Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma
Conditions
Keywords
TH-302, Evofosfamide, Pancreatic Cancer, EMR200592-001
Brief summary
This Phase 3 trial is a randomized, double-blind, placebo-controlled trial of gemcitabine in combination with TH-302 compared to gemcitabine in combination with placebo in subjects with locally advanced unresectable or metastatic pancreatic adenocarcinoma. Randomized subjects will receive TH-302 plus gemcitabine or gemcitabine plus placebo in 4-week cycles until there is evidence of progressive disease, intolerable toxicity, or the subject discontinues from the trial for other reasons (for example, withdrawal of consent). The primary efficacy endpoint is overall survival (OS) time. The data cut-off for statistical analyses of the primary and secondary endpoints will be reached when 508 events (deaths) will be reported. No planned interim analyses will be conducted. An Independent Safety Monitoring Board (ISMB) will provide periodic evaluations of the unblinded safety data to ensure subject safety and the validity and scientific merit of the study. A total of 660 subjects will be enrolled.
Interventions
DRUGTH-302
TH-302 will be administered at a dose of 340 milligrams per square meter (mg/m\^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal.
DRUGGemcitabine
Gemcitabine will be administered at a dose of 1000 (mg/m\^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal.
DRUGPlacebo (5 percent dextrose - D5W)
TH-302 placebo (5 percent dextrose - D5W) will be administered as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal.
Sponsors
Threshold Pharmaceuticals
ImmunoGenesis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 18 years of age * Locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma proven by histology or cytology and previously untreated with chemotherapy or systemic therapy other than: * Radiosensitizing doses of 5-fluorouracil; * Radiosensitizing doses of gemcitabine if relapse occurred at least 6 months after completion of gemcitabine; * Neoadjuvant chemotherapy if relapse occurred at least 6 months after surgical resection; * Adjuvant chemotherapy if relapse occurred at least 6 months after completion of adjuvant chemotherapy * Measurable disease (at least one target lesion outside of previous radiation fields) or non-measurable disease by RECIST v.1.1 criteria * Documentation of disease progression since any prior therapy * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Life expectancy of at least 3 month * Acceptable liver, renal function and acceptable hematological status * Other protocol defined inclusion criteria may apply
Exclusion criteria
* New York Heart Association (NYHA) Class III or IV congestive heart failure, myocardial infarction within 6 months prior to the date of randomization, unstable arrhythmia or symptomatic peripheral arterial vascular disease * Symptomatic ischemic heart disease * Known brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 3 months) * Previous malignancy other than pancreatic cancer in the last 5 years, except for adequately treated non-melanoma skin cancer or pre-invasive cancer of the cervix * Severe chronic obstructive or other pulmonary disease with hypoxemia * Major surgery, other than diagnostic surgery, less than or equal to 28 days prior to the date of randomization. Subject must have completely recovered from surgery * Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy * Treatment of pancreatic cancer with radiation therapy or surgery less than or equal to 28 days prior to the date of randomization * Prior therapy with a hypoxic cytotoxin * Subjects who participated in an investigational drug or device trial less than or equal to 28 days prior to Day 1 of the first cycle * Known infection with Human Immunodeficiency Virus (HIV), or an active infection with Hepatitis B or Hepatitis C * Subjects who have exhibited allergic reactions to a structural compound similar to TH-302 or the drug product excipients or to gemcitabine or its excipients * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | Overall survival is defined as time from randomization to death or last day known to be alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | Progression Free Survival is defined as the time from randomization to either first observation of progressive disease or occurrence of death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Countries
Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gemcitabine Plus TH-302 TH-302: TH-302 will be administered at a dose of 340 milligrams per square meter (mg/m\^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal.
Gemcitabine: Gemcitabine will be administered at a dose of 1000 (mg/m\^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal. | 346 |
| Gemcitabine Plus Placebo Gemcitabine: Gemcitabine will be administered at a dose of 1000 (mg/m\^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal.
Placebo (5 percent dextrose - D5W): TH-302 placebo (5 percent dextrose - D5W) will be administered as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal. | 347 |
| Total | 693 |
Baseline characteristics
| Characteristic | Gemcitabine Plus TH-302 | Gemcitabine Plus Placebo | Total |
|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 9.7 | 63.8 years STANDARD_DEVIATION 9.82 | 64.4 years STANDARD_DEVIATION 9.77 |
| Sex: Female, Male Female | 155 Participants | 168 Participants | 323 Participants |
| Sex: Female, Male Male | 191 Participants | 179 Participants | 370 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 341 / 341 | 338 / 338 |
| serious Total, serious adverse events | 341 / 341 | 338 / 338 |
Outcome results
Primary
Overall Survival
Overall survival is defined as time from randomization to death or last day known to be alive.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gemcitabine Plus TH-302 | Overall Survival | 8.9 months |
| Gemcitabine Plus Placebo | Overall Survival | 7.6 months |
Secondary
Progression Free Survival
Progression Free Survival is defined as the time from randomization to either first observation of progressive disease or occurrence of death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gemcitabine Plus TH-302 | Progression Free Survival | 5.5 months |
| Gemcitabine Plus Placebo | Progression Free Survival | 3.7 months |