Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of KN510, KN713

An Open-label, Dose-escalation and Dose-finding, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of KN510, KN713 as Combination Therapy in Patients With Advanced Solid Tumors

To evaluate the safety and tolerability of the combination therapy of KN510 and KN713 and determine the MTD and RP2D in patients with advanced solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: KN510 60mg/day + KN713 60mg/day; Drug: KN510 120mg/day + KN713 60mg/day; Drug: KN510 120mg/day + KN713 90mg/day; Drug: KN510 120mg/day + KN713 120mg/day

Detailed Description

It is expected that KN510 and KN713 will broaden the range of target patient groups and overcome resistance to the drugs in an innovative manner by targeting the common metabolic process of cancer cells, unlike existing targeted therapies whose application is limited depending on the presence of specific mutation and combination of mutations as they mainly target a single tyrosine kinase.

In this study, the safety and tolerability of combination therapy of KN510 and KN713, including the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), will be evaluated in patients with advance solid tumors and based on this, the recommended phase 2 dose (RP2D) will be determined.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Joon Hee Kang, Ph.D.; Phone Number: +8231-920-2227; Email: wnsl2820@gmail.com

Study Locations

• Korea, Republic of
  • Goyang-si, Korea, Republic of
    • Recruiting
    • National Cancer Center
    • Contact: Sang Myung Woo, PI; Phone Number: 031-920-0743; Email: 73324@ncc.re.kr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and female adults aged 19-75 years
2. Unresectable advanced or metastatic solid tumors that are confirmed as progressive disease (PD) after the standard of care currently known to have clinical benefits, or for which no currently available standard therapies exist due to intolerance, ineligibility, rejection, etc.
3. At least one measurable lesion per RECIST ver1.1
4. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1
5. Life expectancy of at least 12 weeks

6. Confirmed adequate hematologic, renal, and hepatic functions according to the following criteria (Laboratory tests may be repeated once during the screening period):

   A. Hematological function

   • Absolute neutrophil count (ANC) ≥1,500/μL
   • Hemoglobin ≥9 g/dL
   • Platelet count ≥100,000/μL

   B. Renal function: Creatinine clearance (CrCl*) >60 mL/min

   *Cockcroft-Gault equation

   C. Hepatic function

   • Aspartate aminotransferase (AST) ≤3.0 × ULN
   • Alanine aminotransferase (ALT) ≤3.0 × ULN (AST/ALT ≤5 × ULN, if hepatic metastasis is confirmed)
   • Total bilirubin ≤1.5 × ULN (with the exception of confirmed Gilbert's syndrome)

   D. Coagulation function: Prothrombin time international normalized ratio (PT INR) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN

7. Voluntary written consent to participate in this study

Exclusion Criteria:

1. Hypersensitivity to the active ingredient or excipients of KN510 or KN713

2. Any of the following medical (surgical) history or comorbidities at the screening visit:

   A. Major surgery that requires general anesthesia or a respiratory assist device within 4 weeks prior to screening (within 2 weeks for video-assisted thoracoscopic surgery [VATS] or open-and-closed [ONC] surgery)

   B. Clinically significant arrhythmia, acute myocardial infarction, unstable angina, or NYHA Grade Ⅲ or Ⅳ heart failure within 24 weeks prior to screening

   C. Pulmonary thrombosis, deep vein thrombosis, or bronchial asthma, obstructive pulmonary disease or other life-threatening severe lung disorder (e.g., acute respiratory distress syndrome, lung failure) considered ineligible for participation in the study within 24 weeks prior to screening

   D. Grade 3 or higher active infectious conditions which require systemic antibiotics, antivirals, etc. within 2 weeks prior to screening

   E. Clinically significantly symptomatic or uncontrolled central nervous system or brain metastases at screening (except for patients who have discontinued systemic corticosteroid treatment at least 4 weeks prior to baseline and have been stable for at least 4 weeks)

   F. Hematologic malignancy including lymphoma at screening

   G. Uncontrolled hypertension (systolic blood pressure [SBP]/diastolic blood pressure [DBP] ≥160/100 mmHg) at screening

   H. Parkinson's disease, parkinsonian symptoms, tremors, restless leg syndrome, and other related movement disorders at screening

   I. Active hepatitis B* or C† at screening

   * Defined as HBsAg positive at screening; patients on stable antiviral regimen may participate

   † Defined as HCV Ab positive at screening; patients who test negative for HCV RNA may participate

   J. Known human immunodeficiency virus (HIV) infection

   K. Difficulty (e.g., problem swallowing) in oral administration of KN510 and KN713 or disease (celiac disease, Crohn's disease, or intestinal resection which is clinically significant or impacts absorption) which impacts absorption at screening

   L. History or suspected symptoms of gastroesophageal reflux disease (GERD) such as gastric ulcer, duodenal ulcer, and reflux esophagitis at screening

   M. History of autoimmune diseases at screening

   N. Deemed ineligible for the study for having a comorbidity that is uncontrolled or requires treatment

3. Prior treatment with any of the following medications within 2 weeks prior to screening

   A. Proton pump inhibitors (PPIs) other than the IP

   B. Strong CYP2C19 inducers: Rifampicin, Apalutamide, Rifamycin, Rifaximin, Rifapentine

   C. Strong CYP2C19 inhibitors: Fluvoxamine, Ticlopidine, Chloramphenicol, Delavirdine, Gemfibrozil, Stiripentol, Fluoxetine, Imipramine, Clomipramine, Lansoprazole, Isoniazid, Zafirlukast, Tioconazole, Miconazole

