Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare Pharmaceuticals Inc. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare Pharmaceuticals Inc. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 29 JAN 2014 BAY / Page: 1 of Synopsis Date of report: 29 JAN 2014 Study title: Sponsor s study number: NCT number: Sponsor: Clinical phase: Study objectives: An open-label Phase I dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose of BAY in patients with advanced solid tumors National Clinical Trial (NCT) number NCT Bayer HealthCare Pharmaceuticals, Inc., USA I The primary objectives of this Phase I open-label study were Test drug: BAY Name of active ingredient: Dose: To determine the safety and tolerability, pharmacokinetics, and maximum tolerate dose (MTD) of BAY in subjects with advanced, refractory solid tumors. To evaluate the pharmacokinetics of intact immunoconjugate (BAY ), total antibody (intact immunoconjugate [BAY ] + cleaved nonconjugated antibody [BAY ]) and toxophore (BAY ). Secondary objectives included evaluation of biomarkers, tumor response, and immunogenicity assessment. BAY Route of administration: Intravenous infusion 0.15, 0.3, 0.6, 1.2, 2.3, and 4.6 mg/kg every 3 weeks Duration of treatment: Reference drug: Indication: Until disease progression occurred [as measured by modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria] or the investigator felt that the risk/benefit assessment was no longer favorable None Advanced solid tumors

3 29 JAN 2014 BAY / Page: 2 of 10 Diagnosis and main criteria for inclusion: Study design: Methodology Co-ordinating investigator: Investigators: Study centers: Publication(s) based on the study (references): Male or female subjects 18 years of age with advanced, histologically or cytologically confirmed solid tumors, refractory to any standard therapy, having no standard therapy available, or subjects having actively refused any treatment which would have been regarded standard, and / or if, in the judgment of the investigator or designated associate(s), experimental treatment was clinically and ethically acceptable. Open-label, non-randomized, Phase I dose-escalating study BAY was administered as a 1-hour intravenous infusion on Day 1 of each cycle. The starting dose was 0.15 mg/kg. Subjects needed to have received 1 complete infusion of BAY and safety data for the first cycle needed to be available before the start of the next cohort could be considered. Dose escalation for subsequent cohorts was only considered after full evaluation of safety data from the previous cohort. Originally, the dose-escalation phase of the study included 2 parts: (a) an accelerated titration using 1 or 2 subjects per dose level and (b) a standard 3+3 design. During the first phase of the study, after evaluating the starting dose level of 0.15 mg/kg, dose escalation proceeded with the dose levels of 0.3, 0.6, 1.2, 2.3, and 4.6 mg/kg. BAY was safe and generally well tolerated in the dose range of 0.15 mg/kg to 2.3 mg/kg administered every 21 days. However, at the 4.6 mg/kg dose level, 2 subjects died within several days after receiving the study drug. The risk / benefit assessment, including a comprehensive safety and pharmacokinetic (PK) analysis, appeared to justify restarting the study at the dose of 0.6 mg/kg. From that point forward (through Amendment 3), the standard 3+3 design part was modified to enroll 6 subjects sequentially (2+2+2) at each dose level. Dr. Johanna C. Bendell, The Sarah Cannon Research Institute, Nashville, TN, United States of America 2 study centers United States of America None

4 29 JAN 2014 BAY / Page: 3 of 10 Study period: First subject, first visit: 04 NOV 2009 Last subject, last visit: 03 APR 2013 Early termination: The termination of the study was based on an overall assessment of safety data. Number of subjects: Planned: Approximately 30 subjects in the dose escalation phase of the study Analyzed: 12 subjects More details are given in the section on study subjects below. Criteria for evaluation Efficacy / clinical pharmacology: Efficacy Tumor response and progression for solid tumors were evaluated based on RECIST. Clinical pharmacology Pharmacodynamics Summary statistics for biomarker measurements and absolute change in biomarker levels from baseline by visit were calculated for 1) tumor levels of carbonic anhydrase IX (CAIX) (measured in pre-treatment tumor biopsies only), 2) caspase-cleaved cytokeratin 18 (identified by the monoclonal antibody M30) (CK18/M30) in plasma, 3) total soluble cytokeratin 18 (measured by the monoclonal antibody M65) (CK18/M65) in plasma, and 4) CAIX in plasma. Pharmacokinetics The following pharmacokinetic (PK) parameters were derived from the plasma concentration vs. time profiles of: BAY (intact antibody-drug conjugate, ADC): AUC(0-97), AUC(0-97)/D, AUC(0-97)norm, AUC(0-tlast), AUC(0-tlast)/D, AUC(0-tlast)norm, AUC, AUC/D, AUCnorm, Cmax, Cmax/D, Cmax,norm, tmax, tlast, t1/2, CL, and Vz

