Study of NK012 in Patients With Refractory Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to determine whether NK012 is safe and effective in the treatment of refractory solid tumors

Detailed Description
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This is a Phase I dose-escalation study of the intravenous administration of NK012 in patients with refractory solid tumors. Patients will receive NK012 as an intravenous infusion over 30 minutes on Day 1 followed by a 20-day observation period for a total of 21 days (3 weeks) per cycle. Two patient populations will be evaluated separately: patients with UGT1A1*28 genotype homozygous wild type (wt/wt) and heterozygous (wt/*28) variants as one group, and patients with UGT1A1*28 homozygous variant (*28/*28) as another group.

Official Title
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A Phase I Dose-escalation Study of NK012 Administered Intravenously as a Single Dose Every Three Weeks in Patients With Refractory Solid Tumors

Conditions
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Cancer

Intervention / Treatment
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* Drug: NK012


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed malignant solid tumor for which there are no known regimens or protocol treatments of higher efficacy or priority Failed conventional therapy for the cancer or have a malignancy for which a conventional therapy does not exist Recovered from all acute adverse effects of prior therapies, excluding alopecia (hair loss) Life expectancy of at least 12 weeks and an EOCG performance status of 0 or 1 18 years of age or older Adequate kidney, liver, and bone marrow function Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or have not recovered from adverse effects due to agents administered more than 4 weeks earlier Receiving any other investigational agent History of brain metastases or spinal cord compression, unless irradiated a minimum of 4 weeks before study entry and stable without requirement for corticosteroids for > 1 week History of allergic reactions attributed to compounds of similar chemical composition to NK012 Concurrent serious infections (i.e., requiring an intravenous antibiotic) Pregnant women or women of childbearing potential who are not using methods to avoid pregnancy; a negative pregnancy test (urine or serum) must be documented at baseline and before every NK012 administration for women of childbearing potential; no breast-feeding while on study Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris or psychiatric illness/social situations that would limit compliance with study requirements Significant cardiac disease History of serious ventricular arrhythmia Positive for anti-HbsAg, anti-HCV, anti-HIV, or anti-syphilis antibodies

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NK012<br>This is a Phase I dose-escalation study of the intravenous administration of NK012 in patients with refractory solid tumors. Patients will receive NK012 as an intravenous infusion over 30 minutes on Day 1 followed by a 20-day observation period for a total of 21 days (3 weeks) per cycle. Two patient populations will be evaluated separately: patients with UGT1A1*28 genotype homozygous wild type (wt/wt) and heterozygous (wt/*28) variants as one group, and patients with UGT1A1*28 homozygous variant (*28/*28) as another group. Dose-escalation in each patient population will proceed according to the predefined dose level. For UGT1A1*28 (wt/wt and wt/*28) patients, at least 3 evaluable patients will be treated at each dose level. UGT1A1 homozygous (*28/*28) patients will be treated at 50% of the current dose level. Patients will receive up to 6 cycles of NK012, unless they experience unacceptable toxicity or disease progression, requiring withdrawal from the study. | Drug: NK012<br>* 9.0, 12.0, 16.0, 21.0, 28.0 mg/m^2, and to be determined. Intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity of NK012 in patients with UGT1A1*28 (wt/wt and wt/*28) genotype |  | At the end of Cycle 1 (each cycle is 21 days) | 
| Maximum tolerated dose of NK012 in patients with UGT1A1*28 (wt/wt and wt/*28) genotype |  | At the end of Cycle 1 (each cycle is 21 days) | 
| Recommended phase II dose of NK012 in patients with UGT1A1*28 (wt/wt and wt/*28) genotype | After MTD was determined, the administration schedule was changed to every 28 days per cycle, considering patient safety. | At the end of Cycle 1 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity profile of NK012 in all patients |  | Through study completion (6 cycles of study drug administration period and 30 days of follow-up period), an average of 5 months for 21-day cycle or 6 months for 28-days cycle. | 
| Antitumor activity of NK012 according to RECIST criteria in all patients | Overall response will be evaluated every 2 cycles | Through study completion (6 cycles of study drug administration period and 30 days of follow-up period), an average of 5 months for 21-day cycle or 6 months for 28-days cycle. | 
| Pharmacokinetic parameter: Maximum concentration (Cmax) |  | Sampling during Cycle 1 (first 3 weeks) and up to Day 3 of Cycle 2, if applicable, total 24 days for 21-days cycle or 31 days for 28-day cycle. | 
| Pharmacokinetic parameter: Time to reach the maximum concentration (Tmax) |  | Sampling during Cycle 1 (first 3 weeks) and up to Day 3 of Cycle 2, if applicable, total 24 days for 21-days cycle or 31 days for 28-day cycle. | 
| Pharmacokinetic parameter: Terminal-phase half life (T1/2z) |  | Sampling during Cycle 1 (first 3 weeks) and up to Day 3 of Cycle 2, if applicable, total 24 days for 21-days cycle or 31 days for 28-day cycle. | 
| Pharmacokinetic parameter: Area under the concentration-time curve for time zero to infinity (AUCinf) |  | Sampling during Cycle 1 (first 3 weeks) and up to Day 3 of Cycle 2, if applicable, total 24 days for 21-days cycle or 31 days for 28-day cycle. | 
| Pharmacokinetic parameter: Total body clearance (CLtot) |  | Sampling during Cycle 1 (first 3 weeks) and up to Day 3 of Cycle 2, if applicable, total 24 days for 21-days cycle or 31 days for 28-day cycle. | 
| Pharmacokinetic parameter: Volume of distribution at steady-state (Vss) |  | Sampling during Cycle 1 (first 3 weeks) and up to Day 3 of Cycle 2, if applicable, total 24 days for 21-days cycle or 31 days for 28-day cycle. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Refractory solid tumor