Advanced Nonhematologic Malignancies Research Articles

Clinical Benefit of Comprehensive Genomic Profiling for Advanced Cancers in India.

PURPOSEComprehensive genomic profiling (CGP) assay is increasingly used in low-middle–income countries to detect clinically relevant genomic alterations despite its clinical benefits not being well known. Here, we describe the proportion of patients with advanced cancer in India who received targeted therapy for an actionable genetic alteration identified on CGP assays.METHODSThis was a multicenter, retrospective cohort study in adult patients with advanced nonhematologic malignancies who underwent a CGP test. If patients received a targeted therapy for ≥ 6 months, they were considered to have obtained a clinical benefit from the medication, whereas those continuing for ≥ 12 months were considered to have attained an exceptional response. Descriptive statistics were used to describe the proportion of patients with subsequent targeted therapy.RESULTSDuring 2019-2020, 12 medical oncologists provided CGP reports for 297 patients; 221 met the inclusion criteria. Patients received a median of two lines (range: 0-5) of prior systemic therapy. On the basis of the CGP assay, 21 patients (10%) received targeted therapy. Among them, 33% was for human epidermal growth factor receptor 2 (HER2) amplification (nonbreast cancer) and 19% for HER2 or epidermal growth factor receptor exon 20 insertion mutation (lung cancer). After excluding patients with HER2 or epidermal growth factor receptor exon 20 insertions, 8% of 217 patients received targeted therapy. In the overall cohort of 221 patients, clinical benefit was seen in nine patients (4%), of whom two were exceptional responders (1%).CONCLUSIONWe observed that in a low-middle–income country setting, 10% of patients received targeted therapy on the basis of CGP assay. Only 4% of patients who underwent CGP testing obtained a clinical benefit.

19 - A phase 1b multicenter, open-label study of investigational TAK-228 (MLN0128) plus TAK-117 (MLN1117) in adult patients with advanced nonhematologic malignancies

19 - A phase 1b multicenter, open-label study of investigational TAK-228 (MLN0128) plus TAK-117 (MLN1117) in adult patients with advanced nonhematologic malignancies

Clinical Activity of Abemaciclib (LY2835219), a Cell Cycle Inhibitor Selective for CDK4 and CDK6, in Patients with Relapsed or Refractory Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is characterized by a recurrent chromosomal translocation t(11;14) that leads to aberrant expression of Cyclin D1 which, together with cyclin dependent kinases 4 and 6 (CDK4/6), inhibits the retinoblastoma (Rb) tumor suppressor protein and thereby induces malignant proliferation. Abemaciclib, a cell cycle inhibitor selective for CDK4/6 (Gelbert et al, 2014), has shown single agent clinical activity against multiple human tumors including lung cancer and breast cancer (Shapiro et al, ASCO 2013; Goldman et al, ASCO 2014; Patnaik et al, ASCO 2014). Based on molecular pathogenesis and single agent activity in preclinical models of human MCL, abemaciclib was evaluated in a single arm Phase II study for patients with relapsed or refractory MCL.Methods: The primary objective of this study was to estimate the disease control rate, which includes response (complete + unconfirmed complete + partial) plus stable disease, for patients who received abemaciclib for relapsed or refractory mantle cell lymphoma (MCL). Patients were scheduled to receive abemaciclib (200 mg) orally every 12 hours on Days 1 through 28 of each 28-day cycle. Eligibility criteria permitted an unlimited number of prior systemic therapies including high dose chemotherapy with stem cell transplantation, Eastern Cooperative Oncology Group (ECOG) performance status <= 2, absolute neutrophil count >= 1.5 x 109/L, and platelets >= 75 x 109/L. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 were used to grade adverse events. Response Criteria for Non-Hodgkin’s Lymphomas (Cheson et al, 1999) were used to assess clinical activity. Plasma samples for pharmacokinetics were performed both after a single oral dose and after multiple doses at steady state. Flow cytometry was used to isolate circulating MCL cells for evaluation of pharmacodynamic effect on Rb phosphorylation.Results: In this Phase II study, 22 patients with relapsed or refractory MCL received single agent oral treatment with abemaciclib. Among these patients, 91% presented at initial diagnosis with Stage III or IV disease. At the time of study entry, these patients (9 female and 13 male) had a median age of 66 years (range: 53-83), 59% had ECOG performance status of 1 or 2, and all patients had constitutional B symptoms. Eighteen patients received >= 2 prior systemic therapies, and previous treatments for the overall study population included not only high dose chemotherapy with stem cell transplantation but also rituximab (96%), cyclophosphamide-based therapy (86%), cytarabine-based therapy (64%), temsirolimus (55%), and bendamustine (41%). Patients received 1-16 cycles of treatment with abemaciclib and 8 of 22 patients (36%) completed >= 6 cycles. The most common possibly related treatment-emergent adverse events across all grades included diarrhea (55%, including 9% G3/4), nausea (23%, with no G3/4), vomiting (32%, with no G3/4), fatigue (18%, with no G3/4), thrombocytopenia (55%, including 32% G3/4), neutropenia (36%, including 32% G3/4), and anemia (18%, with no G3/4). Plasma concentrations of abemaciclib were comparable to those previously observed and associated with clinical activity in patients with advanced non-hematologic malignancies. For patients with at least one post-treatment radiographic evaluation, preliminary investigator assessment indicates that single agent therapy with abemaciclib was associated with stable disease for 9 patients and partial response for 5 patients, including durable disease control (>= 6 cycles) in 8 of these 14 patients with relapsed or refractory MCL.Conclusions: Abemaciclib, a cell cycle inhibitor, demonstrates evidence of durable disease control as a single agent for patients with relapsed or refractory MCL. DisclosuresHahka-Kemppinen:Eli Lilly and Company: Employment, Equity Ownership. Xiaohui Wang:Eli Lilly and Company: Employment. Brueck:Eli Lilly and Company: Employment. Caldwell:Eli Lilly and Company: Employment. Beckmann:Eli Lilly and Company: Employment, Equity Ownership. Gelbert:Eli Lilly and Company : Consultancy. Cronier:Eli Lilly and Company: Employment. Lin:Eli Lilly and Company: Employment. Li:Eli Lilly and Company: Employment. Chan:Eli Lilly and Company: Employment, Equity Ownership. Pfreundschuh:Amgen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Boerhinger Ingelheim: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Spectrum: Research Funding.

