Clinical Trials/NCT04713891

NCT04713891

Unknown

Phase 1

A Phase I, Multi-Center, Open-Label Study to Evaluate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity of KF-0210 in Patients With Advanced Solid Tumors

Keythera Pharmaceuticals (Australia) Pty Ltd1 site in 1 country64 target enrollmentMarch 9, 2021

Overview

Phase: Phase 1
Intervention: KF-0210 tablets, 120 mg
Conditions: Advanced Solid Tumor
Sponsor: Keythera Pharmaceuticals (Australia) Pty Ltd
Enrollment: 64
Locations: 1
Primary Endpoint: Maximum tolerated dose (MTD) of KF-0210 alone [Tolerability]
Last Updated: 4 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The purpose of this Phase I, Multi-Center, Open-Label Study is to evaluate the safety, tolerability, Pharmacokinetics, Pharmacodynamics and anti-tumor activity of KF-0210 in participants with advanced solid tumors. The study will be conducted in two parts: phase Ia, and phase Ib.

Detailed Description

Phase 1a: The primary objective of the phase 1a part of the study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamic and anti-tumor activity of oral KF-0210 as a single agent in participants with advanced solid tumors, to identify the dose-limiting toxicity and establish the maximum tolerated dose, or maximum administered dose and/or the recommended Phase II dose of KF-0210 in participants with advanced solid tumors. Phase 1b: The primary objective of the phase 1b part of the study is to assess the safety, pharmacokinetics, pharmacodynamic and anti-tumor activity of KF-0210 in combination with Atezolizumab in patients with colorectal cancer (CRC) (MSS), lung cancer (LC), squamous cell carcinoma of the esophagus (SCCE), gastric cancer (GC), and bladder cancer (BC).

Registry

clinicaltrials.gov

Start Date

March 9, 2021

End Date

December 31, 2022

Last Updated

4 years ago

Study Type

Interventional

Study Design

Sequential

Sex

All

Investigators

Sponsor

Keythera Pharmaceuticals (Australia) Pty Ltd

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Age ≥ 18 years old, male and female;
•Patients are confirmed by available pathology records or current biopsy having advanced, nonresectable, or recurrent and progressing solid tumors since last anti-tumor therapy, and who are unavailable or intolerable for available standard therapy or there is no standard available therapy.
•Phase Ia (Dose Escalation): Advanced solid tumors;
•Phase Ib (Expansion Study): Patients must have any of the following tumor type and have not participated in Phase Ia trial of this study: CRC (MSS), LC, SCCE, GC, and BC. Among them, patients with LC, SCCE, or GC must have undergone PD-1/PD-L1 treatment for at least 12 weeks and failed.
•Must have at least 1 measurable lesion, according RECIST V1.1 criteria (CT-scans or MRI no longer than 4 weeks before signing ICF);
•Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
•Life expectancy≥ 3 months;
•Females must not be lactating or pregnant at screening or baseline (negative pregnant test).

Exclusion Criteria

•Patients with prior anti-tumor therapy within 4 weeks prior to first dosing of KF-0210, including chemotherapy, biotherapy, endocrine therapy and immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer);
•Patients with prior definitive radiation therapy within 6 weeks prior to first dosing of KF-0210, and the irradiated lesions showed no signs of progression if it to be considered target lesions. Or patients with prior palliative radiotherapy within 2 weeks prior to first dosing of KF-
•Or the radiotherapy-related side effects have unresolved before the study entry. Or use of radiopharmaceuticals (strontium, samarium) within 8 weeks prior to first dosing of KF-0210;
•Patients who have another active malignancy which is likely to require treatment;
•Patients who have known active central nervous system (CNS) metastases and/or carcinomatous meningitis;
•Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months prior to the first dose of KF-0210; or cardiac arrhythmia requiring medical treatment (including oral anticoagulation);
•Patients with any active autoimmune disease or a documented history of autoimmune disease, poorly controlled asthma or history of syndrome that required systemic steroids or immunosuppressive medications, except for patients with vitiligo or resolved childhood asthma/atopy. Patients with asthma who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study;
•Patients with inflammatory bowel disease or digestive tract diseases (e.g. peptic ulcer disease, including stomach and duodenal ulcer, gastritis and enteritis);
•Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the bioavailability of KF-0210;
•Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids except inhaled or intranasal corticosteroids (with minimal systemic absorption);

Arms & Interventions

Phase 1a: Cohort 1

KF-0210 tablet will be administered at 120 mg as a single agent orally once daily (QD) continuously in cycles (1 cycle=21 days) until the disease progression, intolerance, or informed consent withdrawal.

