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| Name | Class |
|---|---|
| Threshold Pharmaceuticals | INDUSTRY |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Evofosfamide 240 mg | Experimental |
| |
| Evofosfamide 340 mg | Experimental |
| |
| Evofosfamide 480 mg | Experimental |
| |
| Evofosfamide 340 mg + Gemcitabine | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Evofosfamide | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Who Experienced Any Dose-Limiting Toxicity (DLT) During First Cycle - Day 1 to 28 | 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. | Day 1 up to Day 28 of Cycle 1 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Death | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck Serono Co., Ltd., Japan | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Kashiwa | Japan | ||||
| Research Site |
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First participant (informed consent): 18 April 2013. Study completion date: 25 January 2016.
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| ID | Title | Description |
|---|---|---|
| FG000 | Evofosfamide 240 mg | 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. |
| FG001 | Evofosfamide 340 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. |
| FG002 | Evofosfamide 480 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. |
| FG003 | Evofosfamide 340 mg + Gemcitabine | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Safety population included all subjects who received at least 1 dose of the study drug (evofosfamide or gemcitabine).
| ID | Title | Description |
|---|---|---|
| BG000 | Evofosfamide 240 mg | 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. |
| BG001 | Evofosfamide 340 mg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants Who Experienced Any Dose-Limiting Toxicity (DLT) During First Cycle - Day 1 to 28 | 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. | 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. | Posted | Count of Participants | Participants | Day 1 up to Day 28 of Cycle 1 |
Baseline up to 33 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Evofosfamide 240 mg | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bile Duct Obstruction | Hepatobiliary disorders | MedDRA version 17.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Merck KGaA Communication Center | Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@merckgroup.com |
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| ID | Term |
|---|---|
| D010190 | Pancreatic Neoplasms |
| ID | Term |
|---|---|
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004701 | Endocrine Gland Neoplasms |
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| ID | Term |
|---|---|
| C552526 | TH 302 |
| D000093542 | Gemcitabine |
| ID | Term |
|---|---|
| D006571 | Heterocyclic Compounds |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
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| Gemcitabine | Drug | Gemcitabine 1000 mg/m^2 on Day 1, 8 and 15 of each 28-day treatment cycle until progressive disease, unacceptable toxicity or withdrawal. |
|
| Baseline up to 33 months |
| Time to Reach Maximum Plasma Concentration (Tmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| Time to Reach Maximum Plasma Concentration (Tmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) | 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. | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
| Maximum Observed Plasma Concentration (Cmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) | Maximum observed plasma concentration was assessed. | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| Maximum Observed Plasma Concentration (Cmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) | Maximum observed Plasma concentration was assessed. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine. | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
| Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) | 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. | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) | 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. | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
| Apparent Terminal Half-life (t1/2) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) | 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. | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| Apparent Terminal Half-life (t1/2) of of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) | 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. | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
| 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 concentration-time curve from time 0 to the last quantifiable concentration was assessed. | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| 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 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. | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
| 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 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. | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) | 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. | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
| Apparent Total Body Clearance of (CL) of Evofosfamide | 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]). | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| Apparent Total Body Clearance of (CL) of 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]). This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine. | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
| Apparent Volume of Distribution at Steady State (Vss) of Evofosfamide | 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. | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| Apparent Volume of Distribution at Steady State (Vss) of 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. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine. | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
| Apparent Volume of Distribution During Terminal Phase (Vz) of Evofosfamide | 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. | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| Apparent Volume of Distribution During Terminal Phase (Vz) of 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. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine. | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
| Cumulative Amount of Evofosfamide Excreted From Time Zero to Time After Dosing (Ae0-t) | Cumulative amount excreted in urine from time zero to the end of the last measurable concentration was reported. | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| Renal Clearance (CL) for Evofosfamide | Renal clearance is the volume of plasma from which the drug is completely removed by the kidney in a given amount of time. | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
| Best Overall Response (BOR) | 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. | Time from first treatment to final assessment at 33 months |
| Number of Participants With Objective Response | 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. | Time from first treatment to final assessment at 33 months |
| Number of Participants With Disease Control | 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. | Time from first treatment to final assessment at 33 months |
