Clinical Trial Results:
A Multicenter, Open-Label, Randomized, Phase 2 Study to Evaluate the Efficacy and Safety of NKTR-102 Versus Irinotecan in Patients with Second-Line, Irinotecan-Naïve, KRAS-Mutant, Metastatic Colorectal Cancer (mCRC)
Summary
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EudraCT number |
2008-004093-40 |
Trial protocol |
ES BE DE GB SK LV |
Global end of trial date |
12 Dec 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Aug 2017
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First version publication date |
05 Aug 2017
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
08-PIR-03
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00856375 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Nektar Therapeutics
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Sponsor organisation address |
455 Mission Bay Boulevard South, San Francisco, United States, CA 94158
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Public contact |
Nektar Therapeutics, Nektar Therapeutics, 001 415.482.5300, StudyInquiry@nektar.com
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Scientific contact |
Nektar Therapeutics, Nektar Therapeutics, 001 415.482.5300, StudyInquiry@nektar.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Feb 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Dec 2014
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To estimate the progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and duration of response (DoR) with NKTR-102 versus irinotecan, to characterize the safety profile of NKTR-102 and to evaluate the pharmacokinetics (PK) of NKTR-102 or irinotecan and their respective metabolites in a subset of patients.
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Protection of trial subjects |
This study was carried out in compliance with the International Conference on Harmonisation Harmonized Tripartite Guidelines for Good Clinical Practice 1996, the United States (US) 21 Code of Federal Regulations dealing with clinical studies (including Parts 50 and 56 concerning informed consent and IRB regulations) and the Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West, South Africa, 1996, Edinburgh 2000, Washington 2002, Tokyo 2004, and Seoul 2008). Before implementing this study, the protocol, the proposed Informed Consent Form, and other information to patients were reviewed by a properly constituted Institutional Review Board or Independent Ethics Committee.
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Background therapy |
- | ||
Evidence for comparator |
Irinotecan is a topoisomerase I inhibitor approved worldwide. In the US, irinotecan is indicated as a component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin for patients with metastatic carcinoma of the colon or rectum. Irinotecan is also indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. In the European Union, irinotecan is indicated for the treatment of patients with advanced colorectal cancer in combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease, or as a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen. Irinotecan was chosen as the control for this study because irinotecan is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. | ||
Actual start date of recruitment |
25 Feb 2009
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
United Kingdom: 13
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Country: Number of subjects enrolled |
Belgium: 1
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
India: 13
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Country: Number of subjects enrolled |
United States: 50
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Worldwide total number of subjects |
83
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EEA total number of subjects |
20
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
60
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From 65 to 84 years |
23
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Patients must have received 1 but no more than 1 prior fluoropyrimidine-containing regimen for metastatic disease and were to be naïve to irinotecan. The patient may have received a fluoropyrimidine in an adjuvant or neoadjuvant setting. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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NKTR-102 | |||||||||||||||||||||||||||
Arm description |
NKTR-102 was administered as an intravenous (IV) infusion over 90 ± 10 minutes, on Day 1 of each 21-day [± 2 days] cycle) at a dose level of 145 mg/m^2. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
NKTR-102
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
NKTR-102 was administered as an IV infusion over 90 ± 10 minutes, using low sorbing tubing, on Day 1 of each 21-day [± 2 days] cycle at a dose level of 145 mg/m^2. Body surface area was determined based on baseline height and current weight before the start of each cycle. The NKTR-102 drug product was formulated as a sterile lyophilized powder of NKTR-102 in lactate buffer at pH 3.5 supplied in 25 mL type-I amber-coloured glass vials. Each vial contained lyophilized NKTR-102 equivalent to 100 mg of irinotecan. NKTR-102 for injection was reconstituted with commercially available 5% dextrose injection. Specific NKTR-102 dose modifications could be made for drug-related neutropenia, thrombocytopenia, anaemia, diarrhoea, and other drug-related, non-haematological toxicities. Study drug was continued until disease progression, unacceptable toxicity, death, withdrawal by patient, Principal Investigator decision, lost to follow-up, protocol violation, or study termination by Sponsor.