Intervention: KF-0210 tablets, 120 mg

Phase 1a: Cohort 2

KF-0210 tablet will be administered at 240 mg as a single agent orally once daily (QD) continuously in cycles (1 cycle=21 days) until the disease progression, intolerance, or informed consent withdrawal.

Intervention: KF-0210 tablets, 240 mg

Phase 1a: Cohort 3

KF-0210 tablet will be administered at 450 mg as a single agent orally once daily (QD) continuously in cycles (1 cycle=21 days) until the disease progression, intolerance, or informed consent withdrawal.

Intervention: KF-0210 tablets, 450 mg

Phase 1a: Cohort 4

KF-0210 tablet will be administered at 600 mg as a single agent orally once daily (QD) continuously in cycles (1 cycle=21 days) until the disease progression, intolerance, or informed consent withdrawal.

Intervention: KF-0210 tablets, 600 mg

Phase Ib, Cohort 1

KF-0210 (dose RP2D-2, orally once daily)+ Atezolizumab (1200 mg every 3 weeks) continuously until disease progression/recurrence or death from any cause, or serious adverse events (SAE) observed (whichever occurs earlier) for up to 2 years.

Intervention: KF-0210 (dosage RP2D-2) + Atezolizumab

Phase Ib, Cohort 2

KF-0210 (dose RP2D-1, orally once daily)+ Atezolizumab (1200 mg every 3 weeks) continuously until disease progression/recurrence or death from any cause, or serious adverse events (SAE) observed (whichever occurs earlier) for up to 2 years.

Intervention: KF-0210 (dosage RP2D-1) + Atezolizumab

Phase Ib, Cohort 3

KF-0210 (dose RP2D, orally once daily)+ Atezolizumab (1200 mg every 3 weeks) continuously until disease progression/recurrence or death from any cause, or serious adverse events (SAE) observed (whichever occurs earlier) for up to 2 years.

Intervention: KF-0210 (dosage RP2D) + Atezolizumab

Outcomes

Primary Outcomes

Maximum tolerated dose (MTD) of KF-0210 alone [Tolerability]

Time Frame: Up to 21 days after first administration in cycle 1, each cycle is 21 days

The Maximum tolerated dose (MTD) is defined as the highest dose at which ≤1、6 participants occurred dose limiting toxicity at each dose level.

Change of Pulse rate from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

Pulse rate measured per minute

Change of Diastolic pressure from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

Blood pressure measured in mmHg

Change of Creatinine from Baseline [Safety]

Time Frame: On date of screening (within 7 days before the first dose), Day 8, Day15, Day 21 of cycle 1 (each cycle is 21 days), Day 1 of each cycle from the cycle 2, and at the end of treatment/withdrawal (up to approximately 1 year)

Creatinine measured in mg/dL

Change of Total bilirubin from Baseline [Safety]

Total bilirubin measured in mg/dL

Change of Glutamyl transpeptidase from Baseline [Safety]

Glutamyl transpeptidase measured in U/L

Percentage of patient with adverse events / serious adverse events (AEs/SAEs) [Safety and Tolerability]

Time Frame: From consent through 28 days (±7 days) after the last dose or before starting other anti-tumor treatment (whichever occurs earlier)(up to approximately 1 year))

Adverse events will be assessed according to CTCAE V5.0, and be coded according to the MedDRA Dictionary

Change of Body Weight from Baseline [Safety]

Time Frame: On date of screening (within 7 days before the first dose), Day 1 of each cycle (each cycle is 21 days), and at the end of treatment/withdrawal (up to approximately 1 year)

Body Weight measured in kilogram (kg)

Change of Body Temperature from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

Axillary temperature measured in celsius

Change of Systolic pressure from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

Blood pressure measured in mmHg

Change of R-R interval from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

R-R interval measured in millisecond through 12-lead ECG assessment

Change of P-R interval from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

P-R interval measured in millisecond through 12-lead ECG assessment

Change of Total Protein (TP) from Baseline [Safety]

Total Protein (TP) measured in g/dL

Dose limiting toxicity (DLT) of KF-0210 [Tolerability]

Time Frame: From Cycle 1 Day 1 to Cycle 1 Day 21, each cycle is 21 days.