Abstract 213: VS-5584 a dual mTORC1/2 and PI3K inhibitor has anti-tumor activity in multiple in vivo xenograft tumor models and enhanced efficacy in combination with cisplatin or docetaxel

Abstract Verastem is developing VS-5584, a potent and selective dual inhibitor of the mammalian target of rapamycin complexes 1 and 2 (mTOR) and Class I phosphatidylinositide 3-kinases (PI3K), for the treatment of advanced cancer. The PI3K/mTOR signaling pathway is a key regulator in cancer progression and in the survival of cancer stem cells (CSCs). VS-5584 has been shown to be an equipotent inhibitor of all four human Class I PI3K isoforms and the mTOR kinase, and PI3K signaling has been implicated in the maintenance of CSCs in solid tumors. In multiple orthogonal in vitro assays, VS-5584 has been shown to preferentially target CSCs and exhibited significant antiproliferative activity across multiple cancer cell lines. Furthermore, oral administration of VS-5584 has been shown to reduce CSCs in xenograft models. The in vivo antitumor efficacy of once daily and intermittent oral administration of VS-5584 was evaluated in multiple xenograft tumor models representing small cell (SCLC) and non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC) and mesothelioma. Once daily (QD) treatment with VS-5584 demonstrated potent anti-tumor activity, with mean percentage tumor growth inhibition (TGI) ranging from 40% to 97% (P &amp;lt; 0.05). In these models, TGI was dose-dependent with dosages at and above 15 mg/kg showing good antitumor activity (P &amp;lt; 0.05). Interestingly, tumor regression was observed in 33% (3/9) of mice bearing H69 (SCLC) tumors, 60% (6/10) of mice bearing MDA-MB-468 (TNBC) tumors and 50% (5/10) of mice bearing NCI-H226 mesothelioma tumors. This significant antitumor activity was generally observed at well-tolerated dosages. In studies exploring intermittent dosing schedules, efficacy and tolerability were similar or better with a QD 5 days on/2 days off or Monday, Wednesday, Friday schedule compared to continuous daily dosing. We also explored the efficacy of VS-5584 in combination with either cisplatin or docetaxel. In these studies, VS-5584 plus either cisplatin or docetaxel showed significant TGI compared to cisplatin alone in H69 SCLC and docetaxel alone in A549 NSCLC xenograft models (P &amp;lt; 0.05). This potent in vivo anti-tumor activity in xenograft models of NSCLC, SCLC, TNBC and mesothelioma suggests that VS-5584 has the potential for anticancer activity across a variety of cancer types. Intermittent dosing with VS-5584 was sufficient to achieve good efficacy while minimizing side effects, thus allowing a broader therapeutic window compared to QD dosing. VS-5584 in combination with either cisplatin or docetaxel had enhanced anti-tumor activity compared to either chemotherapeutic agent or VS-5584 alone in two in vivo models of lung cancer. VS-5584 is being evaluated in a Phase 1 clinical trial assessing intermittent dosing in subjects with advanced non-hematologic malignancies or lymphoma. Citation Format: Anthony F. Trombino, Vihren N. Kolev, Quentin G. Wright, Qunli Xu, Mahesh V. Padval. VS-5584 a dual mTORC1/2 and PI3K inhibitor has anti-tumor activity in multiple in vivo xenograft tumor models and enhanced efficacy in combination with cisplatin or docetaxel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 213. doi:10.1158/1538-7445.AM2014-213

Abstract C252: A phase 1, dose-escalation study of MLN0128, an investigational oral mammalian target of rapamycin complex 1/2 (mTORC1/2) catalytic inhibitor, in patients (pts) with advanced non-hematologic malignancies.

