E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic pancreatic cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Pancreatic cancer that has spread to other areas of the body |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033605 |
E.1.2 | Term | Pancreatic cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy of CO-1.01 and gemcitabine in patients with metastatic pancreatic adenocarcinoma and low human equilibrative nucleoside transporter 1 (hENT1) expression. |
|
E.2.2 | Secondary objectives of the trial |
• To compare the efficacy of CO-1.01 and gemcitabine in patients with metastatic pancreatic adenocarcinoma and known hENT1 status (all patients and high hENT1 expression).
• To compare the tolerability and toxicity of CO-1.01 with gemcitabine.
• To compare changes in pain severity in patients receiving CO-1.01 and gemcitabine.
• To compare changes in health status in patients receiving CO-1.01 and gemcitabine.
• To perform sparse PK sampling in patients taking CO-1.01 to contribute towards development of a population PK model of CO-1.01.
• To evaluate the clinical utility of the hENT1 diagnostic test |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Metastatic pancreatic ductal adenocarcinoma (i.e., Stage 4).
2. 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.
• Biopsy from metastases must be obtained ≥3 months after any adjuvant chemotherapy (if applicable).
• Paraffin block or freshly fixed tissue sufficient for preparing ≥6 unstained slides for central storage and subsequent hENT1 analysis is required.
3. Adjuvant chemotherapy/radiotherapy (if administered) ≥6 months prior to randomization.
4. Palliative radiotherapy (if administered) ≥1 month prior to randomization.
5. CT scan ≤30 days prior to randomization.
6. Performance Status (ECOG) 0 or 1.
7. Estimated life expectancy ≥12 weeks.
8. Age ≥18 years.
9. Adequate hematological and biological function, which is defined as the following:
Bone marrow function:
• Neutrophils ≥1.5 × 10 to the power 9/L
• Platelets ≥100.0 × 10 to the power 9/L
• Hemoglobin ≥ 9 g/dL
Hepatic function:
• AST ≤2.5 × ULN; if liver metastases, ≤5 × ULN
• Bilirubin ≤1.5 × ULN; if liver metastases, ≤3 × ULN
• Albumin > 3 g/dL
• PT/PTT within 10% ULN
Renal function:
• Serum creatinine ≤1.5 × ULN
10. Written consent on an IRB/IEC-approved Informed Consent Form prior to any studyspecific evaluation. |
|
E.4 | Principal exclusion criteria |
1. Prior palliative chemotherapy for pancreatic cancer.
2. 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.
3. Symptomatic brain metastases.
4. Participation in other investigational drug clinical studies ≤30 days prior to randomization.
5. Concomitant treatment with prohibited medications (e.g., concurrent anticancer therapy including other chemotherapy, radiation, hormonal treatment, or immunotherapy) ≤30 days prior to randomization.
6. History of allergy to gemcitabine or eggs.
7. 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).
8. Any disorder that would hamper protocol compliance.
9. 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.
10. Females who are pregnant or breastfeeding.
11. Refusal to use adequate contraception for fertile patients (females and males during the study and for 6 months after the last protocol-specified 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.
12. Any other reason the investigator considers the patient should not participate in the study. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The overall survival (OS) in patients with low hENT1 expression. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint analysis will take place when 90 events of death
have been observed in the hENT1-low patients |
|
E.5.2 | Secondary end point(s) |
• OS in all patients and patients with high hENT1 expression
• Objective tumor response rate (ORR), duration of response, and
progression free survival (PFS) in patients with measurable/evaluable
disease, using RECIST 1.1.
• CA 19-9 velocity and response rate.
• Drug tolerability and toxicity using clinical AE monitoring, clinical
laboratory testing, ECG outcomes, and dose modifications of protocol specified treatment.
• Change from baseline in pain severity measured by the worst pain on
the Brief Pain Inventory (BPI) short form.
• Change from baseline in health status measured by the European
Quality of Life-5 Dimension (EQ-5D) instrument and European Quality
Visual Analog Scale (EQ VAS).
• PK profile of CO-1.01 based on sparse sampling. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary analyses will occur when 90 events of death have been
observed in the hENT1-low patients. AE will be assessed from the time
informed consent (IC) is obtained through 28 days after the last
protocol-specified treatment adminitration. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
Russian Federation |
Ukraine |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The study will close when the required number of events of death
(approximately 144) have been observed in patients with low hENT1
expression. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |