A comparison of clinical pharmacodynamics of different administration schedules of oral topotecan (Hycamtin)

Prolonged exposure to topotecan in in vitro and in vivo experiments has yielded the highest antitumor efficacy. An oral formulation of topotecan with a bioavailability of 32-44% in humans enables convenient prolonged administration. Pharmacokinetic/pharmacodynamic relationships from four Phase I studies with different schedules of administration of oral topotecan in 99 adult patients with malignant solid tumors refractory to standard forms of chemotherapy were compared. Topotecan was administered as follows: (a) once daily (o.d.) for 5 days every 21 days (29 patients); (b) o.d. for 10 days every 21 days (19 patients); (c) twice daily (b.i.d.) for 10 days every 21 days (20 patients); and (d) b.i.d. for 21 days every 28 days (31 patients). Pharmacokinetic analysis was performed in 55 patients using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic me

Phosphatidylinositol 3-Kinase -Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study

PurposeWe report the first-in-human phase Ia study to our knowledge (ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase (PI3K)-selective inhibitor.Patients and MethodsIn the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily.ResultsOne hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes ( 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%).ConclusionAlpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3K inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors

Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors

Aurora A kinase is critical in assembly and function of the mitotic spindle. It is overexpressed in various tumor types and implicated in oncogenesis and tumor progression. This trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054, a selective small-molecule inhibitor of Aurora A kinase

Physics, Topology, Logic and Computation: A Rosetta Stone

In physics, Feynman diagrams are used to reason about quantum processes. In the 1980s, it became clear that underlying these diagrams is a powerful analogy between quantum physics and topology: namely, a linear operator behaves very much like a "cobordism". Similar diagrams can be used to reason about logic, where they represent proofs, and computation, where they represent programs. With the rise of interest in quantum cryptography and quantum computation, it became clear that there is extensive network of analogies between physics, topology, logic and computation. In this expository paper, we make some of these analogies precise using the concept of "closed symmetric monoidal category". We assume no prior knowledge of category theory, proof theory or computer science.Comment: 73 pages, 8 encapsulated postscript figure

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer

Background: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). Results: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer

A first-in-human study of AO-176, a highly differentiated anti-CD47 antibody, in patients with advanced solid tumors.

Research Funding: Arch Oncology Background:AO-176 is a humanized IgG2 antibody that specifically targets CD47. Expressed by multiple tumor types, CD47 binds to signal regulatory protein a (SIRPa) on phagocytes, including macrophages and dendritic cells. The CD47-SIRPa complex results in a “don’t eat me” signal that allows the tumor to escape removal by the innate immune system, disabling the generation of an adaptive immune response. The differentiated mechanisms of action of AO-176 include promotion of phagocytosis, direct tumor cell killing through programmed cell death type III and induction of damage associated molecular patterns/immunogenic cell death, preferentially binding to tumor cells vs. normal cells, and enhanced binding at an acidic pH as found in tumor microenvironments. AO-176 has negligible binding to RBCs.Methods:In a phase 1/2 first-in-human study (NCT03834948) of AO-176, pts with advanced solid tumors associated with high CD47 expression and an ECOG PS of 0-1 were enrolled into escalating dose cohorts of AO-176 given IV every 7 days. Objectives included evaluation of safety, dose-limiting toxicity (DLT) and recommended phase 2 dose (RP2D), antitumor activity, pharmacokinetic (PK) parameters and exploratory biomarkers.Results:As of 4 Jan 2021, 27 pts were enrolled (median age 64 years; 67% female; 67% ECOG PS 1; median [range] of 4 [1-7] prior therapies for metastatic disease). Dose levels of 1, 3, 10, 20 and 20 (using step-up dosing) mg/kg were evaluated in \u3e250 infusions. Most common (\u3e10%) treatment-related adverse events (TRAEs) of any grade were thrombocytopenia and infusion-related reaction (IRR) (33% each), anemia (22%) with no evidence of hemolysis, nausea (19%), and fatigue (15%). The only G3+ TRAE occurring in \u3e10% of pts was asymptomatic, brief thrombocytopenia (22%). No platelet transfusions were given. DLTs included IRRs in 2 pts dosed at 20 mg/kg, and asymptomatic thrombocytopenia and a cerebrovascular accident in 1 pt each in the 20 mg/kg step-up cohort. The RP2D was 10 mg/kg. Implementation of additional pre-medication and a 6-hr infusion duration in cycle 1 eliminated subsequent IRRs. Dexamethasone tapering and shortening of the infusion duration to 2 hrs was successful in all pts after cycle 1. Interim PK analysis of AO-176 demonstrated consistent exposure with linear PK. The T1/2 was ̃5 days. One pt with endometrial carcinoma who had not responded to any of 4 prior systemic regimens had a confirmed PR and remains on study for \u3e1 year. 7 pts had SD as a best response, with 2 pts (endometrial carcinoma, gastric cancer) on study for \u3e6 mos.Conclusions:AO-176 is a well-tolerated, differentiated anti-CD47 therapeutic. Durable anti-tumor activity was observed. Evaluations of AO-176 in combination with paclitaxel in pts with select solid tumors (NCT03834948) and as a single-agent in pts with multiple myeloma (NCT04445701) are ongoing. Clinical trial information: NCT0383494

Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer

The Correction to this article has been published in BMC Cancer 2019 19:620Background: The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1–associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. Methods: In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan–Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. Results: Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1–containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). Conclusions: In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing