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365 Identification of the recommended phase II dose (RP2D) of the c-Met Inhibitor tepotinib (MSC2156119J) in Japanese patients (pts) with solid tumors: A phase I trial
Abstracts PCa 2b tumors. EC1169 did not show activity in PMSA-negative cell or xenografts, indicating the specificity of EC1169 for PMSA expressing tissues. EC0652 is a novel radiodiagnostic conjugate of a 99mTc chelator and a PSMA-targeting moiety. Rapid tumor uptake of 99mTc-EC0652 and rapid normal tissue clearance result in an enhanced tumor:background ratios with SPECT imaging. Methods: Key inclusion criteria are age 18 years, ECOG PS 0−1, and adequate organ function. Patients must have failed androgen-deprivation therapy, progressed on abiraterone or enzalutamide, and have been previously treated with a taxane unless contraindicated. Patients are to undergo a 99m Tc-EC0652 SPECT scan prior to therapy. EC1169 is administered as an intravenous bolus on 1 of 2 schedules every 21 days: Days 1, 3, 5, 8, 10, 12 (TIW schedule) or Days 1, 8 (QW schedule). EC1169 dosages (mg/m2 ]: 0.2, 0.3, 0.45, 0.6, 0.8). Dose escalation is based upon the continuous reassessment method. Study objectives include determination of EC1169’s MTD and recommended phase 2 dose, safety, pharmacokinetics, antitumor activity and its correlation with PSMA expression as identified on 99m Tc-EC0652 SPECT imaging. Results: Four pts have been treated on the TIW schedule, and 4 pts have been treated on the QW schedule. All patients are Caucasian. Median age is 70.5 (range: 53−77). The median number of administered EC1169 cycles is 3 (range: 1−6). There have been no DLTs, Grade 3−4 drug related adverse events, serious adverse events, or dose omissions/reductions due to toxicity. Cycle 4 was delayed for 2 weeks in 1 pt (0.3 mg/m2 dose level) due to self-limited asymptomatic troponin-I elevation unassociated with symptoms are ECG changes; it was not attributed to EC1169. Only grade 1−2 toxicities have been observed to date. One pt has stable disease lasting more than 4 cycles. Two pts remain on treatment. Conclusions: Thus far, EC1169 is well tolerated on both schedules in pts with heavily pre-treated mCRPC. Dose escalation continues on both schedules. Conflict of interest: Corporate-sponsored Research: Romnee Clark, MD is an employee of Endocyte, Inc. 363 POSTER An ongoing Phase 1 dose-escalation study of the folic acid-tubulysin small-molecule drug conjugate (SMDC) folate-tubulysin EC1456 M. Edelman1 , D. Matei2 , W. Harb3 , R. Clark4 , J. Sachdev5 . 1 University of Maryland, Mediicine, Baltimore, USA; 2 Indiana Univerisity School of Mediciine, Medicine, Indianapolis, USA; 3 Horizon Oncology, Clinical Research, West Lafayette, USA; 4 Endocyte, Inc., Clinical Development, Indianapolis, USA; 5 Virginia G. Piper Cancer Center/TGen, Medicine, Scottsdale, USA Background: The folate receptor (FR) is highly expressed in several epithelial cancers (e.g. ovarian, NSCLC), and is expressed at low levels in most normal tissues. EC1456 is a potent second generation SMDC of folic acid and tubulysin B hydrazide (TubBH). EC1456 acts as a cytotoxic agent by targeting TubBH to FR-expressing (FR+ ) cancer cells, leading to metaphase cell arrest via inhibition of tubulin polymerization. Preclinical studies demonstrate that EC1456 treatment of FR+ xenografts led to complete remissions in 100% of mice, without weight loss or major organ degeneration. Etarfolatide is a folate-containing tripeptide radio-diagnostic agent that chelates technetium-99m for SPECT imaging. 99m Tc-etarfolatide can noninvasively identify FR+ target lesions to select patients for FR-targeted treatment. Phase 2 studies with the first generation therapeutic folate SMDC vintafolide have shown the utility of 99m Tc-etarfolatide in patient selection for FR-targeted therapy. Methods: The primary objective is to determine the MTD of EC1456 administered on 2 schedules (BIW: days 1, 4, 8, 11 q 21 or 28 days [dosages: 0.5−6.0 mg/m2 )], or QW: days 1, 8 q 21 days (dosages: 1.5−6.0 mg/m2 ). Key inclusion criteria: age 18 years, ECOG PS 0−1, and adequate end-organ function. 