Abstract Background: MLN0128 is an investigational, potent, and highly selective inhibitor of mTORC1/2, which are integral to cell proliferation, angiogenesis, and cellular metabolism. This first-in-human study (NCT01058707) aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of oral MLN0128. Methods: Pts aged ≥18 years with advanced solid tumors were enrolled in a 3+3 dose-escalation design initially to receive MLN0128 once daily (QD), and then enrolled in escalating intermittent schedules of once weekly (QW), 3 days/week (QDx3d QW), or 5 days/week (QDx5d QW) dosing, in 28-day cycles. Blood samples were collected at multiple timepoints for PK analysis. PD endpoints were evaluated in skin to determine the effect on mTORC1/2-dependent biomarkers. A preclinical PK-efficacy model was generated (Phoenix NLME v1.1) with tumor xenograft efficacy data, and implemented using clinical PK parameters to simulate tumor volume-time curves for various MLN0128 doses/schedules. Response was assessed by RECIST v1.1. Results: 115 pts received MLN0128 doses in the ranges 2-7 mg QD (n=30), 7-40 mg QW (n=30), 6-20 mg QDx3d QW (n=33), and 7-13 mg QDx5d QW (n=22). Median age was 60 years (range 24-89); 40% were male. The most common tumor types were colorectal (22%), renal (9%), and ovarian (8%) cancer. The MTDs were 6 mg QD, 40 mg QW, 16 mg QDx3d QW, and 10 mg QDx5d QW. Based on the overall safety profiles, the recommended phase 2 doses were 5 mg QD, 40 mg QW, 9 mg QDx3d QW, and 7 mg QDx5d QW. Pts received a median of 2 cycles (range 1-23). The most common drug-related adverse events (AEs) were hyperglycemia (65%), nausea (60%), vomiting (44%), decreased appetite (36%), diarrhea (33%), asthenia (30%), and mucosal inflammation (30%). The most common drug-related grade ≥3 AEs were hyperglycemia (12%), asthenia (9%), and mucosal inflammation (5%). MLN0128 exhibited dose-linear PK with a plasma half-life of ∼8 h, and did not accumulate in plasma with QD dosing. Modeling of preclinical PK-efficacy data and simulation of human tumor volume-time curves using clinical PK parameters suggested potential greater antitumor effect with schedules using more frequent dosing (i.e. QD, QDx5d QW). There was a treatment-related inhibition of mTORC1/2 biomarkers in skin. Two of 10 pts (20%) with renal cancer receiving MLN0128 at 15 and 40 mg QW had a partial response; 5 pts (6%) had stable disease for ≥6 cycles. Conclusions: Based on the safety profile, PK/PD, simulated tumor volume-time curves, and responses, MLN0128 5 mg QD and 40 mg QW were selected for further evaluation in an expansion phase in pts with renal, endometrial, or urothelial cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C252. Citation Format: Jeffrey R. Infante, Josep Tabernero, Andres Cervantes, Shadia Jalal, Howard A. Burris, Teresa Macarulla, J. Alejandro Perez-Fidalgo, Rachel Neuwirth, Chirag Patel, Esha Gangolli, Rachael Brake, Jeffrey Sturm, Eric H. Westin, Michael Gordon. A phase 1, dose-escalation study of MLN0128, an investigational oral mammalian target of rapamycin complex 1/2 (mTORC1/2) catalytic inhibitor, in patients (pts) with advanced non-hematologic malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C252.

Weekly nab-Rapamycin in Patients with Advanced Nonhematologic Malignancies: Final Results of a Phase I Trial

This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) in patients with untreatable advanced nonhematologic malignancies. nab-Rapamycin was administered weekly for 3 weeks followed by 1 week of rest, with a starting dose of 45 mg/m(2). Additional doses were 56.25, 100, 150, and 125 mg/m(2). Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m(2) [grade 3 aspartate aminotransferase (AST) elevation and grade 4 thrombocytopenia], and two DLTs occurred at 125 mg/m(2) (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100 mg/m(2). Most treatment-related adverse events (TRAE) were grade 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash (23%), diarrhea (23%), nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and hypertriglyceridemia (15%). Only one grade 3 nonhematologic TRAE (dyspnea) and one grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response and 2 patients remained on study for 365 days (patient with mesothelioma) and 238 days (patient with neuroendocrine tumor). The peak concentration (Cmax) and area under the concentration-time curve (AUC) of rapamycin increased with dose between 45 and 150 mg/m(2), except for a relatively low AUC at 125 mg/m(2). nab-Rapamycin significantly inhibited mTOR targets S6K and 4EBP1. The clinical dose of single-agent nab-rapamycin was established at 100 mg/m(2) weekly (3 of 4 weeks) given intravenously, which was well tolerated with preliminary evidence of response and stable disease, and produced a fairly dose-proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies.

399 Pharmacokinetics and Pharmacodynamics of TAK-733, an Investigational, Oral MEK Inhibitor, in Patients with Advanced Nonhematologic Malignancies

399 Pharmacokinetics and Pharmacodynamics of TAK-733, an Investigational, Oral MEK Inhibitor, in Patients with Advanced Nonhematologic Malignancies

456P - Multicenter, Dose-Escalation Study of the Investigational Drug Tak-733, An Oral Mek inhibitor, in Patients (PTS) with Advanced Solid Tumors: Preliminary Phase 1 Results

ABSTRACT Background TAK-733 is an investigational, orally available, selective, non-ATP-competitive, allosteric inhibitor of MEK1/2 shown to have anti-tumor activity in multiple xenograft models. In this first-in-human ph 1 study (NCT00948467), we evaluated safety, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and efficacy of TAK-733 in pts with advanced solid tumors. Methods Pts aged ≥18 y, with ECOG PS 0–2 and radiographically or clinically evaluable tumors were eligible. Pts received TAK-733 QD on d 1–21 in 28-d cycles; doses escalated in a modified 3 + 3 design based on dose-limiting toxicities (DLTs) in cycle 1 to determine MTD. Plasma and blood samples for PK and PD analysis were collected pre-dose on d 1, 8, 15 and 21 and post-dose d 1 and 21 in cycle 1. Results As of March 16, 2012, 44 pts median age 58 (range 24 - 75) and 50% male, received TAK-733 (dose mg, [n]: 0.2, [1]; 0.4, [1]; 0.8, [2]; 1.6, [2]; 3.2, [4]; 4.4, [4]; 6, [4]; 8.4, [9]; 11.8, [8]; 16, [9]). 2 pts had DLTs (11.8 and 16.0 mg; both Grade 3 acneiform rash); MTD has not been reached. Pts received a median of 2 cycles (range 1-11, 6 pts ≥6 cycles). Safety and PK data are shown in the table. Maximum inhibition (Emax) of ERK phosphorylationin peripheral blood lymphocytes ranged from 21-95% (TAK-733; 0.2-16 mg QD), median Emax were 63%, 78%, and 92% at 8.4, 11.8, and 16 mg, respectively. In 32 evaluable pts, 1 pt (16 mg dose) with melanoma (BRAF L597R) had partial response confirmed at cycle 6 (RECIST v1.1) and is still on treatment at cycle 8; 12 pts had a best response of stable disease. Conclusions These preliminary data indicate that TAK-733 is generally well tolerated and pharmacodynamically active with signs of anti-tumor activity in pts with advanced non-hematologic malignancies. Dose escalation is continuing to determine the MTD. AEs, NCI-CTCAE v4.0 N = 44 Drug-related AE, n (%) 37 (84) ≥15% Dermatitis acneiform 19 (43) Diarrhoea 8 (18) Grade ≥3 drug-related AE, n (%) 7 (16) ≥5% Dermatitis acneiform 2 (5) Creatine phosphokinase evaluation 2 (5) PK data N = 41 Tmax, h 3 T1/2, h 53 Disclosure P.M. LoRusso: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Research Funding (Millennium Pharmaceuticals Inc.). A. Ribas: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Honoraria (Millennium Pharmaceuticals Inc.). J.A. Sosman: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Honoraria (Millennium Pharmaceuticals Inc.). B. Chmielowski: Consultancy within past 2 years (GSK, Genentech, Prometheus, CytRx, Morphotek). Membership on Board of Directors, Speakers Bureau, Advisory Committee (BMS, Genentech, Prometheus). P. Lipman: Employment (Millennium Pharmaceuticals Inc.). X. Zhou: Employment (Millennium Pharmaceuticals Inc.). V. Bozon: Employment (Millennium Pharmaceuticals Inc.). All other authors have declared no conflicts of interest.