   D. CYP2C19 substrates: Clopidogrel, Citalopram, Cilostazol, Phenytoin, Diazepam

   E. Vitamin K antagonists: Warfarin, Dicoumarol, Phenindione, Phenprocoumon, Acenocoumarol, Ethyl biscoumacetate, Fluindione, Clorindione, Diphenadione, Tioclomarol

   F. Antiretrovirals: Rilpivirine-containing products, Atazanavir, Nelfinavir, Saquinavir

   G. High dose Methotrexate (≥1000 mg/m2)

   H. Digoxin

   I. Cefditoren, Cefuroxime

   J. Levoketoconazole

   K. St John's Wort

   L. Bromopride, Metoclopramide

   M. Other anti-cancer therapies (chemotherapy, radiotherapy, immunotherapy, targeted therapy, hormone therapy, etc. other than the IP) which could impact the efficacy results during the study (However, local radiotherapy to alleviate ostalgia, bronchial obstruction, skin lesion, etc. are permitted. The total irradiation dose must be within the site-specific reference range for palliative therapy, and irradiation sites must be excluded from the tumor assessment.)

   N. Requiring continued treatment with systemic corticosteroids at a dose of prednisone >10 mg/day or equivalent (with exceptions of topical use such as intra-articular, intranasal, intraocular, and inhalational administration and temporary use for treatment and prevention of allergic reactions to a contrast agent or AEs [e.g., vomiting])

4. Pregnant or lactating women, or women of childbearing potential and men who are unwilling to remain abstinent or use adequate methods of contraception* during the study and for 3 months after IP administration

   * Adequate methods of contraception:

   • Hormonal contraceptives
   • Placement of an intrauterine device or intrauterine system
   • Surgical sterilization (vasectomy, tubal ligation, etc.)
5. Received/Used another investigational agent/device within 4 weeks (or 5 half-lives) prior to screening
6. Ineligibility or inability to participate in the study in the judgment of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 1	Drug: KN510 60mg/day + KN713 60mg/day; Once daily with 28 days (4 weeks) as one cycle.
Experimental: Dose Level 2	Drug: KN510 120mg/day + KN713 60mg/day; Once daily with 28 days (4 weeks) as one cycle.
Experimental: Dose Level 3	Drug: KN510 120mg/day + KN713 90mg/day; Once daily with 28 days (4 weeks) as one cycle.
Experimental: Dose Level 4	Drug: KN510 120mg/day + KN713 120mg/day; Once daily with 28 days (4 weeks) as one cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DLT(dose limiting toxicity)	DLTs will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0, and defined as CTCAE Grade ≥3 ADR(Adverse Drug Reaction)s.	Until 28 days from the first IP administration
AEs(Adverse Events)	Any clinically significant medical condition or abnormality observed after IP administration will be collected as an AE.	Through study completion, an average of 5 months
Laboratory tests	For collected laboratory test results, changes between before and after IP administration and/or changes in normality/abnormality will be assessed.	Through study completion, an average of 5 months
Vital signs	For collected vital signs results, changes between before and after IP administration and/or changes in normality/abnormality will be assessed.	Through study completion, an average of 5 months
ECG(Electrocardiogram)	ECG results will be assessed and recorded as normal or abnormal, and any clinically significant changes will be recorded as AEs in the CRF.	Through study completion, an average of 5 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUClast	AUClast of KN510 and KN713	Day 1: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
AUCinf	AUCinf of KN510 and KN713	Day 1: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
Cmax	Cmax of KN510 and KN713	Day 1: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
Tmax	Tmax of KN510 and KN713	Day 1: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
CL/F	CL/F of KN510 and KN713	Day 1: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
Vd/F	Vd/F of KN510 and KN713	Day 1: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
t1/2	t1/2 of KN510 and KN713	Day 1: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
AUCtau,ss	AUCtau,ss of KN510 and KN713	Day 22: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
Cmax,ss	Cmax,ss of KN510 and KN713	Day 22: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
Cmin,ss	Cmin,ss of KN510 and KN713	Day 22: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
Cav,ss	Cav,ss of KN510 and KN713	Day 22: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
peak-trough fluctuation (PTF)	peak-trough fluctuation (PTF) of KN510 and KN713	Day 22: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
Tmax,ss	Tmax,ss of KN510 and KN713	Day 22: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
CLss/F	CLss/F of KN510 and KN713	Day 22: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
Vd,ss/F	Vd,ss/F of KN510 and KN713	Day 22: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
t1/2,ss	t1/2,ss of KN510 and KN713	Day 22: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
accumulation ratio	accumulation ratio of KN510 and KN713	Day 22: 0(pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post-dose
Objective response rate (ORR)*	Proportion of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) *ORR = CR + PR	Through study completion, an average of 5 months
Disease control rate (DCR)**	Proportion of subjects with BOR of CR, PR or stable disease (SD) **DCR = CR + PR + SD	Through study completion, an average of 5 months
Exploratory Efficacy Endpoints [DOR]	Time from initial assessment of confirmed CR or PR to initial assessment of confirmed PD	6 and 12 months
Progression free survival (PFS)	Time from the start of IP treatment to PD per RECIST v1.1 or death from any cause, whichever occurs first	6 and 12 months
Overall survival (OS)	Time from the start of IP treatment to death from any cause	6 and 12 months
Target tumor size	Maximum percentage change in the sum of longest diameters of target lesions	Through study completion, an average of 5 months

Collaborators and Investigators

• Sponsor: New Cancer Cure-Bio Co.,Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2023
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: August 4, 2023
• First Submitted That Met QC Criteria: August 22, 2023
• First Posted (Actual): August 25, 2023

Study Record Updates

• Last Update Posted (Estimated): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 29, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Advanced solid tumors
• Other Study ID Numbers: NCCKN-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No