99m Tc-etarfolatide scan to evaluate FR status is obtained on enrolled pts. Dose escalation follows the “3+3” protocol for BIW cohort, and continuous reassessment method for QW cohort. Cycle 1 DLT evaluation must be completed for each schedule cohort prior to dosing a new cohort. Results: 22 pts have been treated and are evaluable for cycle 1 toxicity. The median age is 67.5 (range: 43−86); 14 patients are female. 13 pts have received 60 cycles of EC1456 BIW (median 2; range: 1−18), and 9 pts have received 32 cycles of EC1456 QW (median 2; range: 1−11). The only DLT and treatment related (TR) SAE of Grade 3 (G3) infusion reaction occurred at 4.5 mg/m2 QW schedule. Subsequent expansion of the 3.5 mg/m2 cohort was uneventful. There have been no TR-deaths, G4 toxicity, or toxicity causing dose delay, omission or reduction. Drug-related G3 toxicities include abdominal pain, anemia, asthenia, and hypophosphatemia (1 pt
S75 each). Most TR-AEs have been Grade 1−2. Durable stable disease (SD) has been observed in 3 pts with FR+ disease on the BIW schedule (mesothelioma [72 weeks], gastroesophageal junction cancer [64 weeks], SCLC [18 weeks]). On the QW schedule, durable was also observed in 1 FR+ pt (NSCLC [24 weeks]) and in 1 FR non-evaluable pt (leiomyosarcoma [33 weeks]). Conclusions: Both schedules of EC1456 appear to be well tolerated in pts with advanced previously treated advanced cancer. Dose escalation is ongoing. Anti-tumor activity of EC1456 is suggested by durable SD in pts with FR+ disease. Updated pharmacokinetic analyses will be available for the conference. Conflict of interest: Corporate-sponsored Research: Romnee Clark, MD is an employee of Endocyte, Inc. 364 POSTER A summary score to assess toxicity of small molecule oral kinase inhibitors (SMOKIs) in randomized clinical trials (RCTs) M. Carbini1 , R.G. Maki1 . 1 Mount Sinai Medical Center, Tisch Cancer Institute, New York, NY, USA Background: Small molecule oral kinase inhibitors (SMOKIs) have fundamentally changed cancer treatment. However, in the clinical development of SMOKIs, the doses approved by regulatory authorities are often too high for an individual patient. We sought to develop a single metric that captures the cumulative toxicity that a patient cohort experiences, in order to simplify how we discuss toxicity between arms of a RCT, and to provide guidance for dose and schedule during a clinical trial. Materials and Methods: Of 41 RCTs of FDA or EMA-approved SMOKIs (11/2004−01/2015, two arms each), we identified 44 comparative study arms from RCTs. Applying phase I Continuous Reassessment Method techniques, we developed a maximum Weighted Toxicity Score (mWTS) for patient cohorts from relevant RCTs. We define the mWTS as the sum of products of (toxicity grade [1−5]) x (toxicity score [investigator defined]) for a given patient cohort. We tested two different weighting scales (linear and exponential) encompassing all 790 defined NCI-CTCAE version 4.03 adverse events to calculate the mWTS. To normalize the data for adverse events associated with the disease itself, we calculated the difference in mWTS between the treatment and control arms and compared this difference to the difference in the frequency of dose reductions between the two arms of the RCT. Results: The frequency of dose reductions in RCTs of SMOKIs ranged from 0−79%. We collapsed tables of adverse event data for cohorts into a single mWTS. The difference in mWTS (treatment-control) varied from 1.33–9.84 using a linear weighting scale, and from 3.16–22.28 using an exponential scale. The most toxic agents by mWTS for multi-targeted VEGFR inhibitors. The difference in mWTS (treatment-control) correlated well with the difference in the frequency of dose reduction (treatmentcontrol), Pearson correlation p = 0.005 (linear scale) and p = 0.0001 (exponential scale). Conclusions: The mWTS captures the toxicity burden of a study cohort in a single number, making simpler the comparison of toxicity between two arms of an RCT. The difference in mWTS by exponential weighting best correlated with the frequency of dose reduction. Monitoring the cumulative mWTS can be employed to adjust the dose and schedule of a SMOKI during a clinical trial, leading to more accurate dosing and fewer adverse events in later stage trials and commercial use. We are examining the mWTS in more complex settings, e.g. studies with two active comparator arms, and RCTs of other classes of anti-cancer agents. We further propose that toxicity in RCTs is reported in a more standardized way to allow for more accurate discussion of adverse events. Conflict of interest: Advisory Board: Robert Maki: Glaxo Smith Kline, Bayer, Imclone/Lilly. Corporate-sponsored Research: Robert Maki: Janssen, Morphotek/Eisai, Plexxikon. Other Substantive Relationships: Translational research lead, Sarcoma Alliance for Research through Collaboration (SARC). 365 POSTER Identification of the recommended phase II dose (RP2D) of the c-Met Inhibitor tepotinib (MSC2156119J) in Japanese patients (pts) with solid tumors: A phase I trial K. Yamazaki1 , T. Tsushima1 , K. Shitara2 , B. Sarholz3 , M. Fujita4 , T. Doi2 . 1 Shizuoka Cancer Center, Division of Gastrointestinal Oncology, Shizuoka, Japan; 2 National Cancer Center Hospital East, Division of Gastrointestinal Oncology, Chiba, Japan; 3 Merck KGaA, Biostatistics, Darmstadt, Germany; 4 Merck Serono Co. Ltd, Clinical Development Center, Tokyo, Japan Background: The RP2D of tepotinib, a highly selective c-Met inhibitor, has been established as 500 mg/day continuously based on a phase
S76 I trial involving pts with advanced solid tumors conducted in the USA and pharmacokinetic/pharmacodynamic (PK/PD) modeling. Phase I/II trials in China, Taiwan, Singapore, and South Korea involving pts with hepatocellular (HCC) and non-small cell lung cancer (NSCLC) are investigating the RP2D in these populations. We conducted a phase I trial (NCT01832506) to evaluate the RP2D in Japanese pts with solid tumors. Material and Methods: Adults with treatment-refractory solid tumors or tumors for which standard therapy was not available were eligible. Pts of ECOG PS 2 or who had received prior c-Met inhibitor therapy were ineligible. Archived tumor samples or pre-treatment tumor biopsies had to be available for determination of c-Met status by immunohistochemistry (IHC) or in situ hybridization (ISH). A standard 3+3 design with 3 dose levels (tepotinib 215, 300, and 500 mg qd po; 21-day cycle) was used. The primary objective was to establish the RP2D; secondary objectives included safety, PK, biomarker analysis, and antitumor activity. Results: 12 pts (215 mg, n = 3; 300 mg, n = 3; and 500 mg, n = 6) have been enrolled (male/female: 8/4; median age: 64.5 [53−75] years; ECOG PS 0/1: 9/3; tumor type: gastric 2, esophageal 2, anal, appendix, biliary tract, breast, lung, rectal, urachal, unknown primary, 1 each; stage IV cancer: 11 [1 recurrent]; median prior lines of therapy: 3 [0−14]). At least 2 cycles of therapy were initiated in all pts (median 2 [2−18]); median time on treatment was 5.86 (3.6–51.1) weeks. All patients are off study treatment (10/12 due to disease progression). No dose-limiting toxicities were observed. Eleven pts had treatment-emergent adverse events (TEAEs); 5 pts had tepotinibrelated TEAEs, of whom 3 had related TEAEs of grade 3 (lipase increase, n = 2; hyponatremia, n = 1, all with tepotinib 500 mg/day). No tepotinibrelated serious AEs were observed. Pts treated at tepotinib doses of 215 and 300 mg/day had a best overall response (BOR) of disease progression (PD). At tepotinib 500 mg/day, 2/6 patients (gastric and urachal cancer) had stable disease (SD) as their BOR. One of 8 evaluable pts showed c-Met overexpression (gastric cancer; IHC 2+; BOR SD); 1 of 7 evaluable pts had c-Met amplification (rectal cancer; BOR PD). PK in Japanese pts were comparable to those reported previously in the phase I trial conducted in the USA. Exploratory biomarker data analysis will be presented. Conclusions: The RP2D of tepotinib in Japanese pts with solid tumors is confirmed as 500mg qd po. Tepotinib was well tolerated: no DLTs were noted and the safety profile was similar to that in earlier trials. If phase II data in HCC and NSCLC are promising, Japanese pts will be enrolled in global phase III trials. Conflict of interest: Other Substantive Relationships: Barbara Sarholz is employed by Merck KGaA, the company that is developing tepotinib. Mitsuhiro Fujita is employed by Merck Serono Co., Ltd., Tokyo, Japan, a subsidiary of Merck KGaA. 366 POSTER Effects of rifampin, a strong metabolic enzyme inducer, on the pharmacokinetics (PK) of alisertib (MLN8237), an investigational Aurora A kinase inhibitor (AAKi), in patients with advanced solid tumors or lymphomas X. Zhou1 , S. Pant2 , J. Sarantopoulos3 , M. Patel4 , J. Nemunaitis5 , A.C. Lockhart6 , B. Zhang7 , M. Bargfrede8 , A. Muehler9 , K. Venkatakrishnan1 . 