Neoplasms

Digestive System Diseases

Gland and Hormone Related Diseases

All Conditions

Rare Diseases

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Antimetabolites

Evofosfamide infusion intravenously at an escalated dose of 240, 340 or 480 milligram per square meter (mg/m\^2) on Day 1, 8 and 15 of each 28-day treatment cycle until progressive disease, unacceptable toxicity or withdrawal.

Evofosfamide

Gemcitabine 1000 mg/m\^2 on Day 1, 8 and 15 of each 28-day treatment cycle until progressive disease, unacceptable toxicity or withdrawal.

Medical Responsible

This is a Japanese Phase 1, open-label, and dose-escalating trial of TH-302 as monotherapy in subjects with solid tumors and in combination with gemcitabine in subjects with pancreatic cancer.

A Japanese Phase 1 Trial of TH-302 in Subjects With Solid Tumors and Pancreatic Cancer

A Japanese Single Center, Open-label, Phase I Trial of TH-302 Given Intravenously to Subjects With Solid Tumors as Monotherapy or to Subjects With Advanced Pancreatic Cancer in Combination With Gemcitabine

A DLT was defined as any of the following toxicities at any dose level that occurred during the first cycle, and were considered to be related to the study drug by the Investigator or the Sponsor: - Grade 3 or Grade 4 non-hematological toxicity, except for Grade 3 or Grade 4 nausea, vomiting and diarrhea, - Grade 3 or higher skin reactions or mucosal toxicities, - Febrile neutropenia, - Grade 3 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation lasting more than 7 days, - Grade 4 neutropenia lasting more than 5 days, - Grade 4 thrombocytopenia, - Grade 4 anemia, - Any non-preexisting Grade 2 or higher non-hematologic toxicity which, in the judgment of the Investigator and the Sponsor, was considered a DLT, - Any Grade 2 or higher non-hematologic toxicity that did not resolve to Grade 0 or Grade 1 toxicity by the start of the next cycle which, in the judgment of the Investigator and the Sponsor, was considered a DLT.

AE was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are events with start date on or after the date of first dose of study treatment and up to and including 30 days after the last dose of study treatment, or events with start date prior to the date of first dose of study treatment, and worsened in severity or become serious during treatment. TEAEs include both Serious TEAEs and non-serious TEAEs.

Tmax was the time to peak concentration in plasma, obtained directly from the concentration versus time curve. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine.

Maximum observed plasma concentration was assessed.

Maximum observed Plasma concentration was assessed. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine.

Terminal rate constant was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

Terminal rate constant was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine.

Terminal half-life was calculated as ln(2)/λz. Where λz is a Terminal rate constant, which was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

Terminal half-life was calculated as ln(2)/λz. Where λz is a Terminal rate constant, which was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine.

Area under the concentration-time curve from time 0 to the last quantifiable concentration was assessed.

Area under the concentration-time curve from time 0 to the last quantifiable concentration was assessed. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine.

Area under the concentration-time curve from time zero extrapolated to infinity, calculated as AUC(0-last) + last observed concentration (Clast)/terminal rate constant (λz), using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations. Where AUC(0-last) is area under the concentration-time curve from time 0 to the last quantifiable concentration was assessed. λz was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

Area under the concentration-time curve from time zero extrapolated to infinity, calculated as AUC(0-last) + last observed concentration (Clast)/terminal rate constant (λz), using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations. Where AUC(0-last) is area under the concentration-time curve from time 0 to the last quantifiable concentration was assessed. λz was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine.

Apparent total clearance (CL/F) was calculated as dose divided by area under the plasma concentration-time profile from time zero extrapolated to infinity (AUC\[inf\]).

Apparent total clearance (CL/F) was calculated as dose divided by area under the plasma concentration-time profile from time zero extrapolated to infinity (AUC\[inf\]). This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine.

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) was the apparent volume of distribution at steady-state.

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) was the apparent volume of distribution at steady-state. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine.

Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by elimination rate constant \[λz\]) following single dose. Area under the plasma concentration-time curve from time zero to infinity, calculated (AUC0-inf) as AUC0-t + AUCextra. AUCextra represents an extrapolated value obtained by Clast / λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured plasma concentration is at or above lower limit of quantification (LLQ) and λz is the elimination rate constant. And the elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data.

Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by elimination rate constant \[λz\]) following single dose. Area under the plasma concentration-time curve from time zero to infinity, calculated (AUC0-inf) as AUC0-t + AUCextra. AUCextra represents an extrapolated value obtained by Clast / λz, where Clast is the calculated serum concentration at the last sampling time point at which the measured plasma concentration is at or above lower limit of quantification (LLQ) and λz is the elimination rate constant. And the elimination rate constant obtained from linear regression of the terminal phase of the log transformed concentration-time data. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine.

Cumulative amount excreted in urine from time zero to the end of the last measurable concentration was reported.

Renal clearance is the volume of plasma from which the drug is completely removed by the kidney in a given amount of time.

BOR was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). BOR was defined as the best response of any of the confirmed complete response (CR), confirmed partial response (PR), stable disease (SD) and progressive disease (PD). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD was defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Number of participants with CR, PR, SD and PD were reported.

OR was determined according to RECIST v1.1. Objective response is defined as a best overall response of confirmed complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Number of participants with OR were reported.

Disease Control was defined as having achieved at least disease stabilization; that is participants with confirmed CR, PR, or SD lasting for at least 16 weeks. CR: Disappearance of all target lesions. PR: A decrease of at least 30% in the sum of the longest diameter of target lesions. PD: PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. SD: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.

Clinical laboratory parameters that were assessed included: hematological parameters, blood chemistry parameters, coagulation and urinalysis and the vital signs that were assessed included: blood pressure, heart rate, respiratory rate, and body temperature.

Twelve-lead ECGs were performed and assessed after at least 5 minutes rest in supine position locally.

ECOG performance status measured to assess subject's performance status on a scale of 0 to 5, where 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity, ambulatory and able to carry out light or sedentary work; 2=Ambulatory (more than 50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5=Death. Number of participants with ECOG performance status score of 2 or higher than 2 were reported.

Threshold Pharmaceuticals

Merck KGaA, Darmstadt, Germany

Participants received evofosfamide infusion intravenously at a dose of 240 milligram per square meter (mg/m\^2) on Day 1, 8 and 15 of each 28-day treatment cycle until progressive disease, unacceptable toxicity or participant withdrawal.

Evofosfamide 240 mg

Participants received evofosfamide infusion intravenously at a dose of 340 mg/m\^2 on Day 1, 8 and 15 of each 28-day treatment cycle until progressive disease, unacceptable toxicity or participant withdrawal.

Evofosfamide 340 mg

Participants received evofosfamide infusion intravenously at a dose of 480 mg/m\^2 on Day 1, 8 and 15 of each 28-day treatment cycle until progressive disease, unacceptable toxicity or participant withdrawal.

Evofosfamide 480 mg

Participants received 340 mg/m\^2 evofosfamide in combination with 1,000 mg/m\^2 gemcitabine intravenously on Day 1, 8 and 15 of each 28-day treatment cycle until progressive disease, unacceptable toxicity or participant withdrawal.

Evofosfamide 340 mg + Gemcitabine

Total

Less than (<) 65 years

Greater than or equal to (>=) 65 years

Age, Customized

Sex: Female, Male

Safety population included all subjects who received at least 1 dose of the study drug (evofosfamide or gemcitabine).

Merck KGaA Communication Center

The DLT Analysis Set included all participants who experienced a DLT during Cycle 1 or who did not experience a DLT, completed Cycle 1 and received 90% or more of all planned total dose of evofosfamide, and gemcitabine for the combination, during Cycle 1.

Number of Participants Who Experienced Any Dose-Limiting Toxicity (DLT) During First Cycle - Day 1 to 28

TEAEs

Serious TEAEs

TEAEs leading to death

Safety population included all participants who received at least 1 dose of the study drug (evofosfamide or gemcitabine).

Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Death

Evofosfamide: Day 1

Evofosfamide: Day 15

Br-IPM: Day 1

Br-IPM: Day 15

The Pharmacokinetics (PK) Analysis Set included all participants who received at least 1 dose of evofosfamide (that is, actual total dose of evofosfamide \> 0) and who provided sufficient data for a concentration-time profile for evofosfamide. Here "Number Analyzed" signifies those participants who were evaluated at the specified time point.

Time to Reach Maximum Plasma Concentration (Tmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])

Gemcitabine: Day 1

Gemcitabine: Day 15

dFdU: Day 1

dFdU: Day 15

The PK Analysis Set included all participants who received at least 1 dose of gemcitabine (that is, actual total dose of gemcitabine \> 0) and who provided sufficient data for a concentration-time profile for gemcitabine. Here "Number Analyzed" signifies those participants who were evaluated at the specified time point.

Time to Reach Maximum Plasma Concentration (Tmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])

The PK Analysis Set included all participants who received at least 1 dose of evofosfamide (that is, actual total dose of evofosfamide \> 0) and who provided sufficient data for a concentration-time profile for evofosfamide. Here "Number Analyzed" signifies those participants who were evaluated at the specified time point.

Maximum Observed Plasma Concentration (Cmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])

The PK Analysis Set included all Participants who received at least 1 dose of gemcitabine (that is, actual total dose of gemcitabine \> 0) and who provided sufficient data for a concentration-time profile for gemcitabine. Here "Number Analyzed" signifies those Participants who were evaluated at the specified time point.

Maximum Observed Plasma Concentration (Cmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])

The PK Analysis Set. Here "Number Analyzed" signifies those Participants who were evaluated at the specified time point. There were no Participants analyzed at certain time points (that is, Number Analyzed = 0) because there was no data collected for respective arms at those time points.

Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])

Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])

The PK Analysis Set. Here "Number Analyzed" signifies those participants who were evaluated at the specified time point. There were no participants analyzed at certain time points (that is, Number Analyzed = 0) because there was no data collected for respective arms at those time points.

Apparent Terminal Half-life (t1/2) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])

Apparent Terminal Half-life (t1/2) of of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Sampling Time With Concentration at or Above the Lower Limit of Quantitation (AUC[0-t]) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Sampling Time With Concentration at or Above the Lower Limit of Quantitation (AUC[0-t]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])

Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])

Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])

Apparent Total Body Clearance of (CL) of Evofosfamide

Apparent Total Body Clearance of (CL) of Gemcitabine

Apparent Volume of Distribution at Steady State (Vss) of Evofosfamide

Apparent Volume of Distribution at Steady State (Vss) of Gemcitabine

Apparent Volume of Distribution During Terminal Phase (Vz) of Evofosfamide

Apparent Volume of Distribution During Terminal Phase (Vz) of Gemcitabine

Cumulative Amount of Evofosfamide Excreted From Time Zero to Time After Dosing (Ae0-t)

Renal Clearance (CL) for Evofosfamide

Complete Response

Partial Response

Stable Disease

Progressive Disease

Efficacy Analysis Set included all participants who received at least 1 planned dose of evofosfamide and who had a baseline tumor assessment and at least 1 tumor assessment according to RECIST version 1.1 after the first dose of study drug.

Spots Global Cancer Trial Database for A Japanese Phase 1 Trial of TH-302 in Subjects With Solid Tumors and Pancreatic Cancer

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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