Doses Of Selumetinib Research Articles

A Population Pharmacokinetic Assessment of the Effect of Food on Selumetinib in Patients with Neurofibromatosis Type 1-Related Plexiform Neurofibromas and Healthy Volunteers.

Selumetinib is clinically used for pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. Until recently, selumetinib had to be taken twice daily, after 2 hours of fasting and followed by 1 hour of fasting, which could be inconvenient. This population analysis evaluated the effect of low- and high-fat meals on the pharmacokinetic (PK) parameters of selumetinib and its active metabolite N-desmethyl selumetinib. The dataset comprised 511 subjects from 15 clinical trials who received ≥1 dose of selumetinib and provided ≥1 measurable postdose concentration of selumetinib and N-desmethyl selumetinib. A 2-compartment model with sequential 0- and 1st-order delayed absorption and 1st-order elimination adequately described selumetinib PK characteristics. A 1-compartment model reasonably described N-desmethyl selumetinib PK characteristics over time simultaneously with selumetinib. Selumetinib geometric mean area under the concentration-time curveratio (1-sided 90% confidence interval [CI] lower bound) was 76.9% (73.3%) with a low-fat meal and 79.3% (76.3%) with a high-fat meal versus fasting. The lower bound of the 1-sided 90% CI demonstrated a difference of <30% between fed and fasted states. Considering the flat exposure-response relationship within the dose range (20-30mg/m2), the observed range of exposure, and the variability in the SPRINT trial, this was not considered clinically relevant.

Pharmacodynamics of PI3K, MEK, and AKT inhibitors through isoform-specific measurements of MEK, ERK, AKT, and ribosomal protein S6 in needle biopsies.

3134 Background: The success of drugs targeting the MAPK or PI3K pathways in cancer has been slowed by insufficient pathway suppression or onset of resistance through rebound or cross-pathway activation. Isoform-specific measurement of key signaling molecules and a pathway convergence marker ribosomal protein S6 (RPS6), may provide valuable pharmacodynamic (PD) evidence to assess drug effectiveness. Methods: We developed Luminex multiplex assays to measure total and phosphorylated forms of RPS6, ERK1, ERK2, MEK1, MEK2, AKT1, AKT2, and AKT3 from a single tumor biopsy. Fit-for-purpose validation was performed with three drugs currently in clinical trials. A SW620 (KRAS G12V) model was tested with selumetinib (NSC741078, 20 mg/kg), MK2206 (NSC756656, 24 mg/kg), and two PTEN-null models (PC3 &amp; HCC70) with AZD8186 (NSC777572, 25 &amp; 50 mg/kg). Tumors were collected at multiple timepoints after single and repeated dosing, processed by a validated method (PMID 27001313) and data analyzed relative to vehicle control (n = 4-5/grp). Results: The multiplexed assays demonstrated satisfactory analytical performance. Treatment of the SW620 model with a single dose of selumetinib suppressed pERK1/2 ( &gt; 90%), MEK1/2 (50%) and pRPS6 (40-60%) up to 4 h (last time point tested) which was reversed by 24 h. AKT inhibitor, MK2206, suppressed pAKT1/2 (75%) and pAKT3 (50%) 2 h post-dose with reversal at 24 h but did not significantly suppress pRPS6, implying limited downstream modulation. Dosing selumetinib for 21 days had no added effect on pERK isoforms. In both PTEN-null models, AZD8186 suppressed all pAKT isoforms by 40-75% up to 4 h post-dose. The pAKT remained suppressed at 7 h in HCC70 but both pAKT and pRPS6 rebounded by 7 h in PC3. The basal pERK1/2 levels were low and unaffected by AZD8186 in PC3 and HCC70. Conclusions: We established the fitness of PD assays to provide critical evidence regarding the duration of on-target effects, timeline of biomarker reversal and effectiveness of pathway suppression for three distinct classes of drugs. The PD assays are ready for an ongoing clinical trial of AZD8186 and to support clinical development of FGFR inhibitors. Funded by NCI Contract HHSN261200800001E.

SELECT-4: Phase I dose escalation trial of selumetinib (AZD6244, ARRY-142886) in combination with durvalumab (MEDI4736) in patients with advanced solid tumors.