1 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Clinical Pharmacology, Cambridge, USA; 2 Oklahoma Health Science Center − Stephenson Cancer Center, Hematology/Oncology, Oklahoma City, USA; 3 Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, Experimental Therapeutics, San Antonio, USA; 4 Florida Cancer Specialists, Sarah Cannon Research Institute, Medical Oncology, Sarasota, USA; 5 Mary Crowley Cancer Research Centers, Immunotherapy, Dallas, USA; 6 Washington University, Medicine, St. Louis, USA; 7 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Biostatistics, Cambridge, USA; 8 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Global Clinical Pharmacology, Cambridge, USA; 9 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Clinical Research, Cambridge, USA Background: Alisertib is an investigational, orally available, selective AAKi currently in clinical development for multiple oncology indications. Alisertib is mainly cleared via metabolism. A primary objective of this phase 1 study (NCT01844583) was to evaluate the effects of the strong metabolic enzyme inducer rifampin on alisertib PK in patients with advanced malignancies, with the aim of informing prescribing/dosing guidance for alisertib in patients taking strong CYP3A inducers. Safety was a secondary objective. Methods: Eligible patients were adults with advanced solid tumors or lymphomas and ECOG performance status 0 or 1. This study used a fixed
Abstracts sequence, 2-cycle, open-label design. Patients received a single dose of alisertib 50 mg PO on cycle 1, day 1 (C1D1) and cycle 2, day 8 (C2D8), and daily doses of rifampin 600 mg PO on cycle 2, days 1−10. Serial blood samples for measurement of alisertib plasma concentrations were collected over a 3-day period (0−72 hours post-single dose alisertib) in cycles 1 and 2. Patients also received twice-daily alisertib 50 mg on cycle 1, days 4−10 and cycle 2, days 11−17. Alisertib PK parameters, including time to maximal plasma concentration (Tmax ) and ratios of geometric means for maximal plasma concentration (Cmax ) and area under the plasma concentration vs time curve from time 0 to infinity (AUC0−inf ), in the presence of rifampin (C2D8) in reference to the absence of rifampin (C1D1) were calculated and associated 90% confidence intervals (CI) were estimated using analysis of variance. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Results: 29 patients were enrolled: 28% male; 90% white; median age 62 years; and mean weight 77 kg. 20 patients completed the protocol-specified dosing and PK assessment requirements and were PK evaluable. Following a single oral dose of alisertib 50 mg, median Tmax in the presence and absence of rifampin was 2 and 4 hours, respectively. The geometric mean of Cmax in the presence of rifampin was similar to that in the absence of rifampin (103%; 90% CI: 84%, 126%). The geometric mean of AUC0−inf in the presence of rifampin was 53% of that in the absence of rifampin (90% CI: 41%, 70%). 27/29 (93%) patients had at least 1 any-grade AE; 18/29 (62%) patients had drug-related AEs. The most common drug-related grade 3 AEs were neutropenia (21%) and leukopenia (14%). 3 patients had serious drug-related AEs. Conclusions: Rifampin reduced single-dose alisertib systemic exposure by approximately 50%. Chronic use of concomitant strong metabolic enzyme inducers such as rifampin should be avoided in patients receiving alisertib. Conflict of interest: Ownership: Bin Zhang: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Corporate-sponsored Research: Xiaofei Zhou, Bin Zhang, Michael Bargfrede, Andreas Muehler, and Karthik Venkatakrishnan: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Other Substantive Relationships: Employment: Xiaofei Zhou, Bin Zhang, Michael Bargfrede, Andreas Muehler, and Karthik Venkatakrishnan are employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. 