| Number of Participants With Clinical Significant Laboratory Abnormalities and Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events | 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. | Baseline up to 33 months |
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings Reported as Treatment Emergent Adverse Events (TEAEs) | Twelve-lead ECGs were performed and assessed after at least 5 minutes rest in supine position locally. | Baseline up to 33 months |
| Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 | 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. | Baseline up to 33 months |
| Tokyo |
| Japan |
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. |
| BG002 | Evofosfamide 480 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. |
| BG003 | Evofosfamide 340 mg + Gemcitabine | 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. |
| BG004 | Total | Total of all reporting groups |
| Subjects |
|
| Participants |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants | Participants |
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| Secondary | Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Death | 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. | Safety population included all participants who received at least 1 dose of the study drug (evofosfamide or gemcitabine). | Posted | Count of Participants | Participants | Baseline up to 33 months |
|
|
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| Secondary | Time to Reach Maximum Plasma Concentration (Tmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) | 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. | Posted | Median | Full Range | hours | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
|
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| Secondary | Time to Reach Maximum Plasma Concentration (Tmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) | 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. | 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. | Posted | Median | Full Range | hours | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
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|
| Secondary | Maximum Observed Plasma Concentration (Cmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) | Maximum observed plasma concentration was assessed. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Nanogram per milliliter (ng/mL) | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
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|
| Secondary | Maximum Observed Plasma Concentration (Cmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) | Maximum observed Plasma concentration was assessed. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
|
|
|
| Secondary | Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Per hour | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
|
|
|
| Secondary | Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Per hour | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
|
|
|
| Secondary | Apparent Terminal Half-life (t1/2) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
|
|
|
| Secondary | Apparent Terminal Half-life (t1/2) of of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
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|
|
| Secondary | 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 concentration-time curve from time 0 to the last quantifiable concentration was assessed. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hour per mL (ng*hour/mL) | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
|
|
|
| Secondary | 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 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hour/mL | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
|
|
|
| Secondary | 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 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hour/mL | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
|
|
|
| Secondary | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hour/mL | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
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|
| Secondary | Apparent Total Body Clearance of (CL) of Evofosfamide | 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]). | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per hour per square meter | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
|
|
|
| Secondary | Apparent Total Body Clearance of (CL) of 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]). This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per hour per square meter | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
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|
| Secondary | Apparent Volume of Distribution at Steady State (Vss) of Evofosfamide | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per square meter | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
|
|
|
| Secondary | Apparent Volume of Distribution at Steady State (Vss) of 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. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per square meter | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
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|
|
| Secondary | Apparent Volume of Distribution During Terminal Phase (Vz) of Evofosfamide | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per square meter | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
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|
|
| Secondary | Apparent Volume of Distribution During Terminal Phase (Vz) of 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. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per square meter | Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15 |
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| Secondary | Cumulative Amount of Evofosfamide Excreted From Time Zero to Time After Dosing (Ae0-t) | Cumulative amount excreted in urine from time zero to the end of the last measurable concentration was reported. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | milligram per square meter | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
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| Secondary | Renal Clearance (CL) for Evofosfamide | Renal clearance is the volume of plasma from which the drug is completely removed by the kidney in a given amount of time. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter per hour per square meter | Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15 |
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| Secondary | Best Overall Response (BOR) | 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. | 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. | Posted | Count of Participants | Participants | Time from first treatment to final assessment at 33 months |
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| Secondary | Number of Participants With Objective Response | 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. | 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. | Posted | Count of Participants | Participants | Time from first treatment to final assessment at 33 months |
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| Secondary | Number of Participants With Disease Control | 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. | 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. | Posted | Count of Participants | Participants | Time from first treatment to final assessment at 33 months |
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| Secondary | Number of Participants With Clinical Significant Laboratory Abnormalities and Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events | 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. | Safety population included all participants who received at least 1 dose of the study drug (evofosfamide or gemcitabine). | Posted | Count of Participants | Participants | Baseline up to 33 months |
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| Secondary | Number of Participants With Abnormal Electrocardiogram (ECG) Findings Reported as Treatment Emergent Adverse Events (TEAEs) | Twelve-lead ECGs were performed and assessed after at least 5 minutes rest in supine position locally. | Safety population included all participants who received at least 1 dose of the study drug (evofosfamide or gemcitabine). | Posted | Count of Participants | Participants | Baseline up to 33 months |
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| Secondary | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2 | 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. | Safety population included all participants who received at least 1 dose of the study drug (evofosfamide or gemcitabine). | Posted | Count of Participants | Participants | Baseline up to 33 months |
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|
|
| 0 |
| 3 |
| 0 |
| 3 |
| 3 |
| 3 |
| EG001 | Evofosfamide 340 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. | 0 | 3 | 0 | 3 | 3 | 3 |
| EG002 | Evofosfamide 480 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. | 0 | 8 | 1 | 8 | 8 | 8 |
| EG003 | Evofosfamide 340 mg + Gemcitabine | 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. | 0 | 6 | 1 | 6 | 6 | 6 |
| Interstitial Lung Disease | Respiratory, thoracic and mediastinal disorders | MedDRA version 17.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Abdominal Pain | Gastrointestinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Cheilitis | Gastrointestinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Haemorrhoids | Gastrointestinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Electrocardiogram QT Prolonged | Investigations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Alanine Aminotransferase Increased | Investigations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Aspartate Aminotransferase Increased | Investigations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Gamma-Glutamyltransferase Increased | Investigations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Neutrophil Count Decreased | Investigations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Blood Cholesterol Increased | Investigations | MedDRA version 17.1 | Non-systematic Assessment |
|
| White Blood Cell Count Decreased | Investigations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Platelet Count Decreased | Investigations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Blood Alkaline Phosphatase Increased | Investigations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Blood Bilirubin Increased | Investigations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Rash Maculo-Papular | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Dry Skin | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Skin Hyperpigmentation | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Palmar-Plantar Erythrodysaesthesia Syndrome | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Dermatitis | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
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| Dermatitis Exfoliative | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Haemorrhage Subcutaneous | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
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| Intertrigo | Skin and subcutaneous tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Non-Cardiac Chest Pain | General disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Oedema Peripheral | General disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Vasculitis | Vascular disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Flushing | Vascular disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Decreased Appetite | Metabolism and nutrition disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Hyperphosphataemia | Metabolism and nutrition disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Tension Headache | Nervous system disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Infusion Related Reaction | Injury, poisoning and procedural complications | MedDRA version 17.1 | Non-systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
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| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
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| Anaemia | Blood and lymphatic system disorders | MedDRA version 17.1 | Non-systematic Assessment |
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| Vertigo | Ear and labyrinth disorders | MedDRA version 17.1 | Non-systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA version 17.1 | Non-systematic Assessment |
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| Hepatic Function Abnormal | Hepatobiliary disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Hiccups | Respiratory, thoracic and mediastinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
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| Oropharyngeal Discomfort | Respiratory, thoracic and mediastinal disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Oral Herpes | Infections and infestations | MedDRA version 17.1 | Non-systematic Assessment |
|
| Tumor Pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA version 17.1 | Non-systematic Assessment |
|
| Conjunctivitis | Eye disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Hypophosphatemia | Metabolism and nutrition disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
| Influenza like illness | General disorders | MedDRA version 17.1 | Non-systematic Assessment |
|
Not provided
| D004066 |
| Digestive System Diseases |
| D010182 | Pancreatic Diseases |
| D004700 | Endocrine System Diseases |
| D011743 |
| Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| Serious TEAEs |
|
| TEAEs leading to death |
|
|
| Evofosfamide: Day 15 |
|
|
| Br-IPM: Day 1 |
|
|
| Br-IPM: Day 15 |
|
|
|
| dFdU: Day 1 |
|
|
| dFdU: Day 15 |
|
|
|
| Evofosfamide: Day 15 |
|
|
| Br-IPM: Day 1 |
|
|
| Br-IPM: Day 15 |
|
|
|
| dFdU: Day 1 |
|
|
| dFdU: Day 15 |
|
|
|
| Evofosfamide: Day 15 |
|
|
| Br-IPM: Day 1 |
|
|
| Br-IPM: Day 15 |
|
|
|
| dFdU: Day 1 |
|
|
| dFdU: Day 15 |
|
|
|
| Evofosfamide: Day 15 |
|
|
| Br-IPM: Day 1 |
|
|
| Br-IPM: Day 15 |
|
|
|
| dFdU: Day 1 |
|
|
| dFdU: Day 15 |
|
|
|
| Evofosfamide: Day 15 |
|
|
| Br-IPM: Day 1 |
|
|
| Br-IPM: Day 15 |
|
|
|
| dFdU: Day 1 |
|
|
| dFdU: Day 15 |
|
|
|
| Evofosfamide: Day 15 |
|
|
| Br-IPM: Day 1 |
|
|
| Br-IPM: Day 15 |
|
|
|
| dFdU: Day 1 |
|
|
| dFdU: Day 15 |
|
|
|
| Evofosfamide: Day 15 |
|
|
|
|
| Evofosfamide: Day 15 |
|
|
|
|
| Evofosfamide: Day 15 |
|
|
|
|
| Evofosfamide: Day 15 |
|
|
|
| Evofosfamide: Day 15 |
|
|
| Partial Response |
|
| Stable Disease |
|
| Progressive Disease |
|
| Subjects with Vital signs Abnormalities |
|