5 29 JAN 2014 BAY / Page: 4 of 10 Efficacy / clinical pharmacology: Safety: Other: Statistical methods: Pharmacokinetics (continued) Total antibody (ADC and free 3ee9 antibody, BAY ): AUC(0-25), AUC(0-25)/D, AUC(0-25)norm, AUC(0-97)norm, AUC(0-tlast), AUC(0-tlast)/D, AUC(0-tlast)norm, AUC, AUC/D, AUCnorm, Cmax, Cmax/D, Cmax,norm, tmax, tlast, t1/2, CL, and Vz BAY (toxophore, monomethyl auristatin E, MMAE): AUC(0-97), AUC(0-97)/D, AUC(0-97)norm, AUC(0-tlast), AUC(0-tlast)/D, AUC(0-tlast)norm, AUC, AUC/D, AUCnorm, Cmax, Cmax/D, Cmax,norm, tmax, tlast, t1/2, CL, and Vz Safety evaluation included the incidence of abnormal findings in measurements for objective tolerability: physical examination, Eastern Co-Operative Oncology Group (ECOG) performance status, vital signs (BP and pulse rate), electrocardiogram (ECG) findings, laboratory findings, and the occurrence of adverse events after drug administration Not applicable The following analysis sets were used in this study: Valid for safety evaluation: All subjects who received at least 1 dose of the study drug and had post-baseline safety data available were included in the safety evaluation. Valid for MTD evaluation: All subjects who completed C1 or discontinued during C1 due to a drug-related adverse event or a dose-limiting toxicity (DLT) were included in the MTD evaluation. Valid for tumor response evaluation: All subjects who received at least 1 dose of the study drug and who had baseline and postbaseline tumor measurement data available were included in the tumor response evaluation. Valid for PK: All subjects with valid PK data were included in the evaluation of plasma concentrations and PK parameters. Valid for biomarker evaluation: All subjects with valid biomarker data were included in the biomarker evaluation. Efficacy Tumor response and progression for solid tumors were evaluated in this study based on RECIST criteria.

6 29 JAN 2014 BAY / Page: 5 of 10 Statistical methods (continued): Pharmacokinetics The plasma concentration vs. time courses of BAY , the total antibody (intact immunoconjugate [BAY ] + cleaved non-conjugated antibody [BAY ]), and toxophore (BAY ) were summarized separated by cohort. The following statistics were calculated for each of the sampling points: arithmetic mean, standard deviation and coefficient of variation (CV), geometric mean, geometric standard deviation (re-transformed standard deviation of the logarithms) and geometric CV, minimum, median, maximum values and the number of measurements. Means at any time were only calculated if at least 2/3 of the individual data had been measured and were above the limit of quantification (LLOQ). For the calculation of the mean value, a data point below LLOQ was substituted by one-half of this limit. In tables showing mean values, where values below LLOQ were included in the calculation of mean values, these means were marked. Individual and mean plasma concentration vs. time curves were plotted by cohort using both linear and semi-logarithmic scales. PK characteristics (tmax and tlast excluded) were analyzed assuming log-normally distributed data and summarized by the statistics mentioned above. tmax and tlast were described using minimum, maximum, and median as well as frequency counts. Safety Adverse events Individual listings were provided for the adverse events reported. The incidence of treatment-emergent (drug-related) adverse events as well as pre-treatment adverse events was summarized by worst Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE) grade using both CTCAE terms and Medical Dictionary for Regulatory Activities (MedDRA) terms (Version 15.1) and by cohort. A treatment-emergent adverse event was defined as any event arising or worsening after the start of study drug administration until 30 days after the last dose of study drug. Frequency tables were also provided for the changes of worst CTCAE grade after start of treatment versus baseline. Listings of deaths, serious adverse events, and adverse events leading to permanent discontinuation of study drug were provided.

7 29 JAN 2014 BAY / Page: 6 of 10 Statistical methods (continued): Substantial protocol changes: Other safety variables Summary statistics were presented by cohort. To pool results from different laboratories, individual standardized laboratory values were normalized to the smallest range of lower limit of normal (LLN) and upper limit of normal (ULN) found in the data. Let max(lln) be the maximum LLN for a given laboratory value and min(uln) the corresponding minimum ULN, then max min max is a transformation of the original value that is standardized with respect to the normal range and can be pooled over laboratories. Laboratory data outside the reference ranges were listed with abnormal values flagged. The incidence of laboratory data outside the reference ranges (low, high) were summarized by cohort in frequency tables. The incidence of laboratory toxicities was also summarized by worst CTCAE grade and by cohort. Frequency tables were also provided for the changes of worst CTCAE grade after start of study drug treatment versus baseline. Protocol amendment 1, dated 01 SEP 2009 The Food and Drug Administration (FDA) had specific comments on the investigational new drug-opening study protocol about accelerated titration design and inclusion of neurological examination as part of brief physical examination. In addition, based on FDA comments on chemistry, manufacturing, and control of the study drug as well as product release specifications, the maximum dose of BAY was determined. Those revisions and additional information were incorporated in this amendment. In addition to the aforementioned revisions, the amendment also allowed the use of 50 ml and 250 ml normal saline bags (for diluting the reconstituted BAY solution) to ease administration of BAY to subjects with low and high body weight. Protocol amendment 2, dated 08 MAR 2010 This amendment specified the revised maximum dose of BAY administered in this study based on revised product release specifications.

8 29 JAN 2014 BAY / Page: 7 of 10 Substantial protocol changes (continued): Protocol amendment 3, dated 17 NOV 2010 Purpose of this amendment was to incorporate FDA recommended changes to the protocol following toxicities observed at 4.6 mg/kg. Two (2) subjects dosed at 4.6 mg/kg died within several days of receiving the study drug. After a comprehensive data review, the study was restarted at the 0.6 mg/kg dose level. Study subjects This clinical study report describes the results from the dose-escalation phase of the study until early termination. In the dose-escalation phase of the study, 12 subjects with advanced, histologically or cytologically confirmed solid tumors received at least 1 dose of BAY and were deemed valid for safety, efficacy, and PK analyses. There were 4 screening failures due to protocol violation (n=2), disease progression, recurrence, or relapse (n=1), and adverse event (pulmonary embolism; n=1). Efficacy / clinical pharmacology evaluation Pharmacodynamics Interpretation of tumor response (efficacy) data needs to take into account that efficacy was not the primary objective of this study. No subjects exhibited complete or partial response by RECIST. However, individual subjects showed stable disease for more than 2 cycles. 1 subject in Cohort 4 (0.6 mg/kg) and 2 subjects in Cohort 5 (1.2 mg/kg) experienced stable disease. One (1) subject with NSCLC, treated at the 1.2 mg/kg dose level, had 28% maximum tumor shrinkage and had a treatment duration of 22 cycles. In the 7 subjects with an event, i.e. documented progressive disease, the progression-free survival ranged from 5 to 689 days. Tumor CAIX data was available for 6 of the 12 subjects treated in this study. Only 2 of the 6 subjects tested had tumor CAIX staining detectable in 10% of tumor cells. One of these 2 subjects, Subject , was treated at the 1.2 mg/kg dose level, had 28% tumor shrinkage, stable disease throughout Cycle 20, and a treatment duration of 22 cycles; the other subject was in Cohort 7 (4.6 mg/kg dose level), and tumor shrinkage could not be evaluated in this subject. Thus, the small amount of tumor CAIX data available were consistent with, or at least did not refute, the hypothesis that sufficient tumor CAIX is required for BAY antitumor activity. Plasma CK18 data was available for all 12 subjects treated in this study. Increases in M30 and in the M30/M65 ratio were observed in Subject , suggesting an increase in the proportion of cells undergoing apoptotic cell death in this subject. Large, early increases in plasma CK18/M30 and CK18/M65 were observed in the 2 subjects treated in Cohort 7 (the 4.6 mg/kg dose level). However, since the CK18 assays cannot determine the tissue source of these plasma proteins, the prevalence and meaning of such large increases are unclear.

9 29 JAN 2014 BAY / Page: 8 of 10 Pharmacokinetics PK parameters for the intact antibody-drug conjugate BAY , total antibody (BAY plus free 3ee9 antibody), and BAY (toxophore, monomethyl auristatin E) were characterized following 1-hour or 2-hour IV infusion of BAY to 4 subjects were enrolled at each of the following 6 dose levels: 0.15, 0.3, 0.6, 1.2, 2.3, and 4.6 mg/kg. The PK conclusions should be interpreted with caution due to the small sample size. In general, a nearly or slightly more than dose-proportional increase in exposure to BAY and total antibody was observed in the 0.15 to 2.3 mg/kg dose range with more than dose-proportional increase at 4.6 mg/kg. The reason for deviation from dose proportionality at the 4.6 mg/kg dose level is not known but may be attributed, in part, to saturation of distribution and /or elimination pathways. The PK of BAY were not consistent and exhibited no increase in exposure between 0.3 and 1.2 mg/kg, doseproportional increase from 1.2 to 2.3 mg/kg, and more than dose-proportional increase from 2.3 to 4.6 mg/kg. There are no explanations for the inconsistent dose-exposure relationship in BAY PK. A formal assessment of inter-subject variability was not possible due to the small cohort size. Overall, inter-subject variability in PK parameters appeared to be moderate to high. Safety evaluation Eleven (11) of the 12 subjects reported at least 1 treatment-emergent adverse event. The most frequent CTCAE categories occurring in at least 6 subjects were gastrointestinal (10 subjects), constitutional symptoms (7 subjects), and neurological (6 subjects). The most common individual treatment-emergent adverse event occurring in at least 6 subjects was diarrhea. Six (6) subjects reported at least 1 treatment-emergent adverse event of CTCAE Grade 3. The 2 subjects of Cohort 7 (4.6 mg/kg) died between Day 1 and Day 30: One (1) subject died from drug-related cardiac arrest (cardiac general - other) 11 days after dosing and the other from drug-related pancreatitis and non-drug-related cardiac arrest 5 days after dosing. The most frequent CTCAE categories of treatment-emergent adverse events of CTCAE Grade 3 occurring in at least 2 subjects were cardiac general and metabolic / laboratory (3 subjects each) as well as gastrointestinal (2 subjects). The only individual treatmentemergent adverse event of CTCAE Grade 3 occurring in 2 subjects was cardiac ischemia / infarction. Nine (9) subjects reported at least 1 drug-related adverse event. The most frequent CTCAE categories occurring in at least 3 subjects were gastrointestinal (7 subjects), constitutional symptoms (4 subjects), and metabolic / laboratory (3 subjects). The most common individual drug-related adverse events occurring in at least 3 subjects were fatigue (4 subjects) and nausea (3 subjects). Four (4) subjects reported at least 1 drug-related adverse event of CTCAE Grade 3. There was only 1 CTCAE category of drug-related adverse events of CTCAE Grade 3 with 1 subject, i.e. metabolic / laboratory (2 subjects). All individual drug-related adverse events of CTCAE Grade 3 occurred in 1 subject each.

10 29 JAN 2014 BAY / Page: 9 of 10 One (1) subject in Cohort 4 (0.6 mg/kg) experienced a DLT reported as Grade 4 amylase, and 1 subject in Cohort 7 (4.6 mg/kg) experienced a DLT reported as Grade 5 cardiac arrest (cardiac general - other). Two (2) subjects in Cohort 7 (4.6 mg/kg) died. Six (6) subjects experienced at least 1 serious adverse event. One (1) subject in Cohort 1 (0.15 mg/kg) experienced serious infection with skin cellulitis and a normal absolute neutrophil count (ANC). One (1) subject in Cohort 2 (0.3 mg/kg) experienced serious back pain, diarrhea, fever, and confusion. One (1) subject in Cohort 4 (0.6 mg/kg) experienced serious cardiac ischemia / infarction, another subject in the same cohort experienced nausea and vomiting. The investigators assessed all aforementioned serious adverse events as not related to study drug. One (1) subject in Cohort 4 (0.6 mg/kg) experienced serious drugrelated elevated amylase and 1 subject of Cohort 5 (1.2 mg/kg) experienced serious drugrelated elevated lipase. Overall, the observed laboratory abnormalities were typical of the selection of subjects in this study. Because of the heterogeneity of subjects, interpretation of the summary findings was difficult. The ECG findings did not show any signal for study drug-related changes in ECG parameters, in particular, no prolongation in QTc (Bazett) or QTc (Fridericia) was observed. A safe dose was not identified and the study was terminated based on the overall assessment of the safety data; in particular, the two Grade 5 adverse events (deaths) at 4.6mg/kg dose level and one dose limiting toxicity (Grade 4 amylase increase) at 0.6mg/kg dose level after restarting the study.

11 29 JAN 2014 BAY / Page: 10 of 10 Overall conclusions BAY was safe and generally well tolerated in the dose range of 0.15 to 2.3 mg/kg administered on Day 1 of a 21-day cycle, whereas both subjects at the 4.6 mg/kg dose level died within several days after receiving the study drug. One (1) subject died from drug-related cardiac arrest 11 days following dosing and the other from drug-related pancreatitis and non-drug-related cardiac arrest 5 days following dosing. The termination of the study was based on an overall assessment of safety data. Individual subjects showed clinical signs of antitumor efficacy: 1 subject in Cohort 4 (0.6 mg/kg) and 2 subjects in Cohort 5 (1.2 mg/kg) experienced stable disease for more than 2 cycles. One (1) subject with NSCLC, treated at the 1.2 mg/kg dose level, had 28% maximum tumor shrinkage and had a treatment duration of 22 cycles. In the 7 subjects with an event, i.e. documented progressive disease, progression-free survival ranged from 5 to 689 days. Up to 2.3 mg/kg, minimal deviation from dose proportionality in BAY and Total Antibody exposure was observed and the pharmacokinetics of BAY exhibited inconsistent dose-exposure relationship. Following dose escalation from 2.3 to 4.6 mg/kg, pharmacokinetic assessments showed an unexpected more than dose-proportional increase in the exposure to intact antibody-drug conjugate BAY , total antibody (BAY plus free 3ee9 antibody), and BAY (toxophore, monomethyl auristatin E).