Dose limiting toxicity (DLT) will be considered to be related to KF-0210 according to CTCAE V5.0 including hematology toxicities, non-hematological toxicities and any other toxicities.

Change of Heart rate from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

Heart rate in beats per minute (Bpm) through 12-lead ECG assessment

Chang of QT interval from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

QT interval measured in millisecond through 12-lead ECG assessment

Change of Albumin (ALB) from Baseline [Safety]

Albumin(ALB) measured in g/dL

Change of Alkaline phosphatase (ALP/AKP) from Baseline [Safety]

Alkaline phosphatase (ALP/AKP) measured in IU/L

Change of Urea from Baseline [Safety]

Urea measured in mg/dL

Change of Creatinine Kinase from Baseline [Safety]

Creatinine Kinase measured in IU/L

Change of Leukocyte Count from Baseline [Safety]

Leukocyte Count measured in K/uL

Change of Basophil Count from Baseline [Safety]

Basophil Count measured in K/uL

Change of Percentage of Basophil from Baseline [Safety]

Percentage of Basophil will be measured

Change of QRS complex from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

QRS complex measured in millisecond through 12-lead ECG assessment

Change of corrected QT (QTc) interval from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

corrected QT (QTc) interval measured in millisecond through 12-lead ECG assessment

Change of Fridericia's Correction QT (QTcF) interval from Baseline [Safety]

Time Frame: From screening to the end of treatment/withdrawal (up to approximately 1 year)

Fridericia's Correction QT (QTcF) interval measured in millisecond through 12-lead ECG assessment.

Change of Total Cholesterol from Baseline [Safety]

Total Cholesterol measured in mmol/L

Change of Triglycerides from Baseline [Safety]

Triglycerides measured in mmol/L

Change of Lymphocyte Count from Baseline [Safety]

Lymphocyte Count measured in K/uL

Change of Monocytes Count from Baseline [Safety]

Monocytes Count measured in K/uL

Change of Percentage of Eosinophils from Baseline [Safety]

Percentage of Eosinophils will be measured

Change of Eastern Cooperative Oncology Group-Performance Status (ECOG PS) from Baseline [Safety]

Time Frame: On date of screening (within 7 days before the first dose), Day 1 of each cycle (each cycle is 21 days), and at the end of treatment/withdrawal (up to approximately 1 year)

The performance status will be evaluated in accordance with the Eastern Cooperative Oncology Group (ECOG) criteria with the score range in 0 to 5. A score of 0 represents fully normal activity and a score of 5 represents death.

Change of Alanine aminotransferase (ALT) from Baseline [Safety]

Alanine aminotransferase (ALT) measured in IU/L

Change of Aspartate aminotransferase (AST) from Baseline [Safety]

Aspartate aminotransferase (AST) measured in IU/L

Change of Direct bilirubin from Baseline [Safety]

Direct bilirubin measured in mg/dL

Change of Indirect bilirubin from Baseline [Safety]

Indirect bilirubin measured in mg/dL

Change of Blood glucose from Baseline [Safety]

Blood glucose measured in mg/dL

Change of Uric acid from Baseline [Safety]

Uric acid measured in mg/dL

Change of Neutrophil Count from Baseline [Safety]

Neutrophil Count in K/uL

Change of Percentage of Neutrophil from Baseline [Safety]

Percentage of Neutrophil will be measured

Change of Percentage of Monocytes from Baseline [Safety]

Percentage of Monocytes will be measured

Change of Eosinophils Count from Baseline [Safety]

Eosinophils Count measured in K/uL

Change of Coagulation test-Prothrombin time (PT) from Baseline [Safety]

Prothrombin time (PT) measured in seconds

Change of Potassium, Sodium, Chloride or Calcium from Baseline [Safety]

Potassium, Sodium, Chloride or Calcium measured in mmol/dL

Change of Percentage of Lymphocyte from Baseline [Safety]

Percentage of Lymphocyte will be measured

Change in Urine Bilirubin result from Baseline [Safety]

Urine bilirubin will be measure in µmol/L

Change in Urine Glucose from Baseline [Safety]

Urine Glucose will be measured in mg/dL

Change in Ketones from Baseline [Safety]

Ketones will be measured in mg/dL

Change in Urine Nitrites from Baseline [Safety]

Urobilinogen will be measured in mg/dL

Change of Erythrocyte Count from Baseline [Safety]

Erythrocyte Count measured in K/uL

Change of Hemoglobin from Baseline [Safety]