Abstract C122: Phase 1b relative bioavailability (BA) study of enteric coated tablet (ECT) in reference to powder in capsule (PIC) formulation of the investigational drug alisertib (MLN8237), an Aurora A Kinase (AAK) inhibitor, in patients with advanced nonhematologic malignancies.

Abstract Background: The investigational drug alisertib (MLN8237) is an orally available, selective AAK inhibitor. Early clinical studies used a PIC formulation; an ECT formulation was recently developed. Here we present relative BA results of ECT referenced to PIC designed to bridge transition to ECT in MLN8237 clinical development. Methods: Eligible patients were age ≥18 years with advanced solid tumors and ECOG PS 0–1. Dose-escalation cohorts received alisertib 10 mg BID (N=1), and 20 mg BID (N=1), before formal relative BA evaluation at 40 mg BID, in a 7-day schedule followed by 14 days' rest (21-day cycles). Patients received MLN8237 40 mg BID as either ECT or PIC in a 2-cycle, 2-way cross-over design. Pharmacokinetic (PK) sampling was performed on Day 7 of cycles 1 and 2 to characterize steady-state PK of alisertib formulated as ECT or PIC for relative BA analysis. PK was also evaluated on Day 1 of ECT dosing. Results: 22 patients were included (N=1 each at 10 and 20 mg BID; N=20 at 40 mg BID); 55% were male, 90% were white, and median age was 56 years. 14 patients were evaluable for relative BA analysis. Following BID oral dosing, absorption was fast (median Tmax ∼2.5 hours for ECT; ∼2 hours for PIC). Relative BA of ECT referenced to PIC was 90% (90% CI: 74.4, 108.8). Steady-state Cmax following ECT was 82% of that from PIC (90% CI: 69.9, 95.5). Mean accumulation ratio of ECT BID was ∼2.8-fold; mean peak-to-trough ratio was ∼2.5. The range of dose-normalized exposures following ECT was within the corresponding range observed with PIC, which has previously been associated with favorable pharmacodynamic effects (Dees et al. Abstract 3010; Cervantes et al. Abstract 3031, J Clin Oncol 2010;28:15s). Conclusions: Systemic exposures following administration of ECT and PIC formulations of alisertib are generally similar, supporting transition from PIC to ECT in clinical development. Taken together with PK, pharmacodynamics, and antitumor activity from other trials, these data indicate that the ECT formulation of alisertib can provide exposures needed for clinically relevant bioactivity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C122.

1210 POSTER Phase 1 Study of MLN9708, an Investigational Proteasome Inhibitor, in Advanced Nonhematologic Malignancies- Updated Results

1210 POSTER Phase 1 Study of MLN9708, an Investigational Proteasome Inhibitor, in Advanced Nonhematologic Malignancies- Updated Results

First-in-human, multicenter, dose-escalation, phase I study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced nonhematologic malignancies and melanoma.

TPS145 Background: The Ras/Raf/MEK/ERK cascade is frequently activated in human cancers; MEK inhibition is an attractive therapeutic target for preventing tumor growth and angiogenesis. The investigational drug TAK-733 is a novel, orally available, selective, non-ATP competitive, allosteric inhibitor of MEK1/2. It has shown in-vivo antitumor activity against multiple human tumor xenograft models, particularly tumors with activating BRAF mutations or RAS mutations, mediated through induction of caspase-driven apoptosis. This study is the first clinical evaluation of TAK-733. Methods: The primary objectives of this phase I study are to evaluate the safety profile, characterize the pharmacokinetics (PK), and determine the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of oral TAK-733. Secondary objectives include evaluating the antitumor activity of TAK-733, including in melanoma pts with BRAF V600E mutation or wild-type. Exploratory objectives include the investigation of potential pharmacodynamic effects in peripheral blood (pERK), and assessment of any associations between antitumor activity and N/KRAS and BRAF mutations that may predict response to treatment. The study is composed of two stages. In the dose-escalation stage, approximately 30 pts with advanced nonhematologic malignancies will receive TAK-733 QD on days 1–21 of 28-day cycles from a starting dose of 0.2 mg; dose escalation will proceed via a single pt-cohort design (100% increments) and then a modified 3+3 design (40% increments) based on DLTs in cycle 1. Dosing of TAK-733 will then be investigated at or below the MTD, until the RP2D is determined. In the expansion stage, approximately 30 MEK/BRAF inhibitor-naïve pts with advanced unresectable melanoma, with either BRAF V600E or BRAF-wild type tumors, will be treated at the RP2D. For both stages, pts aged ≥18 years, with ECOG PS 0–2 and radiographically or clinically evaluable tumors are eligible. To date, 22 pts have been enrolled to the dose-escalation stage. This study is registered with ClinicalTrials.gov (NCT00948467).

Abstract 4508: Nonclinical pharmacokinetics of TAK-441, a hedgehog pathway inhibitor

Abstract TAK-441 is a potent and selective smoothened (Smo) antagonist that blocks hedgehog (Hh) signaling. TAK-441 is being developed for the treatment of advanced nonhematologic and hematologic malignancies. In vivo pharmacokinetic (PK) studies using rats and dogs and various in vitro studies were conducted to describe the PK of TAK-441 to support its clinical development. After oral administration of TAK-441 and/or [14C]TAK-441 to rats and dogs, plasma, urine, feces and bile were collected at designated time points. The concentrations of TAK-441 and total radioactivity in the biological samples were measured by high performance liquid chromatography / tandem mass spectrometry and liquid scintillation counter, respectively. The PK of TAK-441 was characterized in rats and dogs by low plasma clearance (397.9 and 161.3 mL/hr/kg), moderate plasma volume of distribution at steady state (681.6 and 2181.3 mL/kg), a moderate terminal elimination half-life (t1/2) (1.7 and 9.8 hours), and an oral bioavailability of 31.7% and 90.3%, respectively. A potential food effect was observed in dogs with an approximate 2-fold increase in the extent of absorption when TAK-441 was dosed to fed dogs (compared with fasted dogs), producing both a higher maximal drug concentration (Cmax) and area under the plasma concentration versus time curve from 0 to 24 hours (AUC0-24h). At 1 μg/mL, TAK-441 had high plasma protein binding in mice (99.7%) and rats (96.2%) and had lower plasma protein binding in dogs (79.6%) and humans (87.7%). No metabolites unique to humans were detected after incubation in hepatic microsomes. CYP3A4/5 was the major CYP isozyme contributing to the metabolism of TAK-441, followed by CYP2C19 and 2C9. The rank order of contribution of the five major human CYP isozymes to TAK-441 metabolism (determined using chemical inhibitors) was 3A4/5 (80.3%) &amp;gt;2C19 (14.4%) &amp;gt;2C9 (5.2%) &amp;gt;1A2 and 2D6 (&amp;lt;1%). TAK-441 showed no appreciable induction of CYP1A2 or CYP3A4/5 activity in human primary hepatocytes. TAK-441 was a weak inhibitor of CYP2C8 (IC50 of 25 μM) and had no inhibitory effect on the other CYP isoforms. TAK-441 was not a time-dependent CYP inhibitor in human liver microsomes. Taken together, there is a low potential for TAK-441 to affect the PK of other concomitantly administered CYP substrates. However, the PK of TAK-441 could be affected by concomitantly administered strong CYP3A4/5 inhibitors and inducers. TAK-441 was mainly excreted in the feces as metabolites. Urinary excretion of the parent TAK-441 was quite low (LOQ and &amp;lt;1% of dose in rats and dogs, respectively). TAK-441 has high permeability in Caco-2 cells, is a poor substrate for efflux pump P-glycoprotein (P-gp), and is a weak inhibitor of P-gp (IC50 of 6.59 μM). In conclusion, TAK-441 has a favourable nonclinical absorption, distribution, metabolism, and excretion (ADME) profile for clinical evaluation and development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4508. doi:10.1158/1538-7445.AM2011-4508

Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 Monotherapy Studies

AbstractAbstract 1813 Background:Investigational agent MLN9708, a modified dipeptidyl boronic acid, is a potent, reversible and specific inhibitor of the 20S proteasome being evaluated in phase 1 trials of patients with hematologic malignancies and solid tumors. Preliminary plasma pharmacokinetic (PK) data for MLN9708 administered intravenously (IV) and orally (PO) are reported. Both routes of administration are being studied using a twice-weekly schedule (Days 1, 4, 8, and 11 of a 21-day treatment cycle) and a weekly schedule (Days 1, 8, and 15 of a 28-day treatment cycle). MLN9708 completely hydrolyzes to the pharmacologically active boronic acid MLN2238 in aqueous solutions. Methods:Preliminary PK data from four ongoing phase 1 dose-escalation studies with MLN9708 have been analyzed: two studies investigating IV administration (C16001, n=27; C16002, n=7) and two studies of the oral formulation (C16003, n=9; C16004, n=5). In all studies blood samples were collected following the first and final dose of MLN9708 administered in Cycle 1, and trough samples were collected throughout Cycle 1 and at the start of Cycle 2. MLN9708 PK samples were analyzed for MLN2238 plasma and urine concentrations using LCMS/MS with LLOQ of 0.5 ng/mL for plasma samples. Data were analyzed using noncompartmental and compartmental modeling approaches. Plasma exposure parameters (Cmax, Tmax, AUC0-t, and t1/2) were estimated using WinNonlin software v5.2. Results:Following bolus IV administration of MLN9708, MLN2238 showed multi-exponential plasma disposition, characterized by a rapid initial disposition phase (t1/2 of <0.25 hr), an intermediate disposition phase, and a terminal disposition phase with t1/2 of >4 days. For twice-weekly dosing, the Day 1 and Day 11 extrapolated immediate post-IV bolus plasma concentration of MLN2238 (C0) was roughly dose proportional over the dose range (0.125 to 2.34 mg/m2). In contrast, both the Day 1 and Day 11 dosing interval plasma concentration-time AUCs showed dose proportional increases only over the higher dose range (1 to 2.34 mg/m2). There was approximately 3–4 fold accumulation of MLN2238 by Day 11 on the twice-weekly schedule. For weekly IV dosing of MLN9708, only lower dose levels have been studied to date (0.125 to 1.4 mg/m2) but the PK behavior appears to be similar to that for twice-weekly dosing, with the exception that MLN2238 accumulates to a lesser degree (approximately 2-fold). Following oral administration of MLN9708 capsules, there was rapid absorption of MLN2238 (Tmax approximately 1 hr). At the doses studied to date (0.24 to 1.2 mg/m2) for twice-weekly and weekly dosing of MLN9708, systemic exposures achieved with oral dosing were similar to those achieved with IV dosing on the same schedule, indicating that the oral bioavailability of MLN2238 is substantial. Conclusions:MLN9708 (measured as MLN2238) shows approximately dose linear PK over the higher range of doses tested (1 to 2.34 mg/m2). Current data suggest that oral MLN9708 is rapidly absorbed and is substantially bioavailable. Acknowledgment:We thank all study investigators, study managers, and study enrollees participating in studies C16001 (advanced nonhematologic malignancies), C16002 (lymphoma), C16003 (multiple myeloma), and C16004 (multiple myeloma) for providing PK data for analysis. Disclosures:Gupta:Millennium Pharmaceuticals, Inc.: Employment. Off Label Use: Investigational agent in clinical development for the treatment of solid tumors and hematologic malignancies. Liu:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment; Takeda, Inc.: Equity Ownership; Sanofi-Aventis: Equity Ownership; Pfizer: Equity Ownership. Kalebic:Millennium Pharmaceuticals, Inc.: Employment. Gomez-Navarro:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership.

