A Phase 1, First-in-Human of KGX101 to Patients With Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is a first-in-human, multicenter, Phase 1, open-label, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary efficacy of KGX101, a tumor-activated interleukin 12 prodrug, as monotherapy in patients with advanced or metastatic solid tumors.

Detailed Description
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This study will enrol a maximum of 27 participants depending on the number of dose escalations needed. This study will assess the safety and tolerability of KGX101 monotherapy with a modified accelerated titration and a standard 3+3 dose escalation design to identify the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D). The total duration of modified accelerated titration period participation for each participant will be 70 days, including a 28-day screening, a 28-day DLT assessment and a 14-day washout. Dose escalation period, the total duration of participation for each participant will vary depending on events outcome. The participations will receive KGX101 intravenous infusion every 3 weeks at assigned escalating dose until disease progression or discontinuation criterion is met.

Official Title
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A Phase 1, First-in-Human, Multicenter, Open-Label, Dose Escalation Trial of KGX101 Administered as a Monotherapy to Patients With Advanced or Metastatic Solid Tumors

Conditions
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Advanced or Metastatic Solid Tumors

Intervention / Treatment
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* Drug: KGX101- Cohort 1
* Drug: KGX101- Cohort 2
* Drug: KGX101- Cohort 3
* Drug: KGX101- Cohort 4
* Drug: KGX101- Cohort 5
* Drug: KGX101- Cohort 6
* Drug: KGX101- Cohort 7
* Drug: KGX101- Cohort 8


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any histologically or cytologically confirmed solid tumor malignancy that is locally advanced or metastatic and has failed standard therapy, standard therapy does not confer survival benefit, or standard therapy is not available. Age at least 18 years. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 2. Has at least 1 measurable lesion per RECIST 1.1 (lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions). Has adequate organ and bone marrow function as per the study. Willingness of men and women of reproductive potential to observe highly effective birth control for the duration of treatment and for 3 months following the last dose of study drug. Archival tumor tissue available or provide a fresh tumor biopsy. Life expectancy of approximately 3 months or longer in the opinion of the Investigator. Provision of signed and dated written informed consent prior to any study-specific procedures, sampling, and analyses. Exclusion Criteria: A history of another active malignancy (i.e., a second cancer) within the previous 2 years, except for localized cancers that are not related to the current cancer being treated, are considered cured, and, in the opinion of the Investigator, present a low risk of recurrence. These exceptions include but are not limited to basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. Patients with primary CNS malignancies; A history of allogeneic tissue/solid organ transplant. Any evidence of severe or uncontrolled systemic diseases, including: Active, uncontrolled systemic bacterial, viral, or fungal infection; uncontrolled hypertension (Systolic blood pressure more than equal to 160mHG or diastolic blod pressure more than equal to 100mm HG or poor compliance with anti-hypertensive agents; or active bleeding diatheses; Clinically significant arrhythmia, unstable angina pectoris, congestive heart failure (class III or IV of New York Heart Association [NYHA]) or acute myocardial infarction within 6 months; Uncontrolled diabetes or poor compliance with hypoglycemic agents; The presence of chronically unhealed wound or ulcers; Other chronic diseases, which, in the opinion of the Investigator, could compromise safety of the patient or the integrity of study. Active autoimmune disease requiring systemic treatment in the past 2 years. Diagnosis of immunodeficiency, is on immunosuppressive therapy, or is receiving chronic systemic or enteric steroid therapy. A history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease. HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease. Active infection as determined by hepatitis B surface antigen and hepatitis B core antigen antibody, or hepatitis B virus DNA by quantitative polymerase chain reaction (qPCR) testing. Active infection as determined by hepatitis C virus (HCV) antibody or HCV RNA by qPCR testing. Major surgery (excluding placement of vascular access) within 4 weeks prior to the first dose of study drug. Treatment with any of the following: Prior treatment with IL-12 therapy (any form, e.g. recombinant human, prodrug, intratumoral, etc.); Presence of CNS metastases that are symptomatic and/or require local CNS directed therapy (such as XRT or surgery) or increasing doses of corticosteroids within 2 weeks prior to the first dose of study drug. Except patients with treated brain metastases should be neurologically stable and receiving less than equal to 10mg per day of prednisone or equivalent prior to study entry; Investigational agent or anticancer therapy (including chemotherapy, biologic therapy, immunotherapy, anticancer Chinese medicine, or anticancer herbal remedy) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug; Radiotherapy within 2 weeks of the start of study treatment. A 1-week washout is permitted for palliative radiation (less than equal to two weeks of radiotherapy) to non-CNS disease; Received a live or live-attenuated vaccine within 30 days of the first dose of study drug; Note: Administration of killed vaccines or other formats are allowed; Diagnosis of immunodeficiency, on immunosuppressive therapy, or receiving chronic systemic or enteric steroid therapy (dose > 10 mg/day of prednisone or equivalent); Prior receipt of an allogeneic stem cell transplant or allogeneic CAR-T cell therapy; Any unresolved toxicities from prior therapy greater than NCI CTCAE version 5.0 Grade 1 at the time of starting study drug with the exception of alopecia and Grade 2 prior platinum-therapy related neuropathy. Significant electrocardiogram (ECG) abnormalities. Any illness, medical condition, organ system dysfunction, or social situation (including mental illness or substance abuse), that may interfere with a patient's ability to sign the ICF, adversely affect the patient's ability to cooperate and participate in the study, or compromise interpretation of study results. Pregnant (confirmed by serum beta human chorionic gonadotropin [ HCG]) or lactating. History of hypersensitivity to any of the study drug components. Participant is known or suspected of not being able to comply with the study protocol (e.g. because of alcoholism, drug dependency, or psychological disorder) or the participant has any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participant (e.g. compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KGX101- Cohort 1<br>Dosage level: Dose level 1 Dose form: White-like lyophilized powder Route of administration: Intravenous | Drug: KGX101- Cohort 1<br>* Single dose of 0.003 mg/kg of KGX101 every 3 weeks<br>|
| Experimental: KGX101- Cohort 2<br>Dosage level: Dose level 2. Dose form: White-like lyophilized powder Route of administration: Intravenous | Drug: KGX101- Cohort 2<br>* Single dose of 0.006 mg/kg of KGX101 every 3 weeks<br>|
| Experimental: KGX101- Cohort 3<br>Dosage level: Dose level 3 Dose form: White-like lyophilized powder Route of administration: Intravenous | Drug: KGX101- Cohort 3<br>* Single dose of 0.012 mg/kg of KGX101 every 3 weeks<br>|
| Experimental: KGX101- Cohort 4<br>Dosage level: Dose level 4 Dose form: White-like lyophilized powder Route of administration: Intravenous | Drug: KGX101- Cohort 4<br>* Single dose of 0.025 mg/kg of KGX101 every 3 weeks<br>|
| Experimental: KGX101- Cohort 5<br>Dosage level: Dose level 5 Dose form: White-like lyophilized powder Route of administration: Intravenous | Drug: KGX101- Cohort 5<br>* Single dose of 0.05 mg/kg of KGX101 every 3 weeks<br>|
| Experimental: KGX101- Cohort 6<br>Dosage level: Dose level 6 Dose form: White-like lyophilized powder Route of administration: Intravenous | Drug: KGX101- Cohort 6<br>* Single dose of 0.1 mg/kg of KGX101 every 3 weeks<br>|
| Experimental: KGX101- Cohort 7<br>Dosage level: Dose level 7 Dose form: White-like lyophilized powder Route of administration: Intravenous | Drug: KGX101- Cohort 7<br>* Single dose of 0.2 mg/kg of KGX101 every 3 weeks<br>|
| Experimental: KGX101- Cohort 8<br>Dosage level: Dose level 8 Dose form: White-like lyophilized powder Route of administration: Intravenous | Drug: KGX101- Cohort 8<br>* Single dose of 0.3 mg/kg of KGX101 every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Treatment emergent Adverse events (TEAEs) | TEAE will be collected to assess participants' safety after KGX101 treatment. | From baseline to 30 days after the last dose administration. | 
| Number of participants with Dose Limiting Toxicities (DLTs) at week 4 | DLT within 4 weeks after KGX101 will be collected to assess participants' safety after KGX101 treatment. | From Day1 after the first dose of KGX101 full treatment to D28 post dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameters: Maximum Concentration (Cmax) K Parameters: Maximum Concentration (Cmax) PK Parameters: Maximum Concentration (Cmax) | The PK schedule after the 1st and 4th injection of KGX101 are as follows: pre-dose, 0 h, 2, 6, 24, 48, 72, 168 and 336hr post dose. | Dose escalation- From pre-dose of the first dose of KGX101 full treatment to 336 hours after the first and 4th dose of full treatment. | 
| PK Parameters: Time of maximum observed concentration (Tmax) | The PK schedule after the 1st and 4th injection of KGX101 are as follows: pre-dose, 0 h, 2, 6, 24, 48, 72, 168 and 336hr post dose. | Dose escalation- From pre-dose of the first dose of KGX101 full treatment to 336 hours after the first dose of full treatment. In addtion, pre-dose of other KGX101 treatment will be also collected. | 
| PK Parameters: Area under the curve (AUC) | The PK schedule after the 1st and 4th injection of KGX101 are as follows: pre-dose, 0 h, 2, 6, 24, 48, 72, 168 and 336hr post dose. | Dose escalation- From pre-dose of the first dose of KGX101 full treatment to 336 hours after the first dose of full treatment. In addtion, pre-dose of other KGX101 treatment will be also collected. | 
| PK Parameters: Half- life (T1 /2) | The PK schedule after the 1st and 4th injection of KGX101 are as follows: pre-dose, 0 h, 2, 6, 24, 48, 72, 168 and 336hr post dose. | Dose escalation- From pre-dose of the first dose of KGX101 full treatment to 336 hours after the first dose of full treatment. In addtion, pre-dose of other KGX101 treatment will be also collected. | 
| PK Parameters- Trough concentration (Ctrough) | Pre-dose of each KGX101 treatment will be collected to monitor the Ctrough. | Dose escalation- From pre-dose of the first dose of KGX101 full treatment to 336 hours after the first dose of full treatment. In addtion, pre-dose of other KGX101 treatment will be also collected. | 
| PK Parameters- Systemic clearance (CL) | The PK schedule after the 1st and 4th injection of KGX101 are as follows: pre-dose, 0 h, 2, 6, 24, 48, 72, 168 and 336hr post dose. | Dose escalation- From pre-dose of the first dose of KGX101 full treatment to 336 hours after the first dose of full treatment. In addtion, pre-dose of other KGX101 treatment will be also collected. | 
| Immunogenicity- Anti-drug antibody (ADA) | Samples will be collected to assess the immunogeniccity after KGX101 treatment. | Cohort 1-2: Day1 pre-dose and Day22 pre-dose; Cohort 3-8: Pre-dose of every dose, Day 15 post the first full treatment of KGX101 dose and Day 14 post the last dose. |