367 POSTER Effects of alisertib (MLN8237), an investigational Aurora A kinase inhibitor (AAKi), on the QTc interval in patients (pts) with advanced malignancies X. Zhou1 , J. Nemunaitis2 , S. Pant3 , T.M. Bauer4 , M. Patel5 , J. Sarantopoulos6 , A.C. Lockhart7 , D. Goodman8 , B. Zhang9 , C. Dansky Ullmann10 , D.R. Mould11 , K. Venkatakrishnan1 . 1 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Clinical Pharmacology, Cambridge, USA; 2 Mary Crowley Cancer Research Centers, Immunotherapy, Dallas, USA; 3 Oklahoma Health Science Center − Stephenson Cancer Center, Hematology/Oncology, Oklahoma City, USA; 4 Sarah Cannon Research Institute, Tennessee Oncology PLLC, Medical Oncology, Nashville, USA; 5 Florida Cancer Specialists, Sarah Cannon Research Institute, Medical Oncology, Sarasota, USA; 6 Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, Experimental Therapeutics, San Antonio, USA; 7 Washington University, Medicine, St. Louis, USA; 8 Cardiocore Lab, LLC, Clinical Research Services, Rockville, USA; 9 Millennium Pharmaceuticals, Inc. − a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Biostatistics, Cambridge, USA; 10 Millennium Pharmaceuticals, Inc. − a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Oncology Clinical Research, Cambridge, USA; 11 Projections Research Inc., Pharmacokinetics and Pharmacodynamics, Phoenixville, USA Background: Alisertib is an investigational, orally available, selective AAKi currently in clinical development for multiple oncology indications. This study characterized the effects of single-dose and multiple-dose twicedaily (BID) administration of alisertib 50 mg on the electrocardiogram (ECG) QT/QTc interval. Methods: Pts were adults with advanced solid tumors or lymphomas and ECOG PS 0/1. In cycle 1, pts received a single dose of alisertib 50 mg on d 1 followed by multiple dose alisertib 50 mg BID on d 4−10. Pts underwent continuous 12-lead digital ECG (Holter) monitoring for serial collection of triplicate ECGs, time-matched to pharmacokinetic (PK) sampling, following alisertib dosing on d 1 and d 10 (predicted steady state concentration). D-1 triplicate ECGs served as time-matched baseline data. Primary endpoint was change from time-matched baseline in the
S75 each). Most TR-AEs have been Grade 1−2. Durable stable disease (SD) has been observed in 3 pts with FR+ disease on the BIW schedule (mesothelioma [72 weeks], gastroesophageal junction cancer [64 weeks], SCLC [18 weeks]). On the QW schedule, durable was also observed in 1 FR+ pt (NSCLC [24 weeks]) and in 1 FR non-evaluable pt (leiomyosarcoma [33 weeks]). Conclusions: Both schedules of EC1456 appear to be well tolerated in pts with advanced previously treated advanced cancer. Dose escalation is ongoing. Anti-tumor activity of EC1456 is suggested by durable SD in pts with FR+ disease. Updated pharmacokinetic analyses will be available for the conference. Conflict of interest: Corporate-sponsored Research: Romnee Clark, MD is an employee of Endocyte, Inc. 364 POSTER A summary score to assess toxicity of small molecule oral kinase inhibitors (SMOKIs) in randomized clinical trials (RCTs) M. Carbini1 , R.G. Maki1 . 1 Mount Sinai Medical Center, Tisch Cancer Institute, New York, NY, USA Background: Small molecule oral kinase inhibitors (SMOKIs) have fundamentally changed cancer treatment. However, in the clinical development of SMOKIs, the doses approved by regulatory authorities are often too high for an individual patient. We sought to develop a single metric that captures the cumulative toxicity that a patient cohort experiences, in order to simplify how we discuss toxicity between arms of a RCT, and to provide guidance for dose and schedule during a clinical trial. Materials and Methods: Of 41 RCTs of FDA or EMA-approved SMOKIs (11/2004−01/2015, two arms each), we identified 44 comparative study arms from RCTs. Applying phase I Continuous Reassessment Method techniques, we developed a maximum Weighted Toxicity Score (mWTS) for patient cohorts from relevant RCTs. We define the mWTS as the sum of products of (toxicity grade [1−5]) x (toxicity score [investigator defined]) for a given patient cohort. We tested two different weighting scales (linear and exponential) encompassing all 790 defined NCI-CTCAE version 4.03 adverse events to calculate the mWTS. To normalize the data for adverse events associated with the disease itself, we calculated the difference in mWTS between the treatment and control arms and compared this difference to the difference in the frequency of dose reductions between the two arms of the RCT. Results: The frequency of dose reductions in RCTs of SMOKIs ranged from 0−79%. We collapsed tables of adverse event data for cohorts into a single mWTS. The difference in mWTS (treatment-control) varied from 1.33–9.84 using a linear weighting scale, and from 3.16–22.28 using an exponential scale. The most toxic agents by mWTS for multi-targeted VEGFR inhibitors. The difference in mWTS (treatment-control) correlated well with the difference in the frequency of dose reduction (treatmentcontrol), Pearson correlation p = 0.005 (linear scale) and p = 0.0001 (exponential scale). Conclusions: The mWTS captures the toxicity burden of a study cohort in a single number, making simpler the comparison of toxicity between two arms of an RCT. The difference in mWTS by exponential weighting best correlated with the frequency of dose reduction. Monitoring the cumulative mWTS can be employed to adjust the dose and schedule of a SMOKI during a clinical trial, leading to more accurate dosing and fewer adverse events in later stage trials and commercial use. We are examining the mWTS in more complex settings, e.g. studies with two active comparator arms, and RCTs of other classes of anti-cancer agents. We further propose that toxicity in RCTs is reported in a more standardized way to allow for more accurate discussion of adverse events. Conflict of interest: Advisory Board: Robert Maki: Glaxo Smith Kline, Bayer, Imclone/Lilly. Corporate-sponsored Research: Robert Maki: Janssen, Morphotek/Eisai, Plexxikon. Other Substantive Relationships: Translational research lead, Sarcoma Alliance for Research through Collaboration (SARC). 365 POSTER Identification of the recommended phase II dose (RP2D) of the c-Met Inhibitor tepotinib (MSC2156119J) in Japanese patients (pts) with solid tumors: A phase I trial K. Yamazaki1 , T. Tsushima1 , K. Shitara2 , B. Sarholz3 , M. Fujita4 , T. Doi2 . 1 Shizuoka Cancer Center, Division of Gastrointestinal Oncology, Shizuoka, Japan; 2 National Cancer Center Hospital East, Division of Gastrointestinal Oncology, Chiba, Japan; 3 Merck KGaA, Biostatistics, Darmstadt, Germany; 4 Merck Serono Co. Ltd, Clinical Development Center, Tokyo, Japan Background: The RP2D of tepotinib, a highly selective c-Met inhibitor, has been established as 500 mg/day continuously based on a phase
S76 I trial involving pts with advanced solid tumors conducted in the USA and pharmacokinetic/pharmacodynamic (PK/PD) modeling. Phase I/II trials in China, Taiwan, Singapore, and South Korea involving pts with hepatocellular (HCC) and non-small cell lung cancer (NSCLC) are investigating the RP2D in these populations. We conducted a phase I trial (NCT01832506) to evaluate the RP2D in Japanese pts with solid tumors. Material and Methods: Adults with treatment-refractory solid tumors or tumors for which standard therapy was not available were eligible. Pts of ECOG PS 2 or who had received prior c-Met inhibitor therapy were ineligible. Archived tumor samples or pre-treatment tumor biopsies had to be available for determination of c-Met status by immunohistochemistry (IHC) or in situ hybridization (ISH). A standard 3+3 design with 3 dose levels (tepotinib 215, 300, and 500 mg qd po; 21-day cycle) was used. The primary objective was to establish the RP2D; secondary objectives included safety, PK, biomarker analysis, and antitumor activity. Results: 12 pts (215 mg, n = 3; 300 mg, n = 3; and 500 mg, n = 6) have been enrolled (male/female: 8/4; median age: 64.5 [53−75] years; ECOG PS 0/1: 9/3; tumor type: gastric 2, esophageal 2, anal, appendix, biliary tract, breast, lung, rectal, urachal, unknown primary, 1 each; stage IV cancer: 11 [1 recurrent]; median prior lines of therapy: 3 [0−14]). At least 2 cycles of therapy were initiated in all pts (median 2 [2−18]); median time on treatment was 5.86 (3.6–51.1) weeks. All patients are off study treatment (10/12 due to disease progression). No dose-limiting toxicities were observed. Eleven pts had treatment-emergent adverse events (TEAEs); 5 pts had tepotinibrelated TEAEs, of whom 3 had related TEAEs of grade 3 (lipase increase, n = 2; hyponatremia, n = 1, all with tepotinib 500 mg/day). No tepotinibrelated serious AEs were observed. Pts treated at tepotinib doses of 215 and 300 mg/day had a best overall response (BOR) of disease progression (PD). At tepotinib 500 mg/day, 2/6 patients (gastric and urachal cancer) had stable disease (SD) as their BOR. One of 8 evaluable pts showed c-Met overexpression (gastric cancer; IHC 2+; BOR SD); 1 of 7 evaluable pts had c-Met amplification (rectal cancer; BOR PD). PK in Japanese pts were comparable to those reported previously in the phase I trial conducted in the USA. Exploratory biomarker data analysis will be presented. Conclusions: The RP2D of tepotinib in Japanese pts with solid tumors is confirmed as 500mg qd po. Tepotinib was well tolerated: no DLTs were noted and the safety profile was similar to that in earlier trials. If phase II data in HCC and NSCLC are promising, Japanese pts will be enrolled in global phase III trials. Conflict of interest: Other Substantive Relationships: Barbara Sarholz is employed by Merck KGaA, the company that is developing tepotinib. Mitsuhiro Fujita is employed by Merck Serono Co., Ltd., Tokyo, Japan, a subsidiary of Merck KGaA. 366 POSTER Effects of rifampin, a strong metabolic enzyme inducer, on the pharmacokinetics (PK) of alisertib (MLN8237), an investigational Aurora A kinase inhibitor (AAKi), in patients with advanced solid tumors or lymphomas X. Zhou1 , S. Pant2 , J. Sarantopoulos3 , M. Patel4 , J. Nemunaitis5 , A.C. Lockhart6 , B. Zhang7 , M. Bargfrede8 , A. Muehler9 , K. Venkatakrishnan1 . 1 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Clinical Pharmacology, Cambridge, USA; 2 Oklahoma Health Science Center − Stephenson Cancer Center, Hematology/Oncology, Oklahoma City, USA; 3 Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, Experimental Therapeutics, San Antonio, USA; 4 Florida Cancer Specialists, Sarah Cannon Research Institute, Medical Oncology, Sarasota, USA; 5 Mary Crowley Cancer Research Centers, Immunotherapy, Dallas, USA; 6 Washington University, Medicine, St. Louis, USA; 7 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Biostatistics, Cambridge, USA; 8 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Global Clinical Pharmacology, Cambridge, USA; 9 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Clinical Research, Cambridge, USA Background: Alisertib is an investigational, orally available, selective AAKi currently in clinical development for multiple oncology indications. Alisertib is mainly cleared via metabolism. A primary objective of this phase 1 study (NCT01844583) was to evaluate the effects of the strong metabolic enzyme inducer rifampin on alisertib PK in patients with advanced malignancies, with the aim of informing prescribing/dosing guidance for alisertib in patients taking strong CYP3A inducers. Safety was a secondary objective. Methods: Eligible patients were adults with advanced solid tumors or lymphomas and ECOG performance status 0 or 1. This study used a fixed
