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All Drugs and Chemicals

Irinotecan

Etirinotecan pegol

Topoisomerase I Inhibitors

Enzyme Inhibitors

NKTR-102

irinotecan

Study Director

This study will evaluate whether NKTR-102, an investigational drug has an anti-tumor effect in patients with colorectal cancer. This study will also evaluate how the safety and anti-tumor activity of NKTR-102 compares with irinotecan, a cancer drug that is approved for use in the US for treatment of patients with certain types of colorectal cancer.

NKTR-102 (Topoisomerase I Inhibitor Polymer Conjugate) is a polyethylene glycol (PEG) conjugate of irinotecan. 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.

Second-line therapy for colorectal cancer typically involves cetuximab and irinotecan. However, growing evidence indicates that cetuximab (or other EGFR inhibitors) is not appropriate therapy for patients with mutant KRAS. For these patients, irinotecan may be appropriate as a single agent, and a new therapy that could improve upon efficacy and safety would provide an important option for the treatment of advanced colorectal cancer.

NKTR-102 Versus Irinotecan in Patients With Second-Line, Irinotecan-Naïve, KRAS Mutant, Colorectal Cancer

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-Naive, KRAS-Mutant, Metastatic Colorectal Cancer (mCRC)

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 randomized patients who underwent baseline evaluation, with treatment assigned according to randomized 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.

Duration of OS was defined as the time from the date of randomization 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 randomization were censored at the date of randomization.

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.

Progressive Disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that was the smallest on study); in addition to a relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. CR is defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters

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 unfavorable 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.

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.

Nektar Therapeutics

IV every 3 weeks

irinotecan: IV every 3 weeks

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Approximately 174 patients (87 patients per treatment arm) were originally planned to complete the trial. The study was terminated before completing accrual due to evolving standards of care with combination regimens that made recruitment to a Phase 2 study with single agent treatment difficult. Results of the 83 randomized patients (NKTR-102, n=42; irinotecan, n=41) were analyzed.

Kaplan-Meier Estimate of PFS by Central Radiological Review: ITT Population

Kaplan-Meier Estimate of OS: ITT Population

ORR by Central Radiological Review: ITT Population

DoR by Central Radiological Review: ITT Population

Percentage of participants with ≥1 TEAE

Percentage of participants with Diarrhea

Percentage of participants with Neutropenia

Percentage of participants with Abdominal Pain

Percentage of participants with Dehydration

Percentage of participants with Vomiting

Percentage of participants with Nausea

Percentage of participants with Hypokalemia

Percentage of participants with Fatigue

Percentage of participants with Intestinal Obstruction

Percentage of participants with Leukopenia

Percentage of participants with Febrile Neutropenia

Percentage of participants with Alopecia

Percentage of participants with Disease Progression

Percentage of participants with Hyponatremia

Percentage of participants with Acute Prerenal Failure

Percentage of participants with Asthenia

Percentage of participants with Hyperbilirubinemia

Percentage of participants with Performance Status Decreased

Percentage of participants with Sepsis

Percentage of Participants (≥2%) With Treatment-Emergent Adverse Events NCI-CTCAE Grade 3 or Higher

There are no data available for this outcome, due to the very small number of PK samples that were collected from these patients.

PK Parameters of NKTR-102 or Irinotecan and Respective Metabolites

NKTR-102 was administered as an intravenous (IV) infusion on Day 1 of each 21-day cycle at a dose level of 145 mg/m\^2.

Irinotecan was administered as an IV infusion on Day 1 of a 21-day 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.

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
NKTR-102 Versus Irinotecan in Patients With Second-Line, Irinotecan-Naïve, KRAS Mutant, Colorectal Cancer	NCT00856375	Colorectal Canc...	NKTR-102 irinotecan	18 Years -	Nektar Therapeutics
NKTR-102 Versus Irinotecan in Patients With Second-Line, Irinotecan-Naïve, KRAS Mutant, Colorectal Cancer	NCT00856375	Colorectal Canc...	NKTR-102 irinotecan	18 Years -	Nektar Therapeutics
NKTR-102 Versus Irinotecan in Patients With Second-Line, Irinotecan-Naïve, KRAS Mutant, Colorectal Cancer	NCT00856375	Colorectal Canc...	NKTR-102 irinotecan	18 Years -	Nektar Therapeutics

Spots Global Cancer Trial Database for colorectal cancer, second line