Trial Outcomes & Findings for A Japanese Phase 1 Trial of TH-302 in Subjects With Solid Tumors and Pancreatic Cancer (NCT NCT01833546)

Last Updated: 2018-10-15

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

20 participants

Primary outcome timeframe

Day 1 up to Day 28 of Cycle 1

Results posted on

2018-10-15

Participant Flow

First participant (informed consent): 18 April 2013. Study completion date: 25 January 2016.

Participant milestones

Participant milestones
Measure	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.	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.	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.	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.
Overall Study STARTED	3	3	8	6
Overall Study COMPLETED	3	3	8	6
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Evofosfamide 240 mg n=3 Subjects 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 340 mg n=3 Subjects 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 480 mg n=8 Subjects 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 340 mg + Gemcitabine n=6 Subjects 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.	Total n=20 Subjects Total of all reporting groups
Age, Customized Less than (<) 65 years	2 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	3 Participants n=4 Participants	10 Participants n=21 Participants
Age, Customized Greater than or equal to (>=) 65 years	1 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	3 Participants n=4 Participants	10 Participants n=21 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	0 Participants n=7 Participants	5 Participants n=5 Participants	1 Participants n=4 Participants	8 Participants n=21 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	5 Participants n=4 Participants	12 Participants n=21 Participants

PRIMARY outcome

Timeframe: Day 1 up to Day 28 of Cycle 1

Population: 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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=6 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Number of Participants Who Experienced Any Dose-Limiting Toxicity (DLT) During First Cycle - Day 1 to 28	0 Participants	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Death TEAEs	3 Participants	3 Participants	8 Participants	6 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Death Serious TEAEs	0 Participants	0 Participants	1 Participants	1 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Death TEAEs leading to death	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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

Population: 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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Time to Reach Maximum Plasma Concentration (Tmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Evofosfamide: Day 1	0.550 hours Interval 0.25 to 0.7	0.250 hours Interval 0.23 to 0.25	0.392 hours Interval 0.25 to 0.57	0.550 hours Interval 0.53 to 0.58
Time to Reach Maximum Plasma Concentration (Tmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Evofosfamide: Day 15	0.22 hours Interval 0.22 to 0.58	0.533 hours Interval 0.25 to 0.55	0.267 hours Interval 0.22 to 0.53	0.533 hours Interval 0.52 to 0.55
Time to Reach Maximum Plasma Concentration (Tmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Br-IPM: Day 1	0.550 hours Interval 0.53 to 0.92	0.633 hours Interval 0.58 to 1.02	0.575 hours Interval 0.53 to 0.62	0.567 hours Interval 0.53 to 0.98
Time to Reach Maximum Plasma Concentration (Tmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Br-IPM: Day 15	0.600 hours Interval 0.58 to 0.67	0.550 hours Interval 0.53 to 0.68	0.567 hours Interval 0.53 to 0.6	0.533 hours Interval 0.52 to 0.55

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=6 Participants 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 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.	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.	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.
Time to Reach Maximum Plasma Concentration (Tmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) Gemcitabine: Day 1	0.500 hours Interval 0.48 to 0.52	—	—	—
Time to Reach Maximum Plasma Concentration (Tmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) Gemcitabine: Day 15	0.500 hours Interval 0.5 to 0.53	—	—	—
Time to Reach Maximum Plasma Concentration (Tmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) dFdU: Day 1	0.500 hours Interval 0.48 to 0.52	—	—	—
Time to Reach Maximum Plasma Concentration (Tmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) dFdU: Day 15	0.500 hours Interval 0.5 to 0.53	—	—	—

