A Study Comparing CO-1.01 With Gemcitabine as First Line Therapy in Patients With Metastatic Pancreatic Adenocarcinoma (LEAP)

A Phase II Randomized, Open-Label, Multicenter Study Comparing CO-1.01 With Gemcitabine as First-Line Therapy in Patients With Metastatic Pancreatic Adenocarcinoma

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01124786

Enrollment

367

Registered

2010-05-17

Start date

2010-05-31

Completion date

2013-06-30

Last updated

2014-04-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Metastatic Pancreatic Adenocarcinoma

Keywords

cancer, metastatic, pancreatic, pancreas, adenocarcinoma, gemcitabine, human equilibrative nucleoside transporter-1 (hENT1), CO-1.01, CO-101, CO101, Stage 4, Stage IV

Brief summary

The purpose of this study is to determine whether CO-1.01 is safe and effective in the treatment of patients with metastatic pancreatic cancer and low hENT1 expression compared with gemcitabine.

Detailed description

Pancreatic cancer is a very serious form of cancer. The majority of patients present with unresectable disease, and the condition is often not diagnosed until the cancer is relatively advanced. The standard first-line treatment for patients with unresectable pancreatic cancer is gemcitabine monotherapy. Unfortunately many of these patients fail to derive benefit from this treatment. No clinical or molecular marker has been established to predict benefit from gemcitabine therapy, so patients are treated empirically until evidence of disease progression or worsening performance status. The potential for human equilibrative nucleoside transporter-1 (hENT1) expression to predict survival in gemcitabine-treated patients has been studied, and data suggest that patients with low levels of tumor cell hENT1 expression derive less benefit from gemcitabine treatment than patients with high levels of tumor cell hENT1 expression. These data support the hypothesis to be tested in this study that patients with pancreatic tumors expressing low levels of hENT1 will derive minimal benefit from gemcitabine, but will receive benefit from CO-1.01 (gemcitabine elaidate) which enters tumor cells in a hENT1-independent fashion.

Interventions

DRUGCO-1.01

1250 mg/m2 intravenous infusion weekly for 3 weeks every 4 weeks

DRUGGemcitabine

1000 mg/m2 intravenous infusion weekly for 7 weeks followed by 1 week rest, then weekly for 3 weeks every 4 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Metastatic pancreatic ductal adenocarcinoma (i.e., Stage 4). * Histological/cytological confirmation of metastatic tissue (not primary tumor) by a central pathology laboratory (H&E stain) to ensure sufficient material is available for later hENT1 analysis. * Adjuvant chemotherapy/radiotherapy ≥ 6 months prior to randomization. * Palliative radiotherapy (if administered) ≥ 1 month prior to randomization. * CT scan ≤30 days prior to randomization * Performance Status (ECOG) 0 or 1. * Estimated life expectancy ≥ 12 weeks. * Age ≥ 18 years. * Adequate hematological and biological function. * Written consent on an Institutional Review Board/Institutional Ethics Committee-approved Informed Consent Form prior to any study-specific evaluation.

Exclusion criteria

* Prior palliative chemotherapy for pancreatic cancer. * Radical pancreatic resections (e.g., Whipple procedure) are not allowed \< 6 months prior to randomization. Exploratory laparotomy, palliative (e.g., bypass) surgery, or other procedures (e.g., stents) are not allowed \< 14 days prior to randomization. In both cases the patient must be sufficiently recovered and stable. * Symptomatic brain metastases. * Participation in other investigational drug clinical studies ≤ 30 days prior to randomization. * Concomitant treatment with prohibited medications. * History of allergy to gemcitabine or eggs. * Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study (e.g., substance abuse, uncontrolled intercurrent illness including active infection, arterial thrombosis, symptomatic pulmonary embolism). * Any disorder that would hamper protocol compliance. * Prior nonpancreatic malignancy treated with chemotherapy. Prior malignancies treated with surgery or radiotherapy alone must be in remission ≥ 3 years. The following prior malignancies are allowable irrespective of when they occurred: in situ carcinoma of the cervix, in situ ductal breast cancer, low-grade local bladder cancer, and nonmelanotic skin cancer. * Females who are pregnant or breastfeeding. * Refusal to use adequate contraception for fertile patients (females and males during the study and for 6 months after the last study treatment). Adequate forms of contraception are double-barrier methods (condoms or diaphragm with spermicidal jelly or foam); oral, depot, or injectable contraceptives; intrauterine devices; tubal ligation. * Any other reason the investigator considers the patient should not participate in the study.

Design outcomes

Primary

Measure	Time frame
Overall Survival in Patients With Low High Human Equilibrative Nucleoside Transporter 1 (hENT1) Expression	Monthly follow up after treatment discontinuation until death, up to 1.5 years.

Secondary

Measure	Time frame
ORR, Duration of Response, and Progression Free Survival (PFS) in Patients With Measurable/Evaluable Disease, Using RECIST 1.1, up to 1.5 Years	Every 8 weeks
Cancer Antigen (CA)19-9 Response Rates	Every 4 weeks, up to 1.5 years
Drug Tolerability and Toxicity	Every week, up to 1.5 years
Overall Survival in All Patients and Patients With hENT1 Expression	Monthly follow up after treatment discontinuation until death, up to 1.5 years
Change From Baseline in Health Status	Every 4 weeks, up to 1.5 years
Pharmacokinetic (PK) Profile of CO-1.01 Based on Sparse Sampling	30 days after first dose
Change From Baseline in Pain Severity	Every 4 weeks, up to 1.5 years

Countries

Argentina, Australia, Belgium, Brazil, Canada, France, Germany, Italy, Netherlands, Norway, Russia, Sweden, Ukraine, United Kingdom, United States

Participant flow

Recruitment details

This was a multicenter, multinational study conducted at 98 medical centers in Europe, Australia, and the Americas. The first patient was randomized on 04-Aug-2010 and the last patient on 09-April-2012.

Pre-assignment details

Eligible patients were randomized (1:1) to receive either gemcitabine elaidate or gemcitabine. The stratification factors in this model were Eastern Cooperative Group Performance Status (ECOG PS) (0 vs 1) and region (North America/Western Europe/Australia vs Eastern Europe vs South America).

Participants by arm

Arm	Count
Gemcitabine Elaidate CO-1.01 : 1250 mg/m2 intravenous infusion weekly for 3 weeks every 4 weeks	182
Gemcitabine Gemcitabine : 1000 mg/m2 intravenous infusion weekly for 7 weeks followed by 1 week rest, then weekly for 3 weeks every 4 weeks	185
Total	367

Baseline characteristics

Characteristic	Gemcitabine Elaidate	Gemcitabine	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	79 Participants	69 Participants	148 Participants
Age, Categorical Between 18 and 65 years	103 Participants	116 Participants	219 Participants
Age, Continuous	62.5 years STANDARD_DEVIATION 9.62	60.5 years STANDARD_DEVIATION 11.19	61.5 years STANDARD_DEVIATION 10.47
Region of Enrollment Argentina	2 participants	6 participants	8 participants
Region of Enrollment Australia	4 participants	5 participants	9 participants
Region of Enrollment Belgium	6 participants	4 participants	10 participants
Region of Enrollment Brazil	7 participants	3 participants	10 participants
Region of Enrollment Canada	5 participants	2 participants	7 participants
Region of Enrollment France	19 participants	10 participants	29 participants
Region of Enrollment Germany	14 participants	17 participants	31 participants
Region of Enrollment Italy	8 participants	9 participants	17 participants
Region of Enrollment Norway	2 participants	3 participants	5 participants
Region of Enrollment Russian Federation	45 participants	40 participants	85 participants
Region of Enrollment Sweden	1 participants	7 participants	8 participants
Region of Enrollment Ukraine	40 participants	47 participants	87 participants
Region of Enrollment United Kingdom	11 participants	10 participants	21 participants
Region of Enrollment United States	18 participants	22 participants	40 participants
Sex: Female, Male Female	74 Participants	74 Participants	148 Participants
Sex: Female, Male Male	108 Participants	111 Participants	219 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	171 / 179	164 / 181
serious Total, serious adverse events	82 / 179	82 / 181

Outcome results

Primary

Overall Survival in Patients With Low High Human Equilibrative Nucleoside Transporter 1 (hENT1) Expression

Time frame: Monthly follow up after treatment discontinuation until death, up to 1.5 years.

Population: Analysis was per protocol and included hENT-1 low Intent to Treat (IIT) population.

Arm	Measure	Value (MEDIAN)
CO-1.01	Overall Survival in Patients With Low High Human Equilibrative Nucleoside Transporter 1 (hENT1) Expression	5.7 months
Gemcitabine	Overall Survival in Patients With Low High Human Equilibrative Nucleoside Transporter 1 (hENT1) Expression	6.1 months

Comparison: If the median Overall Survival (OS) for the CO-1.01-treated patients is 7.7 months and the median OS for gemcitabine-treated patients with hENT1-low status is 4 months (hazard ratio of 0.53), then a total of 144 events of death in the hENT1-low subgroup will provide over 90% power at a 0.05 (2 sided) significance level for the comparison of CO-1.01 to gemcitabine in the hENT1-low patients.p-value: <0.97395% CI: [0.746, 1.326]Log Rank

Secondary