| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | Refractory Solid Tumors (Colorectal Cancer)
Tumores sólidos refractarios (Cáncer colorrectal) | |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10061451 | | E.1.2 | Term | Colorectal cancer | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10065147 | | E.1.2 | Term | Malignant solid tumor | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | To estimate the progression-free survival (PFS) with NKTR-102 versus irinotecan. | |
| E.2.2 | Secondary objectives of the trial | ?To estimate the overall survival (OS) with NKTR-102 versus irinotecan
?To determine the objective response rate (ORR) and response duration with NKTR-102 versus irinotecan
?To characterize the safety profile of NKTR-102
?To evaluate the pharmacokinetics (PK) of NKTR-102, or irinotecan, and their respective metabolites, in a subset of patients. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Each patient must meet the following criteria to be enrolled in this study:
1. Provide signed and dated informed consent prior to study-specific screening procedures.
2. ? 18 years old.
3. Patients must have histological confirmation of colorectal adenocarcinoma. Patients must have metastatic or locally advanced disease with at least 1 uni-dimensionally measurable lesion meeting RECIST guidelines (at least 10 mm in longest diameter by spiral CT scan, or at least 20 mm by standard techniques). Either CT or magnetic resonance imaging (MRI) scanning is acceptable.
4.KRAS mutation determined from tumor tissue (primary tumor or metastasis). The presence of a KRAS mutation may be determined from patients? original diagnostic block.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Patients must have received at least 1 but no more than 1 prior fluoropyrimidine containing regimen in the metastatic setting and must be naïve to irinotecan. Patients may also have received a fluoropyrimidine in the adjuvant settting.
7. Standard prior radiation therapy for rectal cancer is allowed. Patients must have recovered from the toxic effects of radiation prior to study enrollment. Prior radiotherapy must be completed 28 days before study entry. Lesions that have been radiated in the advanced setting cannot be included as sites of measurable disease unless clear tumor progression has been documented in these lesions since the end of radiation therapy.
8. Adequate organ and bone marrow function at the Screening Visit defined as:
a.Absolute neutrophil count ? 1,500/mm3 without GCSF support for 21 days preceding the lab assessment
b.White blood cell (WBC) count ? 3,000/mm3 without GCSF support for 21 days preceding the lab assessment
c.Platelet count ? 100,000/mm3, without transfusion within 7 days preceding the lab assessment
d.Hemoglobin ? 9 g/dL, without transfusion support within 7 days preceding the lab assessment and without erythropoietin support within 21 days preceding the lab assessment
e.Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ? 3 x upper limit of normal (ULN) (? 5 x ULN if the presence of liver metastasis is confirmed). Bilirubin must be within normal limits.
9.Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at the predose visit of each cycle.
10.Women of childbearing potential, or men whose female partners are of childbearing potential, must agree to use at least 2 forms of contraception, 1 of which includes a barrier method (condom) by the male partner, during the treatment period and for at least 3 months after the last dose of the study drug.
11.Patients must be able and willing to comply with the study visit schedule and study procedures. | |
| E.4 | Principal exclusion criteria | Patients who meet any of the following criteria will not be permitted entry to the study:
1.Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to Day 1 of Cycle 1, and have not, as deemed by the Investigator, recovered to CTC Grade 0 or 1 toxicity (any CTC grade of alopecia is allowed) associated with previous treatment irrespective of the interval from the last treatment.
2.Patients who have had any major surgery within 4 weeks prior to Day 1 of Cycle 1 or minor surgery within 2 weeks of Day 1 of Cycle 1.
3.Administration of any of the following CYP3A4 inducer or inhibitor: phenytoin, phenobarbital, carbamazepine, rifampin, rifabutin, St. John?s Wort, ketoconazole, neuromuscular agents or atazanavir sulfate (Section 8.6.2) within 2 weeks prior to the first day of study drug treatment.
4.Growth factors within 21 days of Day 1 Cycle 1.
5.Known or suspected central nervous system metastases.
6.Pregnant or lactating.
7.Other malignancy within the past 3 years except for any of the following: non-melanoma skin cancer, carcinoma in situ of the cervix, or any another malignancy with no evidence of recurrence for more than 5 years. Patients with a history of low-grade (Gleason score less than or equal to 6) localized prostate cancer will be eligible even if diagnosed less than 5 years previously.
8.Clinically significant obstructive gastrointestinal symptoms, intestinal bleeding, or chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom.
9.Liver cirrhosis.
10.Interstitial pneumonitis or interstitial fibrosis.
11.Any other significant co-morbid conditions that, in the judgment of the Investigator, would impair study participation or cooperation.
12. Patients with a history of hypersensitivity to other PEGylated drugs. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | The primary endpoint of this study is progression-free survival (PFS), which is defined as the time from the date of randomization to the date of progressive disease (PD), death due to any cause, premature removal from the study due to unacceptable toxicity or the initiation of new therapy. | |
| 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 | No |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 | Information not present in EudraCT |
| 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 | |
| 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 | For analysis purposes, the trial will be considered clinically complete when:
? 123 primary endpoint events have occurred and
? All enrolled patients have either completed at least a 6 month treatment period or had a primary endpoint event
Justification
Because of the nature of colorectal cancer and the possibility of long-term treatment, the end of trial was defined as indicated above. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