Pharmacokinetics and Safety of Bortezomib In Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Results of the Phase 1 National Cancer Institute Organ Dysfunction Working Group Study NCI 6432

AbstractAbstract 3975Background: Bortezomib (btz, VELCADE®) is approved in the US for the treatment of patients (pts) with multiple myeloma, and for the treatment of pts with mantle cell lymphoma who have received at least one prior therapy. Btz is oxidatively metabolized by hepatic cytochrome P450 enzymes to pharmacologically inactive deboronated metabolites. Thus, btz pharmacokinetics (PK) may be altered in pts with hepatic impairment (HI). This phase 1 study was undertaken to evaluate the PK and safety of btz in pts with varying grades of HI and to inform dosing recommendations in these subpopulations. Here we present the available interim results. Methods: Pts with advanced malignancies were assigned to four groups based on hepatic function (bilirubin and aspartate aminotransferase [AST] levels relative to the upper limit of normal [ULN]) using the classification developed for organ dysfunction studies by the National Cancer Institute's Cancer Therapy Evaluation Program. Normal function was defined as bilirubin and AST ≤ULN. Pts with mild HI had bilirubin ≤ULN and AST >ULN, or bilirubin >1.0–1.5 × ULN (with any AST). Moderate and severe HI were defined as bilirubin >1.5–3 × ULN and >3 × ULN, respectively, with any AST. Pts received btz on days 1, 4, 8, and 11 of 21-day cycles. Pts with normal hepatic function received btz at the standard dose of 1.3 mg/m2. Pts with severe, moderate, and mild HI received escalating doses of btz from starting doses of 0.5, 0.7, and 1.0 mg/m2, respectively, via a standard 3+3 design to 1.3 mg/m2. Serial blood samples were collected for 24 hours post-dose on days 1 and 8 of cycle 1 for measurement of btz plasma concentrations. Individual values of dose-normalized (DN) area under the concentration–time curve from time zero to the point of last quantifiable concentration (AUC) and maximum concentration (Cmax) were calculated by noncompartmental analysis. PK parameters were summarized by hepatic function and subject to an analysis of variance to estimate the ratio of geometric means and 90% confidence intervals (CIs) for each HI group relative to the control group. Results: A total of 53 pts were treated, 14 with normal hepatic function, and 16, 9, and 14 with mild, moderate, and severe HI, respectively. Median age was 62 years (range 30–85), 53% were female, 94% were white, and 11/58/30% had ECOG performance status 0/1/2. Dose escalation proceeded to 1.3 mg/m2 in pts with mild HI; data collection is ongoing at 1.0 mg/m2 in pts with moderate and severe HI. The most common adverse events (AEs) were fatigue (53%), nausea (42%), and dyspnea (32%). For most AEs, no association was apparent between increased incidence and poorer hepatic function; the incidence of elevated AST was 7, 25, 33, and 36% in the normal group and mild, moderate, and severe HI groups, respectively. PK data were available for 51 pts. Geometric mean DN AUC was 30.2, 23.0, 50.3, and 47.7 (ng.hr/mL)/(mg/m2) on day 1 and 52.2, 51.9, 83.4, and 80.3 (ng.hr/mL)/(mg/m2) on day 8 in pts with normal hepatic function and mild, moderate, and severe HI, respectively. Respective values for geometric mean DN Cmax were 56.7, 38.2, 66.0, and 84.2 (ng/mL)/(mg/m2) on day 1, and 88.9, 79.6, 59.2, and 96.1 (ng/mL)/(mg/m2) on day 8. Geometric least square mean ratios for DN AUC and DN Cmax between groups are shown in the table. Compared to pts with normal hepatic function, mild HI did not alter DN AUC and DN Cmax. However, mean DN AUC was increased by approximately 60% in pts with moderate or severe HI. Conclusions: Pts with mild HI do not require a starting dose adjustment and should be treated per the recommended dose of btz. Pts with moderate or severe HI should be started at a reduced dose of 0.7 mg/m2 during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on pt tolerance. These data have resulted in an update to the US Prescribing Information for VELCADE®.Comparison vs normalGeometric least square mean ratio (90% CI)Day 1Day 8DN AUCMild HI0.833 (0.603–1.151)0.954 (0.664–1.371)Moderate HI1.662 (1.136–2.430)1.538 (0.969–2.440)Severe HI1.578 (1.139–2.186)1.477 (1.046–2.085)Average of moderate/severe HI1.619 (1.199–2.186)1.507 (1.075–2.113)DN CmaxMild HI0.697 (0.446–1.090)0.879 (0.528–1.463)Moderate HI1.162 (0.688–1.962)0.612 (0.318–1.178)Severe HI1.483 (0.947–2.323)1.023 (0.633–1.653)Average of moderate/severe HI1.313 (0.868–1.986)0.791 (0.493–1.271) Disclosures:Venkatakrishnan:Millennium Pharmaceuticals: Employment. Off Label Use: Discussion of Velcade in patients with advanced non-hematologic malignancies is included. Takimoto:Johnson & Johnson: Employment, Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Millennium Pharmaceuticals: Employment, Equity Ownership. LoRusso:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

