E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Irinotecan-Naïve, KRAS-Mutant, Metastatic Colorectal Cancer (mCRC) |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic Colorectal Cancer (mCRC) |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065147 |
E.1.2 | Term | Malignant solid tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061451 |
E.1.2 | Term | Colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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.
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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 PK of NKTR-102 or irinotecan and their respective
metabolites, in a subset of patients |
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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 disease with at least 1 uni-dimensionally measurable lesion meeting RECIST version 1.1 guidelines (see Section 12.1.1). Either computed tomography (CT) or magnetic resonance imaging (MRI) scanning is acceptable. Patients must have an acceptable quality radiologic exam as assessed by Sponsor or Sponsor’s designee.
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 or neoadjuvant setting.
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 myeloid growth factor support for 21 days preceding the lab assessment
b. White blood cell (WBC) count ≥ 3,000/mm3 without myeloid growth factor 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
e. Total bilirubin ≤ 2 mg/dL
f. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 x ULN (≤ 5 x ULN if the presence of liver metastasis is confirmed)
g. Creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 60 mL/min
9. Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at Cycle 1 Day 1.
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 (male condom) by the male partner, during the treatment period. Appropriate contraception must be used for at least 8 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. |
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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 NCI-CTCAE Grade 0 or 1 toxicity (any NCI-CTCAE 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. Patients who have received biologic agents including antibodies (e.g., bevacizumab, trastuzumab, etc.) as well as investigational agents within 28 days prior to the first day of study drug treatment.
5. Patients who have received any treatment with a camptothecin derivative (e.g., irinotecan, topotecan, SN-38 investigational agents, etc.).
6. Known or suspected central nervous system metastases.
7. Pregnant or lactating.
8. Other malignancy within the past 5 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.
9. Liver cirrhosis.
10. Interstitial pneumonitis.
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 or intolerance to other PEGylated drugs or to the excipients of irinotecan/Camptosar.
13. Patients with inflammatory bowel disease (e.g., Crohn’s disease and ulcerative colitis), unresolved bowel issues (e.g., diverticulitis, ileitis, colitis, complete bowel obstruction etc.) or patients with chronic or acute gastrointestinal disorders with diarrhea as a major symptom. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is PFS, which is defined as the time from the date of randomization to the date of progressive disease (PD) or death due to any cause. For patients whose disease does not progress or who do not die, the PFS time will
be censored at the time of last tumor assessment demonstrating lack of disease
progression. For patients with only a screening radiographic assessment available will have their data censured as of Cycle 1 Day 1). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Date of progressive disease (PD) or death due to any cause. For patients
whose disease does not progress or who do not die, PFS will be censored
at the time of last tumor assessment demonstrating lack of disease
progression (or on the date of randomization if the patient did not
undergo repeated imaging on-study). |
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E.5.2 | Secondary end point(s) |
- Overall survival
- Objective response rate and response duration
- Incidence and duration of toxicities, with severity grading according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0
- Descriptive PK parameters of NKTR-102 or irinotecan and their
respective metabolites, in a subset of patients. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time from the date of randomization to death from any cause.
Patients will have their OS time censored at the time they were last
known to be alive. |
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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 | 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
| 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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
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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
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For analysis purposes, the trial will be considered clinically complete when:
123 primary endpoint events have occurred
Justification
Because of the nature of colorectal cancer and the possibility of long-term treatment, the end of trial was defined as indicated above.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
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 | 3 |
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 |