Hemoglobin measured in mg/dL

Change of Hematocrit Platelets from Baseline [Safety]

Hematocrit Platelets measured in K/uL

Change of Coagulation test-Activated partial thromboplastin time (APTT) from Baseline [Safety]

Activated partial thromboplastin time (APTT) measured in seconds

Change in Occult blood result from Baseline [Safety]

The result will be recorded as either positive or negative

Change in Urine protein from Baseline [Safety]

Urine protein will be measured in mg/dL

Change of Coagulation test-Fibrinogen(FIB) from Baseline [Safety]

Fibrinogen(FIB) measured in mmol/L

Change of Coagulation test-Thrombin time (TT) from Baseline [Safety]

Thrombin time (TT) measured in seconds

Change of Urine pH from Baseline [Safety]

pH value will be measured

Change of Specific gravity of urine from Baseline [Safety]

Specific gravity value will be measured

Change in Urobilinogen from Baseline [Safety]

Urobilinogen will be measured in EU/dL

Change in Urinary leukocyte from Baseline [Safety]

Urinary leukocyte will be counted in K/uL

Change in Urine erythrocytes from Baseline [Safety]

Urine erythrocytes will be counted in K/uL

Clinically significant abnormality in physical examinations

Time Frame: On date of screening (within 7 days before the first dose), Day 1 of each cycle (each cycle is 21 days), and at the end of treatment/withdrawal (up to approximately 1 year)

Physical examination includes skin, head, eyes, ears, nose and throat, lymph nodes, heart, chest, abdomen and extremities, and nervous system (speech, cranial nerves, motor ability, tendon reflexes, sensations, free movement)

Secondary Outcomes

Area under the plasma concentration-time curve from time-zero extrapolated to infinite time (AUC0-inf)(Phase I a: specific time points from Cycle 1 Day 1 to Cycle 1 Day 8; Phase 1b: specific time points from Cycle 1 Day 1 to Cycle 4 Day 15. Each cycle is 21 days.)
Accumulation ratio (Rac)(Phase I a: specific time points from Cycle 1 Day 1 to Cycle 1 Day 8; Phase 1b: specific time points from Cycle 1 Day 1 to Cycle 4 Day 15. Each cycle is 21 days.)
Blood cytokines/chemokines levels(Up to 21 days after first administration in cycle 1, each cycle is 21 days.)
Terminal half-life (T1/2) of KF-0210(Phase I a: specific time points from Cycle 1 Day 1 to Cycle 1 Day 8; Phase 1b: specific time points from Cycle 1 Day 1 to Cycle 4 Day 15. Each cycle is 21 days.)
Change in tumor size from baseline(From screening through the last dose of treatment, each cycle is 21 days.)
Disease control rate (DCR)(From screening through the last dose of treatment, each cycle is 21 days.)
Maximum observed plasma concentration (Cmax)(Phase I a: specific time points from Cycle 1 Day 1 to Cycle 1 Day 8; Phase 1b: specific time points from Cycle 1 Day 1 to Cycle 4 Day 5, each cycle is 21 days.)
Urine prostaglandin metabolites level(Up to 21 days after first administration in cycle 1, each cycle is 21 days.)
Tumor T cell infiltration(Up to 21 days after first administration in cycle 1, each cycle is 21 days.)
Time of maximum plasma concentration (Tmax)(Phase I a: specific time points from Cycle 1 Day 1 to Cycle 1 Day 8; Phase 1b: specific time points from Cycle 1 Day 1 to Cycle 4 Day 15. Each cycle is 21 days.)
Area under the plasma concentration-time curve from time-zero to the time of the last measurable concentration (AUC0-t) of KF-0210(Phase I a: specific time points from Cycle 1 Day 1 to Cycle 1 Day 8; Phase 1b: specific time points from Cycle 1 Day 1 to Cycle 4 Day 15. Each cycle is 21 days.)
Cmin to Cmax fluctuation between dose time and Tau (DF)(Phase I a: specific time points from Cycle 1 Day 1 to Cycle 1 Day 8; Phase 1b: specific time points from Cycle 1 Day 1 to Cycle 4 Day 15. Each cycle is 21 days.)
Objective response rate (ORR)(From screening through the last dose of treatment, each cycle is 21 days.)
Duration of response (DOR) (days)(From screening through the last dose of treatment, each cycle is 21 days.)
Progression free survival (PFS)(From screening through the last dose of treatment, each cycle is 21 days.)