Abstracts sequence, 2-cycle, open-label design. Patients received a single dose of alisertib 50 mg PO on cycle 1, day 1 (C1D1) and cycle 2, day 8 (C2D8), and daily doses of rifampin 600 mg PO on cycle 2, days 1−10. Serial blood samples for measurement of alisertib plasma concentrations were collected over a 3-day period (0−72 hours post-single dose alisertib) in cycles 1 and 2. Patients also received twice-daily alisertib 50 mg on cycle 1, days 4−10 and cycle 2, days 11−17. Alisertib PK parameters, including time to maximal plasma concentration (Tmax ) and ratios of geometric means for maximal plasma concentration (Cmax ) and area under the plasma concentration vs time curve from time 0 to infinity (AUC0−inf ), in the presence of rifampin (C2D8) in reference to the absence of rifampin (C1D1) were calculated and associated 90% confidence intervals (CI) were estimated using analysis of variance. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Results: 29 patients were enrolled: 28% male; 90% white; median age 62 years; and mean weight 77 kg. 20 patients completed the protocol-specified dosing and PK assessment requirements and were PK evaluable. Following a single oral dose of alisertib 50 mg, median Tmax in the presence and absence of rifampin was 2 and 4 hours, respectively. The geometric mean of Cmax in the presence of rifampin was similar to that in the absence of rifampin (103%; 90% CI: 84%, 126%). The geometric mean of AUC0−inf in the presence of rifampin was 53% of that in the absence of rifampin (90% CI: 41%, 70%). 27/29 (93%) patients had at least 1 any-grade AE; 18/29 (62%) patients had drug-related AEs. The most common drug-related grade 3 AEs were neutropenia (21%) and leukopenia (14%). 3 patients had serious drug-related AEs. Conclusions: Rifampin reduced single-dose alisertib systemic exposure by approximately 50%. Chronic use of concomitant strong metabolic enzyme inducers such as rifampin should be avoided in patients receiving alisertib. Conflict of interest: Ownership: Bin Zhang: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Corporate-sponsored Research: Xiaofei Zhou, Bin Zhang, Michael Bargfrede, Andreas Muehler, and Karthik Venkatakrishnan: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Other Substantive Relationships: Employment: Xiaofei Zhou, Bin Zhang, Michael Bargfrede, Andreas Muehler, and Karthik Venkatakrishnan are employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. 367 POSTER Effects of alisertib (MLN8237), an investigational Aurora A kinase inhibitor (AAKi), on the QTc interval in patients (pts) with advanced malignancies X. Zhou1 , J. Nemunaitis2 , S. Pant3 , T.M. Bauer4 , M. Patel5 , J. Sarantopoulos6 , A.C. Lockhart7 , D. Goodman8 , B. Zhang9 , C. Dansky Ullmann10 , D.R. Mould11 , K. Venkatakrishnan1 . 1 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Clinical Pharmacology, Cambridge, USA; 2 Mary Crowley Cancer Research Centers, Immunotherapy, Dallas, USA; 3 Oklahoma Health Science Center − Stephenson Cancer Center, Hematology/Oncology, Oklahoma City, USA; 4 Sarah Cannon Research Institute, Tennessee Oncology PLLC, Medical Oncology, Nashville, USA; 5 Florida Cancer Specialists, Sarah Cannon Research Institute, Medical Oncology, Sarasota, USA; 6 Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio, Experimental Therapeutics, San Antonio, USA; 7 Washington University, Medicine, St. Louis, USA; 8 Cardiocore Lab, LLC, Clinical Research Services, Rockville, USA; 9 Millennium Pharmaceuticals, Inc. − a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Biostatistics, Cambridge, USA; 10 Millennium Pharmaceuticals, Inc. − a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Oncology Clinical Research, Cambridge, USA; 11 Projections Research Inc., Pharmacokinetics and Pharmacodynamics, Phoenixville, USA Background: Alisertib is an investigational, orally available, selective AAKi currently in clinical development for multiple oncology indications. This study characterized the effects of single-dose and multiple-dose twicedaily (BID) administration of alisertib 50 mg on the electrocardiogram (ECG) QT/QTc interval. Methods: Pts were adults with advanced solid tumors or lymphomas and ECOG PS 0/1. In cycle 1, pts received a single dose of alisertib 50 mg on d 1 followed by multiple dose alisertib 50 mg BID on d 4−10. Pts underwent continuous 12-lead digital ECG (Holter) monitoring for serial collection of triplicate ECGs, time-matched to pharmacokinetic (PK) sampling, following alisertib dosing on d 1 and d 10 (predicted steady state concentration). D-1 triplicate ECGs served as time-matched baseline data. Primary endpoint was change from time-matched baseline in the