A Randomized, Double-Blind, Phase III Study of the Efficacy and Safety of Gemcitabine in Combination With TH-302 Compared With Gemcitabine in Combination With Placebo in Previously Untreated Subjects With Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma

Summary

This Phase iii trial is a randomized, double-blind, placebo-controlled trial of gemcitabine in combination with TH-302 (G+TH-302, investigational arm) compared to gemcitabine in combination with placebo (G+Pbo, control arm) in subjects with locally advanced unresectable or metastatic pancreatic adenocarcinoma. Randomized subjects will receive G+TH-302 or G+Pbo in 28-day cycles until there is evidence of progressive disease (PD), intolerable toxicity, or the subject withdraws from study drug for other reasons. The primary 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) are 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.

Following the completion of screening and determination of eligibility, qualified subjects will be randomized (1:1 ratio stratified by 1] locally advanced unresectable versus metastatic disease, 2] eCoG performance status of 0 versus 1, and 3] geographic region [uS/Canada, europe, and rest of world]) to receive G+TH-302 or G+Pbo. Subjects should receive their first dose of study drug [LessThanorequalTo]3 days following randomization and [LessThanorequalTo]21 days following the initiation of screening.

The Randomized Treatment Phase starts at the day of randomization and continues in 28-day treatment cycles.
* Placebo or TH-302 (at a dose of 340 mg/m2) will be administered by iV infusion over 30 minutes on Days 1, 8, and 15 of the treatment cycle. Longer infusion durations are permitted based on investigator judgment of the time required to administer the infusion volume.
* Gemcitabine will be administered at a dose of 1000 mg/m2 via iV infusion over 30 minutes on Days 1, 8 and 15 of each 28-day treatment cycle. When administered in combination with TH-302/placebo, the gemcitabine infusion will begin 2 to 2.5 hours after the completion of the TH-302/placebo infusion.

in the G+placebo arm, placebo for TH-302 will be 5% Dextrose in Water (D5W) for injection in a non-DeHP for clinical use infusion bag. D5W (placebo) will be administered on Days 1, 8, and 15 of all cycles.
* D5W will not be supplied. D5W will be used from commercially available sources. The
D5W to be used as placebo must be obtained from the same source as the D5W used for the
dilution of TH-302.

enpoints:
The primary endpoint is oS time.

Secondary endpoints:
* Tumor assessment endpoints: PFS and tumor response as measured by oR and disease control, based on ReCiST 1.1 criteria.
* The primary health-related quality of life (HRQoL) endpoint is based on Time to Definitive Deterioration
(TuDD) assessed using eoRTC QLQ-C30 (version 3). in addition, HRQoL will be evaluated using eQ-5D-5L, and TuDD of pain as measured by a nRS.
* The safety and tolerability endpoints consist of treatment-emergent adverse events (Teae) graded
according to national Cancer institute Common Terminology Criteria for adverse events (nCi
CTCae v.4.03), treatment-emergent serious adverse events (Saes), and deaths. in addition, drug exposure
and standard laboratory studies (hematology, biochemistry, urinalysis, pregnancy testing in women with childbearing potential), electrocardiograms (eCGs), physical examinations, and assessments of weight and vital signs also will be performed.
* Population PK endpoints include parameters such as clearance (Cl) and volume of distribution (V) derived
from plasma concentrations of TH-302 and if feasible bromo-isophosphoramide mustard (Br-iPM).

Participant Eligibility

Inclusion Criteria
For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
1. At least 18 years of age.
2. Ability to understand the purposes and risks of the trial and has signed a written informed consent form approved by the investigator[Single Quote]s Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
3. 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.
4. Measurable disease (at least one target lesion outside of previous radiation fields) or non-measurable disease by RECIST 1.1 criteria (see Appendix III of the protocol).
5. Documentation of disease progression since any prior therapy.
6. ECOG performance status of 0 or 1 (see Appendix II of the protocol). Two observers must assess performance status <=5 days prior to randomization. If discrepant, the poorer performance status is used.
7. Life expectancy of at least 3 months.
8. Acceptable liver function:
a. Bilirubin <=1.5 times upper limit of normal (ULN); does not apply to subjects with Gilbert[Single Quote]s syndrome.
b. Aspartate aminotransferase (AST [SGOT]) and alanine aminotransferase (ALT [SGPT]) <=3 times ULN; if liver metastases are present, then <=5 times ULN is allowed.
9. Acceptable renal function:
a. Serum creatinine <=1.5 times ULN or calculated creatinine clearance >=60 mL/min (by the Cockcroft-Gault formula:

CLcr (mL/min) = [140 x age (years)] x weight (kg) / 72 x serum creatinine (mg / dL) {x0.85 for female patients}

10. Acceptable hematologic status (without growth factor support or transfusion dependency):
a. Absolute neutrophil count (ANC) >=1500 cells/μL.
b. Platelet count >=100,000/μL.
c. Hemoglobin >=9.0 g/dL.