SECONDARY outcome

Population: 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 was assessed.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Maximum Observed Plasma Concentration (Cmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Evofosfamide: Day 1	6502.3 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 29.8	10009.8 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 8.4	14016.7 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 14.5	9303.4 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 7.2
Maximum Observed Plasma Concentration (Cmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Evofosfamide: Day 15	7159.9 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 5.3	10248.2 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 5.9	14661.2 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 9.9	8720.8 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 12.8
Maximum Observed Plasma Concentration (Cmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Br-IPM: Day 1	63.37 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 32.7	103.74 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 64.8	224.95 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 25.4	86.55 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 58.3
Maximum Observed Plasma Concentration (Cmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Br-IPM: Day 15	62.01 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 30.7	149.36 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 11.2	207.88 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 22.0	124.92 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 33.5

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

Population: 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 was assessed. This outcome was applicable for only combination arm in which evofosfamide was administered along with gemcitabine.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=6 Participants 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 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.	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.	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.
Maximum Observed Plasma Concentration (Cmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) Gemcitabine: Day 1	22596.2 ng/mL Geometric Coefficient of Variation 22.3	—	—	—
Maximum Observed Plasma Concentration (Cmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) Gemcitabine: Day 15	21355.5 ng/mL Geometric Coefficient of Variation 4.0	—	—	—
Maximum Observed Plasma Concentration (Cmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) dFdU: Day 1	33923.9 ng/mL Geometric Coefficient of Variation 23.1	—	—	—
Maximum Observed Plasma Concentration (Cmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) dFdU: Day 15	33631.4 ng/mL Geometric Coefficient of Variation 22.6	—	—	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Evofosfamide: Day 1	1.012 Per hour Geometric Coefficient of Variation 6.0	1.100 Per hour Geometric Coefficient of Variation 12.3	1.094 Per hour Geometric Coefficient of Variation 6.0	1.146 Per hour Geometric Coefficient of Variation 10.3
Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Evofosfamide: Day 15	1.007 Per hour Geometric Coefficient of Variation 6.2	1.032 Per hour Geometric Coefficient of Variation 2.5	0.951 Per hour Geometric Coefficient of Variation 27.0	1.177 Per hour Geometric Coefficient of Variation 6.0
Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Br-IPM: Day 1	1.478 Per hour Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated as there was only 1 participant analyzed in this reporting group.	2.436 Per hour Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated as there was only 1 participant analyzed in this reporting group.	1.758 Per hour Geometric Coefficient of Variation 18.8	—
Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Br-IPM: Day 15	1.669 Per hour Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated as there was only 1 participant analyzed in this reporting group.	2.701 Per hour Geometric Coefficient of Variation 35.7	1.581 Per hour Geometric Coefficient of Variation 19.5	—

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=6 Participants 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 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.	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.	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.
Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) Gemcitabine: Day 1	3.241 Per hour Geometric Coefficient of Variation 9.6	—	—	—
Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) Gemcitabine: Day 15	3.171 Per hour Geometric Coefficient of Variation 9.9	—	—	—
Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) dFdU: Day 1	0.0895 Per hour Geometric Coefficient of Variation 45.4	—	—	—
Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) dFdU: Day 15	0.0870 Per hour Geometric Coefficient of Variation 54.0	—	—	—

SECONDARY outcome

Population: 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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Apparent Terminal Half-life (t1/2) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Evofosfamide: Day 1	0.6850 hours Geometric Coefficient of Variation 6.0	0.6304 hours Geometric Coefficient of Variation 12.3	0.6334 hours Geometric Coefficient of Variation 6.0	0.6049 hours Geometric Coefficient of Variation 10.3
Apparent Terminal Half-life (t1/2) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Evofosfamide: Day 15	0.6881 hours Geometric Coefficient of Variation 6.2	0.6716 hours Geometric Coefficient of Variation 2.5	0.7285 hours Geometric Coefficient of Variation 27.0	0.5889 hours Geometric Coefficient of Variation 6.0
Apparent Terminal Half-life (t1/2) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Br-IPM: Day 1	0.4691 hours Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated as there was only 1 participant analyzed in this reporting group.	0.2846 hours Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated as there was only 1 participant analyzed in this reporting group.	0.3942 hours Geometric Coefficient of Variation 18.8	—
Apparent Terminal Half-life (t1/2) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM]) Br-IPM: Day 15	0.4153 hours Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated as there was only 1 participant analyzed in this reporting group.	0.2566 hours Geometric Coefficient of Variation 35.7	0.4384 hours Geometric Coefficient of Variation 19.5	—