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Arm title
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Irinotecan | |||||||||||||||||||||||||||
Arm description |
Irinotecan was administered as an IV infusion over 90 ± 10 minutes on Day 1 of a 21-day (± 2 days) treatment cycle at a dose level of 350 mg/m^2. Patients aged 65 or older, or those with prior abdominal or pelvic irradiation, were given a lower dose of 300 mg/m^2. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
Irinotecan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Irinotecan was administered as an IV infusion over 90 ± 10 minutes on Day 1 of a 21-day (± 2 days) treatment cycle at a dose level of 350 mg/m^2. Patients aged 65 or older, or those with prior abdominal or pelvic irradiation, were given a lower dose of 300 mg/m^2. Body surface area was determined based on baseline height and current weight before the start of each cycle. The storage, preparation, dosage, and administration of the irinotecan and the irinotecan infusion solution were conducted per the product labelling for the commercial product. Specific irinotecan dose modifications could be made for drug-related neutropenia, thrombocytopenia, anaemia, diarrhoea, and other drug-related, non-haematological toxicities. Study drug was continued until disease progression, unacceptable toxicity, death, withdrawal by patient, Principal Investigator decision, lost to follow-up, protocol violation, or study termination by Sponsor.
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Baseline characteristics reporting groups
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Reporting group title |
NKTR-102
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Reporting group description |
NKTR-102 was administered as an intravenous (IV) infusion over 90 ± 10 minutes, on Day 1 of each 21-day [± 2 days] cycle) at a dose level of 145 mg/m^2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Irinotecan
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Reporting group description |
Irinotecan was administered as an IV infusion over 90 ± 10 minutes on Day 1 of a 21-day (± 2 days) treatment cycle at a dose level of 350 mg/m^2. Patients aged 65 or older, or those with prior abdominal or pelvic irradiation, were given a lower dose of 300 mg/m^2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
NKTR-102
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Reporting group description |
NKTR-102 was administered as an intravenous (IV) infusion over 90 ± 10 minutes, on Day 1 of each 21-day [± 2 days] cycle) at a dose level of 145 mg/m^2. | ||
Reporting group title |
Irinotecan
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Reporting group description |
Irinotecan was administered as an IV infusion over 90 ± 10 minutes on Day 1 of a 21-day (± 2 days) treatment cycle at a dose level of 350 mg/m^2. Patients aged 65 or older, or those with prior abdominal or pelvic irradiation, were given a lower dose of 300 mg/m^2. |
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End point title |
Kaplan-Meier Estimate of PFS by Central Radiological Review: ITT Population | ||||||||||||
End point description |
PFS was defined as the time from the date of randomisation to the date of disease progression (assessed by central radiological review according to Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) or death due to any cause, whichever comes first. PFS was determined using the intention-to-treat (ITT) population which included all randomised patients who underwent baseline evaluation, with treatment assigned according to randomised arm. For patients whose disease did not progress or who did not die, the PFS time was censored at the time of the last tumor assessment that demonstrated lack of disease progression. For patients who received new anti-cancer therapy, the PFS time was censored at the time of last tumor assessment prior to the new anti-cancer therapy starts.
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End point type |
Primary
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End point timeframe |
Every 6 weeks (± 5 days) from Cycle 1, Day 1 until documented disease progression, start of new therapy for cancer, death, or end of study.
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Statistical analysis title |
Analysis of PFS | ||||||||||||
Comparison groups |
NKTR-102 v Irinotecan
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Number of subjects included in analysis |
83
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
P-value |
= 0.07 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.645
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.4 | ||||||||||||
upper limit |
1.041 | ||||||||||||
Notes [1] - Hazard Ratio and 95% CI from univariate Cox regression model |
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End point title |
Kaplan-Meier Estimate of OS: ITT Population | ||||||||||||
End point description |
Duration of OS was defined as the time from the date of randomisation to the date of death due to any cause. Patients were followed until their date of death, loss to follow-up, withdrawal of consent for further follow-up for survival, or final database closure. Patients who were lost-to-follow-up or were not known to have died were censored at last date they were shown to be alive. Patients who did not have any follow-up since the date of randomisation were censored at the date of randomization.
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End point type |
Secondary
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End point timeframe |
From randomisation to death, loss to follow-up, withdrawal of consent for further follow-up for survival, or final database closure.
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Statistical analysis title |
Analysis of OS | ||||||||||||
Comparison groups |
NKTR-102 v Irinotecan
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Number of subjects included in analysis |
83
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | ||||||||||||
P-value |
= 0.706 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.91
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.557 | ||||||||||||
upper limit |
1.486 | ||||||||||||
Notes [2] - Hazard ratio and 95% CI from univariate Cox regression model. |
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End point title |
ORR by Central Radiological Review: ITT Population | ||||||||||||
End point description |
ORR was defined as the proportion of patients with a complete response (CR) or a partial response (PR) per RECIST 1.1 based upon the best response as assessed by central radiological review; confirmation of response was not required. The analyses were performed for patients in the ITT population who had measurable disease as determined by the central imaging facility at baseline.
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End point type |
Secondary
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End point timeframe |
Every 6 weeks (± 5 days) from Cycle 1, Day 1 until documented disease progression, start of new therapy for cancer, death, or end of study.
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Statistical analysis title |
Analysis of ORR | ||||||||||||
Comparison groups |
NKTR-102 v Irinotecan
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Number of subjects included in analysis |
83
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Analysis specification |
Pre-specified
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Analysis type |
[3] | ||||||||||||
P-value |
= 0.676 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
2.054
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.355 | ||||||||||||
upper limit |
11.9 | ||||||||||||
Notes [3] - ORR 95% CI based on Exact (Clopper-Pearson) confidence limits. Odds ratio 95% CI based on asymptotic confidence limits. |
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End point title |
DoR by Central Radiological Review: ITT Population | ||||||||||||
End point description |
DoR was defined as the time from the first documented CR or PR, the date of PD (assessed by central radiological review according to RECIST 1.1), or death due to any cause, whichever came first. Patients who were alive without documented PD per RECIST were censored at the date of last tumor assessment without disease progression or start of new anti-cancer therapy for the study disease, whichever was earlier.
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End point type |
Secondary
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End point timeframe |
From the time measurement criteria for CR/PR (whichever was first recorded) were first met until the first date that recurrent disease or PD or death was objectively documented.
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Statistical analysis title |
Analysis of DoR | ||||||||||||
Comparison groups |
NKTR-102 v Irinotecan
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Number of subjects included in analysis |
83
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.018 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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End point title |
Incidence of Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher With Incidence Rate ≥ 2% in Either Treatment Group | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
An adverse event (AE) was any untoward medical occurrence in a patient administered a pharmaceutical product which did not necessarily have a causal relationship with the treatment. An AE could have been any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Pre-existing events, which increased in frequency or severity or changed in nature during or as a consequence of use of the study medication were also considered as AEs. All AEs were assessed for severity using the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0. If a particular AE was not listed in the NCI CTCAE Version 3.0, the following criteria were used: Grade 3 = severe; Grade 4 = life threatening or disabling; Grade 5 = death.
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End point type |
Secondary
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End point timeframe |
From the first dose of study medication through the End-of-Treatment visit (30 ± 3 days from last dose of study drug).
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No statistical analyses for this end point |
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End point title |
PK Parameters of NKTR-102 or Irinotecan and Respective Metabolites | ||||||||||||
End point description |
Blood samples for PK analysis were collected from 4 patients only, 3 from the irinotecan treatment arm and 1 from the NKTR-102 treatment arm. NKTR-102, irinotecan, SN38, SN38-G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin, and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin concentration levels were determined. However, due to the limited number of patients with PK samples, no further PK analysis was conducted.
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End point type |
Secondary
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End point timeframe |
Days 1, 2, 3, 4, 8 and 15 of Cycles 1 and 3 and Day 1 of Cycles 2, 4 and all subsequent cycles.
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Notes [4] - Due to the limited number of patients with PK samples, no PK analysis was conducted. [5] - Due to the limited number of patients with PK samples, no PK analysis was conducted. |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events and serious adverse events were reported from the time the patient received the first dose of study drug through the End-of-Treatment Visit (i.e., 30 ± 3 days after the last dose of study drug).
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.0
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Reporting groups
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Reporting group title |
NKTR-102
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Irinotecan
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Mar 2009 |
“Locally advanced” was removed throughout.
Length of study period was increased.
Treatment with NKTR-102 & irinotecan was concluded at 12 months from randomization.
Exclusion of erythroid stimulating agents was removed.
Patients discontinuing due to toxicity were followed in quarterly follow-up visits.
Unnecessary duplication between the Investigator’s Brochure & protocol was removed.
Quarterly follow-up visits were added.
Patient eligibility criteria were modified to reflect criteria used for NKTR-102 Phase 1 study.
Patients & partners with child-bearing potential must use at least 2 forms of contraception for at least 8 months after last dose of NKTR-102.
Exclusion of patients receiving concomitant anti-cancer biologic therapy was added.
Exclusion of patients who previously treated with a camptothecin derivative or with past intolerance to excipients of irinotecan was added.
Patients should not have had any cancer within the last 5 years
Exclusion of patients with past history of bowel disorders considered at increased risk to toxicity related to irinotecan therapy was added.
Clarified patient withdrawal from study.
Screening window was increased from 14 to 28 days
Patients were required to provide a sample for UGT1A1 status.
Non-treatment study day visits were removed.
Repeated urinalyses were removed.
Dose modifications based upon non-hematologic & non-diarrhoea toxicities were added.
For study treatment delays, Sponsor/Investigator consideration was allowed for continuing therapy for delays beyond two weeks.
Storage & Accountability & Reconstitution & Handling of NKTR-102 text was updated.
In the anti-diarrheal therapy for toxicity management, “initiate” was changed to “recommend” anti-microbial therapy.
For patients with Grade 3 neutropenia, requirements that patients “must” have daily laboratories was changed to “recommended”.
Pharmacokinetic assessment & procedures were clarified.
Other administrative changes were made. |
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26 Mar 2009 |
Lowered the starting dose of NKTR-102 to 145 mg/m^2 from 170 mg/m^2 based on safety data from the Phase 1 study with NKTR-102.
Pregnancy test was added to end of study treatment visit as the risks of the study drug on the fetus are unknown. This assessment, which was in the original protocol, was removed in Amendment 1.0 in error. |
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18 Dec 2009 |
Nektar terminated the contract with PRA for services on the 08-PIR-03 study; as a result, the following changes are made to the administrative structure of study 08-PIR-03:
1. Nektar re-assigned all safety reporting responsibilities from PRA to Fulcrum Pharma Europe (Ltd).
2. Except as described in item 1, Nektar resumed primary responsibility for all remaining operational activities that had previously been delegated to PRA. To facilitate the change in scope, Nektar re-assigned medical monitoring and trial management activities.
3. The language identifying the analytical laboratory was corrected to better reflect the planned analysis of biological sample. |
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12 Apr 2010 |
Updated Study Drug Treatment Discontinuation Withdrawal from Study reasons.
Clarified that patients who withdrew for a reason other than disease progression, withdrawal of consent or death were followed for progression by serial radiographic imaging.
Clarified censoring rules for PFS and OS.
Clarified that (with adoption of RECIST version 1.1 in the protocol) confirmation of response was not required.
Radiographic imaging should have occurred at the end-of-treatment visit if these tests had not been performed within the prior 6 weeks.
Clarified acceptable methods of determining KRAS mutation status.
Slight modifications were made to inclusion/exclusion criteria.
GGT was removed for assessments for liver function tests; AST and ALT continued to be required.
The time frame in which patients had screening laboratory tests performed prior to study entry (up to 3 days) and the time frame from randomization to first study drug administration (up to 24 hours) were made more flexible.
Clarified dose modification guidelines in a setting of nausea / vomiting.
The time frame in which information regarding concomitant medications should be captured was clarified.
Added language defining adequate forms of birth control to the protocol and informed consent document.
Updated the pH of the formulation of NKTR-102 and the storage duration of reconstituted NKTR-102. Provided a window of ± 10 minutes for the 90-minute infusion time for NKTR-102 and irinotecan.
Section 10 (Adverse Event Reporting) was made consistent with the language in other Phase 2 NKTR-102 protocols.
Updated clinical and PK data (Sections 2.1.2.1, 2.1.2.2 and 2.1.2.3) were provided.
Section 12.3.4.1 (Evaluation of Target Lesions) was updated to remove any reference to “New Lesions”, as assessment of new lesions are discussed in the overall assessment of response.
Updated the Sponsor Medical Monitor information to reflect current team’s roles and responsibilities. |
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29 Jul 2011 |
Updated guidance on dose modifications & dose delays for dose-limiting toxicities, especially gastrointestinal & hematological toxicities, occuring following NKTR-102 or Irinotecan administration.
Updated anti-diarrheal therapy text to indicate that prophylactic antidiarrheal medications should not be used to treat diarrhea AEs.
Updated sponsor address and clinical contact.
Updated address and fax numbers for the sponsor’s pharmacovigilance designee.
Updated the date of the Camptosar® package insert to the most recent version.
Specified that radiographic imaging should be performed every 6 weeks (±5 days) until progressive disease, start of new therapy for cancer, or end of study participation.
Added to Inclusion Criteria that a patient was eligible if they had received prior fluoropyrimidine therapy in the neoadjuvant setting, clarifying the existing entry criterion.
Updated estimated overall duration of the study to be about 42 months.
Clarified that a local pathology laboratory may be used to determine KRAS mutation status, if approved by Nektar.
Updated that 10 tumor tissue slides were needed by the Central Pathology Laboratory for KRAS mutation status instead of 5 to 6.
Clarified that microscopic analysis of urine by the Central Laboratory was only needed if dipstick findings were abnormal.
Removed the option that an alternate randomization system provided by the sponsor may be used, since only an IVRS was used in this study.
Included a ± 2-day window for the duration of the 21-day treatment cycle.
Removed a limit of 12 months from date of randomization for patients to receive study treatment.
Corrected the acceptable methods of birth control for women to not include a male partner who has had a vasectomy.
Updated text describing 2 patients who experienced kidney failure after treatment with NKTR-102 to include a third patient to be consistent with the most recent Investigator’s Brochure. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |