Anthony W. Tolcher

E13045 Background: Tesetaxel, a novel, orally absorbed taxane that is not a substrate for P-glycoprotein, has demonstrated antitumor activity in pts with breast, gastric, and other solid tumors. Neutropenia is the most common dose-limiting effect. To date, tesetaxel has solely been administered using a once every 3 weeks schedule with an MTD of 27 mg/m². Since other taxanes such as docetaxel and paclitaxel exhibit schedule-dependent effects, we evaluated a weekly dosing regimen of tesetaxel in escalating fixed doses. Threshold models predict taxane pharmacodynamics, and times above a threshold concentration (tC) correlate with both tumor response and toxicity; for paclitaxel, for instance, tC > 0.05 micromol/L was the best predictor of objective response and severe neutropenia (Joerger et al., Clin Cancer Res, 2007). Methods: Eligible pts had advanced solid tumors, ECOG PS 0-2, and adequate organ function. Tesetaxel was given once weekly for 3 weeks in 28-day cycles, beginning at a flat dose of 25 mg per cycle (e.g., 10 mg in Weeks 1 and 2 and 5 mg in Week 3), with progressive increase in total dose per cycle to 30, 45, 60 mg, and continued escalation in 15-mg increments to the MTD. Serial blood samples were collected, and parent compound was assayed by HPLC. Results: To date, 12 pts (3 pts/level) have been treated. Weekly dosing has been well tolerated up to 60 mg. No dose-limiting reactions have been observed, and the MTD has not been reached. Tesetaxel has a long T_1/2 (~180 hrs), and low plasma concentrations in the range of 0.3–2.5 nmol/mL were detectable prior to the next dose. There was no substantial drug accumulation over multiple cycles. Conclusions: Weekly oral administration of tesetaxel is feasible and provides long-term, low-level exposure to this taxane. Given threshold effects observed with other taxanes, this finding may similarly predict clinical outcome and toxicity with tesetaxel. The MTD of this weekly regimen has not been reached, but exceeds the MTD of the every-3-week regimen.

3074 Background: Amuvatinib is an oral multi-targeted TKI which inhibits the mutant forms of c-kit, and PDGFRα. It also disrupts DNA repair probably through suppression of Homologous Recombination protein Rad51. Methods: Adults with cancer diagnosis appropriate for one of the 5 SOC regimens to be studied received amuvatinib (dry-powder capsules) in combination with SOC. The 5 SOC regimens were: paclitaxel/carboplatin (PC), carboplatin/etoposide (CE), topotecan (T), docetaxel (D), and erlotinib (E). Amuvatinib doses were escalated until the MTD of the drug in combination with SOC agents was reached. The primary objectives of the study were to determine the MTD, DLTs, and quantify the effects of amuvatinib on the PK of SOC agents. Other objectives included pharmacodynamic parameters and tumor response. Results: 100 patients, mean age of 58 (range, 25–84) years were enrolled. M/F:35/65. ECOG PS 0/1/2:15/78/7, respectively. 90% of patients had prior cancer treatment. Patients were treated with amuvatinib plus: PC (23 patients); CE (22); T (20); D (15), and E (20). Amuvatinib doses were escalated from 100 mg PO QD to 400 mg PO BID on a continuous basis. Amuvatinib did not alter the PK of SOC agents, except D. The MTD was not reached and amuvatinib-related DLTs were not identified in this study. Most common (≥ 15% of patients) adverse events (AEs) related to treatment were expected AEs of SOC: neutropenia, fatigue, alopecia, diarrhea, thrombocytopenia, and anemia. Overall, 12 PRs and 44 SDs by RECIST criteria were observed for an overall disease control rate of 56% (95% CI, 46–66). The PC and CE combination arms with amuvatinib showed the most activity with 6 and 5 PRs, respectively. Small Cell Lung Cancer (SCLC) and Neuroendocrine (NE) tumors were the most sensitive with 5 of 11 SCLC or NE patients achieving PR. Rad51 modulation and increased DNA damage (53BP1 foci) was observed in skin punch biopsies. Conclusions: Amuvatinib is well tolerated in combination with 5 SOC regimens. Several PRs were observed. The results support further investigation of amuvatinib in combination with CE or PC in SCLC and NE tumors.

3037^ Background: AKT is a key regulator of cellular proliferation, apoptosis and growth. A range of cancers have genetic aberrations that involve the PI3K/AKT pathway, leading to abnormal AKT hyperactivation and tumor progression. MK-2206 is a novel potent investigational AKT inhibitor, which was initially administered orally in a QOD schedule, where the maximum tolerated dose (MTD) was established at 60mg, based on safety and biomarker studies (Yap et al, ASCO 2010). In view of a long half-life (t1/2) (60-80h), a QW schedule was subsequently pursued to explore the potential of less frequent dosing to circumvent feedback activation of alternative signaling pathways in response to sustained and uninterrupted AKT inhibition. Methods: Eligible patients with advanced solid tumors were recruited in a phase I, multi-center, dose escalation study. Patients had regular safety assessments and blood sampling for pharmacokinetic (PK) studies. Pharmacodynamic (PD) and/or predictive biomarker analyses were undertaken on paired tumor samples (mandatory biopsies at MTD), platelet-rich plasma, hair follicles and circulating nucleic acids in plasma. Results: 30 patients (17 M; median age 60 yr; ECOG PS 0/1: 11/19) received MK-2206 at 90, 135, 200, 250 and 300 mg QW. Grade 3 rash was the dose limiting toxicity (DLT) at 300mg (n=3) and 250mg (n=2). Expansion of the 200mg QW resulted in grade 3 rash DLT in 4 of 15 patients. An intermediate dose of 150mg QW is being investigated. Common reversible MK-2206-related toxicities included rash (32.3%), fatigue (9.7%) and nausea, vomiting, diarrhea, pruritus, stomatitis, dry skin and dysguesia, each occurring at 6.5%. No MK-2206-related grade 5 toxicities were observed. PK analysis showed a median Tmax of 6 hr and a mean apparent terminal t1/2 of 78.6 hr. PD analysis of platelet-rich plasma at 200mg QW (n=9) showed suppression of pAKT up to 96 hours post-dose (p<0.001). Biomarker analyses of tumor samples are ongoing. Conclusions: MK-2206 has shown an acceptable toxicology profile, significant and sustained AKT blockade and a PK-PD profile allowing for QW dosing.

3004 Background: The PI3K-Akt and RAF/MEK/ERK pathways represent two of the most frequently activated growth factor signaling pathways in human cancer. Inhibition of both pathways could yield greater benefits than inhibiting either pathway alone. The objectives of this phase I study were to examine the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of the novel combination of MK-2206 with selumetinib. This investigational study represents a new approach to early-stage drug development with the collaboration of two pharmaceutical companies co-developing early stage targeted agent combinations (NCT01021748). Methods: Eligible patients with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered continuously either once daily (QD) or twice daily (BID). Results: To date, 33 patients have been treated on five dose levels. In the MK-2206 QOD dosing schedule, dose-limiting Grade 3 macular skin rash was reported in 2/3 evaluable patients at MK-2206 45 mg QOD with selumetinib 75mg BID; the tolerable dose was MK-2206 45 mg QOD with selumetinib 75 mg QD. For QW MK-2206, dose-limiting acneiform rash (n=1), stomatitis (n=1) and detached retinal pigment epithelium (n=1) were observed in 3/7 evaluable patients treated at MK-2206 90 mg QW with selumetinib 75mg BID; dose reduction to MK-2206 90mg QW/ selumetinib 50 mg BID was not tolerated due to dose-limiting acneiform rash in 2/ 4 evaluable patients. An intermediate dose of MK-2206 90mg once weekly with selumetinib 75mg QD was tolerable. Preliminary assessment of PK/PD data suggest no apparent drug-drug interactions with the PK profile of each drug administered in this combination. Conclusions: MK2206 at 45 mg QOD, or 90 mg QW is well tolerated in combination with selumetinib 75 mg QD in patients with advanced cancer.

3001^ Background: MK-2206 is a novel allosteric inhibitor of all 3 isoforms of AKT, which are targets implicated in malignant progression. Methods: The investigational agent MK-2206 was given orally QOD to patients (pt) with advanced solid tumors. PD studies of AKT and downstream protein phosphorylation (p) were carried out in tumor biopsies and platelet-rich plasma with MesoScale Discovery (MSD) ELISA, and hair follicles with immunofluorescence. Tumor biopsies were sequenced with Sequenom Oncocarta panel for putative predictive biomarkers and stained with IHC for PTEN expression. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), MR spectroscopy (MRS) and diffusion weighted imaging (DWI) were conducted. Results: 71 pt (37 M; median age 59y; ECOG PS 0/1: 22/49) received MK-2206 at 30, 60, 75, 90 mg QOD. G3 rash (n=6) was dose limiting at 75-90 mg QOD, establishing MTD at 60mg QOD. Four MTD expansion cohorts were then undertaken: paired tumor biopsies (n=14), functional imaging (n=13), ovarian cancer (n=11) and castration resistant prostate cancer (n=14). MK-2206 related toxicities included rash, nausea, fatigue, and hyperglycemia. C-peptide levels increased on MK-2206. No G5 toxicities were seen. PK was dose proportional. Steady state trough MK-2206 concentrations ≥60mg QOD were above those required for both pAKT inhibition and antitumor activity in preclinical models. PD studies in patients treated at the MTD demonstrated that on commencement of MK-2206: 1) pAKT was inhibited in all on-treatment tumor biopsies (p=.002); 2) pAKT, pPRAS40, and pGSK3β were suppressed in platelet-rich plasma from 3h to 48h (all p<.05); 3) pPRAS40 was inhibited 6h to day 15 in hair follicles (p=.03). Median tumor DWI apparent diffusion coefficients increased significantly in 4 pt at day 7 and 2 pt at Day 21 of MK-2206, supporting intratumoral necrosis; DCE-MRI and MRS did not change post MK-2206. 9 pt had RECIST stable disease >4 months with minor responses in 3 pt and CA125 declines observed. Conclusions: MK-2206 can safely induce significant and sustained AKT pathway blockade at the MTD with early signs of clinical activity observed.

2600 Background: LY2523355 is an allosteric inhibitor of Eg5 which selectively inhibits bipolar mitotic spindle formation. The objective of this Phase 1 study is to determine the Phase 2 dose and schedule of LY2523355 that can be safely administered to patients with advanced malignancies. Methods: Study I1Y-MC-JFBB is an open-label, dose-escalation study in patients with advanced malignancy. The study consists of a 3+3 dose escalation phase followed by a dose confirmation phase. Eligible patients receive LY2523355 as a 1 hr infusion on either Days 1, 5, and 9; Days 1, and 8; or Days 1, and 5 with peg on Day 6; of a 21-day cycle. Due to the multiple doses per cycle schedule, the traditional maximum tolerated dose (MTD) definition was conservatively modified to include dose omissions (DO) and dose reductions (DR) in addition to standard dose limiting toxicities (DLT). Patients were assessed every 2 cycles per RECIST criteria. IHC expression of pHH3, Ki-67, and Eg5 was quantified in serial skin biopsies. Results: 46 patients have been enrolled in the study as of October 2010. The most frequent AEs (≥10%) reported include neutropenia, fatigue, nausea, vomiting, rash and anorexia. Toxicities qualifying as DLT or DR/DO were neutropenia or febrile neutropenia. To date, 16 patients have had stable disease for greater than 2 cycles. Single and multiple dose pharmacokinetics (PK) of LY2523355 and metabolite were characterized. LY2523355 clearance was dose-independent and exposure increased in a dose-dependent manner. There was negligible intra- and inter-cycle accumulation of LY2523355. Several PK and other parameters were examined for correlation with DR/DO/DLT for the Days 1, 5 and 9 and the Days 1 and 8 schedules but none were identified as significant. Eg5 inhibitor treatment-related dose and exposure dependent changes in pHH3, and Eg5 expression in skin have been demonstrated. Conclusions: Recently, the MTD for the Days 1, 5 and 9; and Days 1 and 8 schedules has been established at 8 mg/m²/d. This dose has shown a PD response in surrogate skin biopsies for both schedules. Dose escalation and expansion on the Days 1, and 5 plus peg is on-going.