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=6 Participants 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 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.	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.	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.
Apparent Terminal Half-life (t1/2) of of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) Gemcitabine: Day 1	0.2139 hours Geometric Coefficient of Variation 9.6	—	—	—
Apparent Terminal Half-life (t1/2) of of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) Gemcitabine: Day 15	0.2186 hours Geometric Coefficient of Variation 9.9	—	—	—
Apparent Terminal Half-life (t1/2) of of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) dFdU: Day 1	7.741 hours Geometric Coefficient of Variation 45.4	—	—	—
Apparent Terminal Half-life (t1/2) of of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) dFdU: Day 15	7.964 hours Geometric Coefficient of Variation 54.0	—	—	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
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]) Evofosfamide: Day 1	5266.9 nghour per mL (nghour/mL) Geometric Coefficient of Variation 8.3	7864.2 nghour per mL (nghour/mL) Geometric Coefficient of Variation 13.0	10416.1 nghour per mL (nghour/mL) Geometric Coefficient of Variation 14.4	5989.5 nghour per mL (nghour/mL) Geometric Coefficient of Variation 11.5
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]) Evofosfamide: Day 15	5232.4 nghour per mL (nghour/mL) Geometric Coefficient of Variation 2.4	8191.1 nghour per mL (nghour/mL) Geometric Coefficient of Variation 17.8	10742.8 nghour per mL (nghour/mL) Geometric Coefficient of Variation 16.7	5616.4 nghour per mL (nghour/mL) Geometric Coefficient of Variation 21.0
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]) Br-IPM: Day 1	38.1 nghour per mL (nghour/mL) Geometric Coefficient of Variation 41.1	61.7 nghour per mL (nghour/mL) Geometric Coefficient of Variation 84.4	153.8 nghour per mL (nghour/mL) Geometric Coefficient of Variation 25.0	47.7 nghour per mL (nghour/mL) Geometric Coefficient of Variation 66.5
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]) Br-IPM: Day 15	41.4 nghour per mL (nghour/mL) Geometric Coefficient of Variation 24.3	101.2 nghour per mL (nghour/mL) Geometric Coefficient of Variation 18.6	149.4 nghour per mL (nghour/mL) Geometric Coefficient of Variation 23.6	77.0 nghour per mL (nghour/mL) Geometric Coefficient of Variation 23.6

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=6 Participants 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 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.	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.	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.
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]) Gemcitabine: Day 1	10001.2 ng*hour/mL Geometric Coefficient of Variation 21.8	—	—	—
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]) Gemcitabine: Day 15	9576.0 ng*hour/mL Geometric Coefficient of Variation 7.2	—	—	—
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]) dFdU: Day 1	139397.1 ng*hour/mL Geometric Coefficient of Variation 25.1	—	—	—
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]) dFdU: Day 15	116487.7 ng*hour/mL Geometric Coefficient of Variation 28.6	—	—	—

SECONDARY outcome

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
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]) Evofosfamide: Day 1	5296.2 ng*hour/mL Geometric Coefficient of Variation 8.2	7904.7 ng*hour/mL Geometric Coefficient of Variation 13.2	10459.6 ng*hour/mL Geometric Coefficient of Variation 14.5	6049.5 ng*hour/mL Geometric Coefficient of Variation 11.9
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]) Evofosfamide: Day 15	5261.3 ng*hour/mL Geometric Coefficient of Variation 2.4	8233.3 ng*hour/mL Geometric Coefficient of Variation 18.0	10786.6 ng*hour/mL Geometric Coefficient of Variation 16.8	5664.9 ng*hour/mL Geometric Coefficient of Variation 21.3
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]) Br-IPM: Day 1	90 ng*hour/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated as there was only 1 participant analyzed in this reporting group.	105 ng*hour/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated as there was only 1 participant analyzed in this reporting group.	174.6 ng*hour/mL Geometric Coefficient of Variation 21.9	—
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]) Br-IPM: Day 15	51 ng*hour/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated as there was only 1 participant analyzed in this reporting group.	115.1 ng*hour/mL Geometric Coefficient of Variation 17.2	171.8 ng*hour/mL Geometric Coefficient of Variation 16.8	—

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=6 Participants 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 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.	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.	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.
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) Gemcitabine: Day 1	10719.5 ng*hour/mL Geometric Coefficient of Variation 24.5	—	—	—
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) Gemcitabine: Day 15	9996.0 ng*hour/mL Geometric Coefficient of Variation 1.3	—	—	—
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) dFdU: Day 1	159014.1 ng*hour/mL Geometric Coefficient of Variation 35.3	—	—	—
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU]) dFdU: Day 15	133203.0 ng*hour/mL Geometric Coefficient of Variation 46.3	—	—	—

SECONDARY outcome

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\[inf\]).

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Apparent Total Body Clearance of (CL) of Evofosfamide Evofosfamide: Day 1	45.83 Liter per hour per square meter Geometric Coefficient of Variation 8.0	43.05 Liter per hour per square meter Geometric Coefficient of Variation 13.1	46.07 Liter per hour per square meter Geometric Coefficient of Variation 14.6	56.23 Liter per hour per square meter Geometric Coefficient of Variation 11.8
Apparent Total Body Clearance of (CL) of Evofosfamide Evofosfamide: Day 15	45.74 Liter per hour per square meter Geometric Coefficient of Variation 1.5	41.74 Liter per hour per square meter Geometric Coefficient of Variation 18.0	44.59 Liter per hour per square meter Geometric Coefficient of Variation 17.7	60.43 Liter per hour per square meter Geometric Coefficient of Variation 21.0

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=6 Participants 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 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.	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.	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.
Apparent Total Body Clearance of (CL) of Gemcitabine Gemcitabine: Day 1	93.29 Liter per hour per square meter Geometric Coefficient of Variation 24.5	—	—	—
Apparent Total Body Clearance of (CL) of Gemcitabine Gemcitabine: Day 15	101.04 Liter per hour per square meter Geometric Coefficient of Variation 1.9	—	—	—

SECONDARY outcome

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Apparent Volume of Distribution at Steady State (Vss) of Evofosfamide Evofosfamide: Day 1	21.71 Liter per square meter Geometric Coefficient of Variation 15.0	21.54 Liter per square meter Geometric Coefficient of Variation 2.4	21.79 Liter per square meter Geometric Coefficient of Variation 15.2	39.03 Liter per square meter Geometric Coefficient of Variation 7.1
Apparent Volume of Distribution at Steady State (Vss) of Evofosfamide Evofosfamide: Day 15	20.26 Liter per square meter Geometric Coefficient of Variation 16.4	18.83 Liter per square meter Geometric Coefficient of Variation 9.6	21.35 Liter per square meter Geometric Coefficient of Variation 5.2	41.55 Liter per square meter Geometric Coefficient of Variation 9.0

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=6 Participants 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 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.	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.	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.
Apparent Volume of Distribution at Steady State (Vss) of Gemcitabine Gemcitabine: Day 1	34.41 Liter per square meter Geometric Coefficient of Variation 21.9	—	—	—
Apparent Volume of Distribution at Steady State (Vss) of Gemcitabine Gemcitabine: Day 15	43.71 Liter per square meter Geometric Coefficient of Variation 18.3	—	—	—

SECONDARY outcome

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Apparent Volume of Distribution During Terminal Phase (Vz) of Evofosfamide Evofosfamide: Day 1	44.85 Liter per square meter Geometric Coefficient of Variation 10.3	39.16 Liter per square meter Geometric Coefficient of Variation 1.2	42.10 Liter per square meter Geometric Coefficient of Variation 15.3	49.07 Liter per square meter Geometric Coefficient of Variation 11.4
Apparent Volume of Distribution During Terminal Phase (Vz) of Evofosfamide Evofosfamide: Day 15	45.41 Liter per square meter Geometric Coefficient of Variation 5.3	40.44 Liter per square meter Geometric Coefficient of Variation 17.5	46.86 Liter per square meter Geometric Coefficient of Variation 19.5	51.34 Liter per square meter Geometric Coefficient of Variation 17.3

SECONDARY outcome

Timeframe: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=6 Participants 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 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.	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.	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.
Apparent Volume of Distribution During Terminal Phase (Vz) of Gemcitabine Gemcitabine: Day 1	28.78 Liter per square meter Geometric Coefficient of Variation 29.8	—	—	—
Apparent Volume of Distribution During Terminal Phase (Vz) of Gemcitabine Gemcitabine: Day 15	30.14 Liter per square meter Geometric Coefficient of Variation 1.2	—	—	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Cumulative Amount of Evofosfamide Excreted From Time Zero to Time After Dosing (Ae0-t) Evofosfamide: Day 1	22.913 milligram per square meter Geometric Coefficient of Variation 43.6	17.135 milligram per square meter Geometric Coefficient of Variation 66.6	38.771 milligram per square meter Geometric Coefficient of Variation 33.3	22.691 milligram per square meter Geometric Coefficient of Variation 82.0
Cumulative Amount of Evofosfamide Excreted From Time Zero to Time After Dosing (Ae0-t) Evofosfamide: Day 15	11.674 milligram per square meter Geometric Coefficient of Variation 139.2	22.605 milligram per square meter Geometric Coefficient of Variation 53.7	40.049 milligram per square meter Geometric Coefficient of Variation 66.0	30.025 milligram per square meter Geometric Coefficient of Variation 31.6

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Renal Clearance (CL) for Evofosfamide Evofosfamide: Day 1	4.35 Liter per hour per square meter Geometric Coefficient of Variation 41.4	2.18 Liter per hour per square meter Geometric Coefficient of Variation 59.9	3.72 Liter per hour per square meter Geometric Coefficient of Variation 34.4	3.79 Liter per hour per square meter Geometric Coefficient of Variation 81.4
Renal Clearance (CL) for Evofosfamide Evofosfamide: Day 15	2.23 Liter per hour per square meter Geometric Coefficient of Variation 137.0	2.76 Liter per hour per square meter Geometric Coefficient of Variation 76.4	3.73 Liter per hour per square meter Geometric Coefficient of Variation 83.1	5.35 Liter per hour per square meter Geometric Coefficient of Variation 15.4

SECONDARY outcome

Timeframe: Time from first treatment to final assessment at 33 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Best Overall Response (BOR) Progressive Disease	2 Participants	3 Participants	4 Participants	3 Participants
Best Overall Response (BOR) Complete Response	0 Participants	0 Participants	0 Participants	0 Participants
Best Overall Response (BOR) Partial Response	0 Participants	0 Participants	0 Participants	0 Participants
Best Overall Response (BOR) Stable Disease	0 Participants	0 Participants	2 Participants	2 Participants

SECONDARY outcome

Timeframe: Time from first treatment to final assessment at 33 months

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Number of Participants With Objective Response	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Time from first treatment to final assessment at 33 months

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Number of Participants With Disease Control	0 Participants	0 Participants	2 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Number of Participants With Clinical Significant Laboratory Abnormalities and Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events Subjects with Lab Abnormalities	3 Participants	3 Participants	8 Participants	6 Participants
Number of Participants With Clinical Significant Laboratory Abnormalities and Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events Subjects with Vital signs Abnormalities	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to 33 months

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

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

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Number of Participants With Abnormal Electrocardiogram (ECG) Findings Reported as Treatment Emergent Adverse Events (TEAEs)	0 Participants	0 Participants	3 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline up to 33 months

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

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.

Outcome measures

Outcome measures
Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2	0 Participants	0 Participants	1 Participants	0 Participants

Adverse Events

Evofosfamide 240 mg

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Evofosfamide 340 mg

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Evofosfamide 480 mg

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Evofosfamide 340 mg + Gemcitabine

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Evofosfamide 240 mg n=3 participants at risk 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 340 mg n=3 participants at risk 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 480 mg n=8 participants at risk 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 340 mg + Gemcitabine n=6 participants at risk 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.
Hepatobiliary disorders Bile Duct Obstruction	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Respiratory, thoracic and mediastinal disorders Interstitial Lung Disease	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months

Other adverse events

Additional Information

Merck KGaA Communication Center

Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER

Measure	Evofosfamide 240 mg n=3 Participants 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 340 mg n=3 Participants 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 480 mg n=8 Participants 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 340 mg + Gemcitabine n=6 Participants 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.
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]) Evofosfamide: Day 1	5266.9 nghour per mL (nghour/mL) Geometric Coefficient of Variation 8.3	7864.2 nghour per mL (nghour/mL) Geometric Coefficient of Variation 13.0	10416.1 nghour per mL (nghour/mL) Geometric Coefficient of Variation 14.4	5989.5 nghour per mL (nghour/mL) Geometric Coefficient of Variation 11.5
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]) Evofosfamide: Day 15	5232.4 nghour per mL (nghour/mL) Geometric Coefficient of Variation 2.4	8191.1 nghour per mL (nghour/mL) Geometric Coefficient of Variation 17.8	10742.8 nghour per mL (nghour/mL) Geometric Coefficient of Variation 16.7	5616.4 nghour per mL (nghour/mL) Geometric Coefficient of Variation 21.0
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]) Br-IPM: Day 1	38.1 nghour per mL (nghour/mL) Geometric Coefficient of Variation 41.1	61.7 nghour per mL (nghour/mL) Geometric Coefficient of Variation 84.4	153.8 nghour per mL (nghour/mL) Geometric Coefficient of Variation 25.0	47.7 nghour per mL (nghour/mL) Geometric Coefficient of Variation 66.5
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]) Br-IPM: Day 15	41.4 nghour per mL (nghour/mL) Geometric Coefficient of Variation 24.3	101.2 nghour per mL (nghour/mL) Geometric Coefficient of Variation 18.6	149.4 nghour per mL (nghour/mL) Geometric Coefficient of Variation 23.6	77.0 nghour per mL (nghour/mL) Geometric Coefficient of Variation 23.6