TPS2607Background: Preclinical studies suggest that intermittent dosing with selumetinib, an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life, should be evaluated in combination with durvalumab, a selective, high-affinity human IgG1 mAb, that blocks PD-L1 binding to PD-1 and CD80. Selumetinib may prime the immune response and also potentially inhibit T-cell function, thereby maximizing tumor cell damage and antigen presentation during the period of MEK inhibition; intermittent dosing with selumetinib will allow maximal relief of T-cell checkpoint blockade by durvalumab. The SELECT-4 study (NCT02586987) aims to evaluate this combination for the first time in pts. Methods: SELECT-4 is a Phase I, open-label, multicenter, dose escalation study investigating the safety and tolerability of intermittent doses of selumetinib combined with durvalumab in pts with advanced solid tumors for which no standard therapy exists. Selumetinib (starting dose 50 mg po bid, increasing until...

Selective MEK Inhibition with AZD-6244 (selumetinib) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A University of Chicago Phase II Consortium Trial

Introduction: The biology of DLBCL is complex, with a number of clinicopathologic and molecular features impacting outcome. MCT-1 is an oncogene that promotes lymphomagenesis via enhanced cell survival signaling, increased G1 cyclin/CDK activity and overriding cell cycle checkpoints; its expression is substantially elevated in DLBCL without a clear difference in germinal center versus non-germinal center subtypes. Our preliminary studies showed that 1) 85% of DLBCL samples have strong or increased expression of MCT-1via IHC, 2) MCT-1 knockdown induces apoptosis in cell lines, and 3) mutant MCT-1 protein expression attenuates the malignant phenotype via translational changes. (Dai Ca Res 2009 69(19): p. 7835-43) MCT-1 levels are directly regulated by MEK/ERK signaling, providing a rationale to test MEK pathway inhibition as a therapeutic target in DLBCL. AZD-6244 (ARRY-142886, selumetinib) is a novel second generation oral small molecule MEK inhibitor that induces dose dependent apoptosis in DLBCL cell lines and attenuates tumor growth in xenograft models. (Bhalla Blood 2011 118(4): p. 1052-61) In patients with solid tumors, AZD-6244 75mg twice daily has been established as the recommended phase II dose (RP2D). (Adjei JCO 2008 26(13): p. 2139-46)Methods: Eligible relapsed/refractory (R/R) DLBCL patients received AZD6244 hydrogen sulfate at a dose of 75 mg by mouth twice daily continuously for up to eight 28-day cycles or until disease progression or unacceptable toxicity. The primary objective of the study was overall response rate (ORR) with secondary objectives including safety, progression free survival (PFS), overall survival (OS) and pharmacodynamic (PD) analyses. The statistical design used a Simon two-stage design. Due to excessive early toxicity, the protocol was amended to reduce the dose to 50mg twice daily.Results: Sixteen R/R DLBCL pts (9 male, 7 female) with a median age of 70 years (range, 29-86 yrs), median 3 prior regimens (range, 0-6) were enrolled. Cell-of-origin was not prospectively determined, but only 3/10 pts were CD10 positive and 5/9 were MUM1 positive. The median Lactate Dehydrogenase (LDH) at study entry was 483 (range, 194-1128). Two patients withdrew consent prior to treatment exposure. Of 14 patients receiving at least one dose of selumetinib, two had stable disease and the remainder progressed. The median number of treatment cycles was one (range, 1-5). This was partly due to toxicity causing frequent dose interruptions of AZD-6244. Grade ³3 toxicities were observed in 37.5% (15.2 - 64.6%) and included anemia (44%), thrombocytopenia (25%), diarrhea (31%), transaminitis 44%), fatigue (44%); other infrequent toxicities included AV block, LV dysfunction, anorexia and rash. Median progression-free survival (PFS) in all patients was 34 days [95% CI 14-73 days]. Median overall survival (OS) was 129 days [CI 58-134 days]; all but 3 patients (including one patient lost to follow-up) have expired.Conclusion: Despite excellent preclinical rationale to test selective MEK antagonism as a means of modulating MCT-1 and MEK/ERK in DLBCL, AZD-6244 was not well tolerated and had limited clinical activity. Other MEK/ERK inhibitors with a more favorable toxicity profile and/or use of rational synergistic combination therapy should be considered to further evaluate the role of MEC inhibition in this heavily pretreated patient population. (Patel Cancer 2014 19(4): p. 799-805 (Supported by NCI contract N01-CM-2011-00071C) [Display omitted] DisclosuresPetrich:Seattle Genetics: Consultancy, Honoraria, Research Funding. Westin:Spectrum: Research Funding. Gordon:Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending.