33–13.54, niraparib) and 11.43 months (9.53–not estimable, placebo); HR = 1.03 (95% CI: 0.62–1.73, p = 0.9052). Median investigator-evaluated PFS was 1.48 months (1.41–2.56, niraparib) and 1.41 months (1.31–2.00, placebo); HR = 0.88 (95% CI: 0.61–1.26; p = 0.4653). Grade greater than or equal to 3 adverse events occurred in 34.4% (niraparib) and 25.0% (placebo) of patients.ConclusionsZL-2306-005 did not reach primary end points. Nevertheless, niraparib as maintenance therapy modestly improved PFS in patients with platinum-responsive ES-SCLC, with acceptable tolerability profile and no new safety signal.