Measure	Evofosfamide 240 mg n=3 participants at risk 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 340 mg n=3 participants at risk 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 480 mg n=8 participants at risk 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 340 mg + Gemcitabine n=6 participants at risk 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.
Gastrointestinal disorders Constipation	0.00% 0/3 • Baseline up to 33 months	66.7% 2/3 • Baseline up to 33 months	75.0% 6/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Gastrointestinal disorders Nausea	0.00% 0/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	37.5% 3/8 • Baseline up to 33 months	33.3% 2/6 • Baseline up to 33 months
Gastrointestinal disorders Abdominal Pain	33.3% 1/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Gastrointestinal disorders Cheilitis	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Gastrointestinal disorders Diarrhoea	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Gastrointestinal disorders Dyspepsia	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Gastrointestinal disorders Stomatitis	0.00% 0/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	33.3% 2/6 • Baseline up to 33 months
Gastrointestinal disorders Vomiting	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Gastrointestinal disorders Haemorrhoids	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Investigations Electrocardiogram QT Prolonged	0.00% 0/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	25.0% 2/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Investigations Alanine Aminotransferase Increased	33.3% 1/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Investigations Aspartate Aminotransferase Increased	33.3% 1/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Investigations Gamma-Glutamyltransferase Increased	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	25.0% 2/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Investigations Neutrophil Count Decreased	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	37.5% 3/8 • Baseline up to 33 months	83.3% 5/6 • Baseline up to 33 months
Investigations Blood Cholesterol Increased	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Investigations White Blood Cell Count Decreased	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	25.0% 2/8 • Baseline up to 33 months	83.3% 5/6 • Baseline up to 33 months
Investigations Platelet Count Decreased	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	66.7% 4/6 • Baseline up to 33 months
Investigations Blood Alkaline Phosphatase Increased	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	33.3% 2/6 • Baseline up to 33 months
Investigations Blood Bilirubin Increased	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Rash Maculo-Papular	0.00% 0/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	37.5% 3/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	25.0% 2/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Dry Skin	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Rash	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Skin Hyperpigmentation	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	33.3% 2/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Palmar-Plantar Erythrodysaesthesia Syndrome	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	33.3% 2/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Dermatitis	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Dermatitis Exfoliative	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Haemorrhage Subcutaneous	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Skin and subcutaneous tissue disorders Intertrigo	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
General disorders Fatigue	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	25.0% 2/8 • Baseline up to 33 months	50.0% 3/6 • Baseline up to 33 months
General disorders Pyrexia	0.00% 0/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
General disorders Non-Cardiac Chest Pain	33.3% 1/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
General disorders Oedema Peripheral	0.00% 0/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Vascular disorders Vasculitis	33.3% 1/3 • Baseline up to 33 months	100.0% 3/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	50.0% 3/6 • Baseline up to 33 months
Vascular disorders Flushing	0.00% 0/3 • Baseline up to 33 months	66.7% 2/3 • Baseline up to 33 months	25.0% 2/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Metabolism and nutrition disorders Decreased Appetite	0.00% 0/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	50.0% 3/6 • Baseline up to 33 months
Metabolism and nutrition disorders Hyperglycaemia	33.3% 1/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months	50.0% 3/6 • Baseline up to 33 months
Metabolism and nutrition disorders Hyperphosphataemia	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Metabolism and nutrition disorders Hypertriglyceridaemia	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Metabolism and nutrition disorders Hypoalbuminaemia	0.00% 0/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	50.0% 3/6 • Baseline up to 33 months
Metabolism and nutrition disorders Hypoglycaemia	33.3% 1/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Nervous system disorders Dysgeusia	0.00% 0/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Nervous system disorders Headache	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Nervous system disorders Tension Headache	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Injury, poisoning and procedural complications Infusion Related Reaction	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	25.0% 2/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Blood and lymphatic system disorders Anaemia	0.00% 0/3 • Baseline up to 33 months	33.3% 1/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	83.3% 5/6 • Baseline up to 33 months
Ear and labyrinth disorders Vertigo	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Psychiatric disorders Insomnia	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Hepatobiliary disorders Hepatic Function Abnormal	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Respiratory, thoracic and mediastinal disorders Hiccups	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Respiratory, thoracic and mediastinal disorders Oropharyngeal Discomfort	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Infections and infestations Nasopharyngitis	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Infections and infestations Oral Herpes	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor Pain	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	0.00% 0/8 • Baseline up to 33 months	16.7% 1/6 • Baseline up to 33 months
Eye disorders Conjunctivitis	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
Metabolism and nutrition disorders Hypophosphatemia	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months
General disorders Influenza like illness	0.00% 0/3 • Baseline up to 33 months	0.00% 0/3 • Baseline up to 33 months	12.5% 1/8 • Baseline up to 33 months	0.00% 0/6 • Baseline up to 33 months