First-in-human, phase I dose-escalation study of investigational drug MLN9708, a second-generation proteasome inhibitor, in advanced nonhematologic malignancies.

3071 Background: The investigational drug MLN9708 has shown antitumor efficacy in a wide range of tumor xenografts. It dissociates from the proteasome faster and has greater tissue penetration than...

Pharmacokinetics (PK) of PF-562271, a focal adhesion kinase (FAK) inhibitor, and its effect on CYP3A in patients with advanced nonhematologic malignancies.

2553 Background: FAK transduces signaling from integrins and growth factors to modulate tumor cell invasion, proliferation, and survival. PF-562271, a potent FAK inhibitor, is under development as an anticancer agent. Preclinical studies demonstrated that PF-562271 is an inhibitor of its primary metabolizing enzyme, CYP3A. PF-562271 PK and its effect on CYP3A were investigated in a dose-escalation trial in patients with nonhematologic malignancies. Methods: Escalating doses of PF-562271 were administered orally to a total of 67 patients twice a day (BID) or once a day (QD), with or without food. Serial serum samples were collected after the first dose and at steady state to determine PK of PF-562271. To evaluate the effect of PF-562271 on CYP3A activity, plasma PK of orally administered midazolam were determined prior to PF-562271 administration and after repeated PF-562271 dosing to steady state in 8 patients who received the recommended phase 2 dose of 125 mg BID. Serum PF-562271 and plasma midazolam concentrations were determined using validated HPLC-MS/MS methods. The concentration-time data for PF-562271 and midazolam were analyzed by noncompartmental methods. Results: After a single oral dose, PF-562271 was readily absorbed with the maximum serum concentration achieved in 0.5 to 6 hours. The increases in systemic exposure (AUCinf) were dose proportional over the 5 to 25 mg range, but greater than dose proportional from 35 to 225 mg. After multiple oral doses, PF-562271 demonstrated nonlinear accumulation in exposure; the mean ratio of steady state AUC during a dose interval to AUCinf after the first dose ranged from 1.3 to 5.3, indicating time-dependent PK. Similar PK parameters for PF-562271 were observed at comparable doses given with or without food. When co-administered, PF-562271 (125 mg BID) increased total midazolam plasma exposure approximately 5.9-fold. Conclusions: PF-562271 displayed time- and dose-dependent nonlinear PK, and is a potent CYP3A inhibitor. The nonlinear PK of PF-562271 likely resulted from auto-inhibition of CYP3A. In the limited number of subjects evaluated, food did not substantially alter the PK of PF-562271. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer

Safety, tolerability, and pharmacokinetics of TAK-701, a humanized anti-hepatocyte growth factor (HGF) monoclonal antibody, in patients with advanced nonhematologic malignancies: First-in-human phase I dose-escalation study.

3081 Background: TAK-701 binds to HGF and inhibits HGF/C-MET-mediated human tumor proliferation in preclinical studies. Methods: Patients aged ≥18 y with advanced nonhematologic malignancies for which standard curative or life-prolonging treatment was not available or no longer effective received up to twelve 28-d cycles of TAK-701 at 5 dose levels: 2, 5, 10, 20 and 30 mg/kg. In cycle 1, pts received a single IV infusion of TAK-701 at twice the assigned dose level on day 1; in subsequent cycles pts received TAK-701 at the assigned dose level on days 1 and 15 of 28-d cycles. Dose escalation was based on dose-limiting toxicities (DLTs) during cycle 1. Primary objectives were to assess safety and serum pharmacokinetics (PK), and determine the maximum tolerated dose (MTD). Secondary objectives included blood pharmacodynamics (PD) and response assessments. Results: At data cut-off (Dec 8, 2009), 20 pts had been enrolled to the first 4 dose levels: 3, 3, 3 and 11 to the 2, 5, 10 and 20 mg/kg cohorts, respectively. Pts received a median of 2 cycles (range 1–6). 4 of 8 evaluable pts achieved investigator-assessed stable disease. The most common adverse events (AEs) were cough (4 pts), abdominal pain, constipation and fatigue (3 pts each), all grade 1/2. There were 3 grade 3 AEs (gastrointestinal ileus, pleural effusion, urinary tract infection) and 1 grade 4 AE (dyspnea). There were 4 deaths, all due to progressive disease. There were no DLTs; the MTD has not been reached. No pt discontinued due to AEs. Preliminary PK/PD analyses for the 2, 5 and 10 mg/kg cohorts indicate dose-proportional PK (Cmax and AUC(0–28 d)). Mean (SD) half-life estimates based on day 1 dosing were 9.56 (2.93), 8.64 (4.19) and 14.1 (4.76) days, respectively. All pts showed increases in total serum HGF following TAK-701 administration; no free serum HGF was detected throughout the dosing interval. Human antihuman antibody analyses are ongoing. Conclusions: TAK-701 up to 20 mg/kg bi-weekly was well tolerated; enrolment to the 30 mg/kg dose level is ongoing. Updated safety, PK/PD, and preliminary response data for all phase I pts will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Millennium Millennium Millennium