TPS123 Background: Taxanes such as docetaxel and paclitaxel are among the most active agents in metastatic breast cancer (MBC). Tesetaxel is an active novel taxoid that overcomes disadvantages of these standard agents. Among other features, the drug is taken by mouth as an oral capsule. Tesetaxel is not a substrate for P-glycoprotein, a major cause of taxane resistance. The drug is not associated with hypersensitivity reactions, thus obviating the need for both premedications and extended medical/nursing observation. Preclinical studies in human tumor xenografts show activity in taxane-resistant BC as well as reduced peripheral neuropathy. In dose-ranging studies, 8 of 13 evaluable patients (pts) (62%) with MBC achieved prolonged stable disease (SD) (i.e., up to 24 cycles) when the drug was administered once every 3 weeks (wks). A phase II trial of tesetaxel (27-35 mg/m² p.o. Q3 wks) showed a 38% partial response (PR) rate among 34 pts who had progressed after an anthracycline-containing regimen. Based on these favorable data, we have initiated a multicenter study to assess the efficacy and safety of tesetaxel as 1^st-line therapy in MBC. Methods: Eligible patients have: Stage IV, HER2-negative MBC; ECOG PS 0-1; adequate organ function; no prior chemotherapy for MBC, although 1 adjuvant regimen is allowed. Tesetaxel is administered Q3 wks at a starting dose of 27 mg/m² p.o., which can be increased to 35 mg/m² depending on tolerability. A Simon mini-max two-stage design is being used. Target accrual is 25 pts. Response rate, per RECIST 1.1 criteria, is the primary endpoint. Other objectives include progression-free survival and safety. Assuming initial results are favorable, we will examine a weekly dosing schedule in a second pt cohort.

E13088 Background: Ridaforolimus (RIDA) (AP23573; MK-8669), a unique rapamycin analog and potent inhibitor of mTOR signaling, is being developed for treatment of solid tumors. We aimed to assess the effect of a single supratherapeutic dose of 100 mg RIDA on the QTc interval in advanced cancer patients. This dose was used to achieve an exposure similar to that following the clinical dose regimen. Methods: This was a partially blind, placebo-controlled, 2-part study of RIDA in advanced cancer patients. In Part 1, 2 days of ECG were performed for QTc assessment in a fixed sequence. On Day 1, patients received a single oral dose of placebo; on Day 2 they received a single oral dose of RIDA 100 mg. Each dose was followed by 24 h of Holter ECG. Blood samples for RIDA were measured at pre- and up to 24 h postdose on Day 2. In Part 2, patients had continued access to RIDA for potential clinical benefit, with only safety data collected. Results: 23 patients (8 males; 15 females) were enrolled. For Day 1 placebo treatment, 22 patients were included in the QTcF data; for Day 2 RIDA treatment, 20 were included in the QTcF data and 21 in the pharmacokinetic data. RIDA 100 mg did not prolong the QTcF interval. Upper bound of the 90% CI of the placebo-adjusted mean QTcF interval change-from-baseline was 450 ms (on both placebo and RIDA) and none had values >480 ms. Neither placebo nor treatment patients had a QTcF change-from-baseline >30 ms. Exposures after single dose RIDA 100 mg were a geometric mean whole blood AUC_0-24 of 1875 h·ng/mL and C_max of 186 ng/mL, approximating steady state exposure with the clinical dose regimen of 40 mg po QD x 5 consecutive days/week. However, these values do not achieve supratherapeutic exposure. RIDA was generally well tolerated, with no patients discontinued from Part 1 due to drug-related AEs. Conclusions: A single dose of RIDA (100 mg) does not prolong the QTc interval in advanced cancer patients and achieved exposures that approximated steady state exposures at the maximally tolerated clinical dose and regimen.