Pharmacodynamic effects of MLN4924, a novel NAE inhibitor, on blood and skin

2562 Background: MLN4924 is a first-in-class, small molecule inhibitor of NEDD8 Activating Enzyme (NAE) with potent antitumor activity in animal models. Inhibition of NAE by MLN4924 leads to decreased neddylation and inhibition of cullin-RING ubiquitin ligase (CRL) activity. CRLs are enzyme complexes that control the ubiquitination and degradation of proteins with important roles in cell cycle and survival. Potent antitumor activity in animal models correlates with accumulation of substrates of the CRLs associated with DNA replication (e.g.Cdt-1), stress response (e.g.Nrf-2), and signal transduction (e.g. pIκB). Methods: A primary objective of this phase I trial in patients (pts) with advanced non-hematologic malignancies was to evaluate the pharmacodynamic (PD) effects of MLN4924 as measured by accumulation of pIκB in peripheral blood mononuclear cells (PBMCs) and Cdt-1 and Nrf-2 in skin. Pts were treated with a daily infusion of MLN4924 for 5 days of a 21-day cycle. PBMCs were isolated for analysis of pIκB levels at screening, baseline, and at selected time points following its administration. Skin biopsies for assay of Cdt-1 and Nrf-2 were performed at baseline and following the second dose of MLN4924. Results: 10 pts have been treated at 3 dose levels. Treatment emergent adverse events include elevations in transaminases, bilirubin and alkaline phosphatase. PK analysis indicated approximately dose-proportional increases in MLN4924 exposure with an estimated half life of 5 to 15 hours and no readily apparent drug accumulation. Analysis of pIκB levels in PBMCs demonstrated accumulation from baseline levels following administration of MLN4924. Cdt-1 and Nrf-2 levels in skin rose above baseline following the second dose of MLN4924. Conclusions: Treatment of pts with MLN4924 results in accumulation of substrates associated with inhibition of NAE in both peripheral blood and skin. Inhibition occurs at exposure levels that are comparable to those resulting in pharmacodynamic activity and in vivo tumor activity in xenograft models. Evidence of PD modulation of NAE activity through the accumulation of CRL substrates has been established in this early analysis, and dose escalation is ongoing to establish the MTD of this agent. [Table: see text]

Phase I Dose Escalation Study of the Anti–Insulin-Like Growth Factor-I Receptor Monoclonal Antibody CP-751,871 in Patients with Refractory Solid Tumors

This phase I study was undertaken to define the maximum tolerated dose, safety, and pharmacokinetic profile of CP-751,871. Using a rapid dose escalation design, patients with advanced nonhematologic malignancies were treated with CP-751,871 in four dose escalation cohorts. CP-751,871 was administered i.v. on day 1 of each 21-day cycle. Pharmacokinetic evaluation was done in all treatment cohorts during cycles 1 and 4. Twenty-four patients received 110 cycles at four dose levels. The maximum tolerated dose exceeded the maximal feasible dose of 20 mg/kg and, thus, was not identified. Treatment-related toxicities were generally mild. The most common adverse events were hyperglycemia, anorexia, nausea, elevated aspartate aminotransferase, elevated gamma-glutamyltransferase, diarrhea, hyperuracemia, and fatigue. At 20 mg/kg, 10 of 15 patients experienced stability of disease. Two of these patients experienced long-term stability. There were no objective responses. Pharmacokinetic analysis revealed a dose-dependent increase in CP-751,871 exposure and approximately 2-fold accumulation on repeated dosing in 21-day cycles. Plasma concentrations of CP-751,871 attained were several log-fold greater than the biologically active concentration. Treatment with CP-751,871 increased serum insulin and human growth hormone levels, with modest increases in serum glucose levels. CP-751,871 has a favorable safety profile and was well tolerated when given in continuous cycles. At the maximal feasible dose of 20 mg/kg, there was a moderate accumulation in plasma exposure, and most of the treated patients experienced stability of disease.

Increased Bioavailability of Intravenous Versus Oral CI-1033, a Pan erbB Tyrosine Kinase Inhibitor: Results of a Phase I Pharmacokinetic Study

In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability. Fifty-three patients with advanced nonhematologic malignancies received i.v. CI-1033 via 30-minute infusions (10-500 mg) on a thrice-weekly schedule. Pharmacokinetic samples were collected on days 1 and 8 and evaluated using noncompartmental analysis. Dose levels evaluated were 10, 20, 30, 45, 67.5, 100, 150, 225, 337.5, and 500 mg. The maximum administered dose was 500 mg, whereas the maximum tolerated dose was 225 mg. The most common treatment-related grade 1 to 2 adverse events were rashes (38% of patients), nausea (17%), vomiting (17%), stomatitis (14%), and diarrhea (13%). Most common grade 3 adverse events were hypersensitivity reactions (7.5%), rashes (3.8%), and diarrhea (3.8%). No grade 4 toxicities were observed. Ten of the 53 (19%) patients had disease stabilization at their first efficacy evaluation visit (including two with minor responses). A 5- to 10-fold increase in i.v. C(max) was noted with a 3-fold increase in AUC compared with oral CI-1033 at equivalent doses. Treatment-related gastrointestinal adverse events were notably less frequent with this i.v. regimen. CI-1033 was safely given i.v. up to 225 mg/dose on a thrice-weekly schedule, with evidence of antitumor activity. At equivalent doses, the bioavailability of i.v. CI-1033 is thrice that of the oral formulation. Treatment with i.v. CI-1033 is feasible and may be warranted when increased drug exposures are desired.