A Study of JK08, an IL-15 Antibody Fusion Protein Targeting CTLA-4, in Patients With Unresectable Locally Advanced or Metastatic Cancer

Study Overview
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Brief Summary
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This is a Phase 1/2, open-label, multi-center, first-in-human, dose escalation and cohort expansion study evaluating multiple doses and schedules of subcutaneously administered JK08 in patients with unresectable locally, advanced or metastatic cancer.

Detailed Description
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This Phase 1/2, open label, dose escalation and cohort expansion study is designed to evaluate and characterize the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-tumor activity of JK08 administered subcutaneously in patients with unresectable locally, advanced or metastatic cancer. The study consists of a Dose Escalation phase to determine the maximum tolerated dose/recommended phase 2 dose of JK08, followed by a Cohort Expansion phase to further define the safety and initial efficacy of JK08 in three tumor specific cohorts (melanoma, colorectal cancer, and breast cancer) and a basket cohort of mixed solid tumors.

Official Title
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A Phase 1/2, Multicenter, Open Label, Dose Escalation & Dose Expansion Study of JK08, an IL-15 Antibody Fusion Protein Targeting CTLA-4, in Patients With Unresectable Locally Advanced or Metastatic Cancer

Conditions
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Cancer, Tumor, Solid, Advanced Solid Tumor, Metastatic Cancer, Melanoma, Colorectal Cancer, Breast Cancer

Intervention / Treatment
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* Drug: JK08


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old. Signed informed consent and willing and able to comply with study procedures and scheduled visits. For Dose Escalation, patients with one of the following histologically diagnosed unresectable, locally advanced, or metastatic tumor types: Non-small cell lung cancer (NSCLC). Small cell lung cancer (SCLC). Melanoma. Clear cell or papillary renal cell carcinoma (RCC). Urothelial cancer (UC). Head and neck squamous cell cancer (HNSCC). Luminal B (ER+, PR-, any HER2 status) or triple-negative breast cancer. Gastric or gastro esophageal adenocarcinoma (GC/GEJ). Esophageal squamous cell cancer. Skin squamous cell carcinoma (SCC). Pancreatic adenocarcinoma. Hepatocellular carcinoma (Childs-Pugh A or B7 only). Colorectal adenocarcinoma (CRC). Epithelial ovarian cancer. Cervical cancer. Endometrial adenocarcinoma. Thyroid cancer (follicular or papillary). For the escalation cohorts, patients must have experienced progressive disease on or be intolerant to an established standard systemic anti-cancer therapy for a given tumor type or have been intolerant to such therapy, or in the opinion of the Investigator have been considered ineligible for a particular form of standard therapy on medical grounds. Patients must have no available proven curative or life prolonging therapies. For Cohort Expansion, four tumor specific cohorts of the following tumor types: Melanoma Cohort: histologically confirmed diagnosis of advanced and/or metastatic cutaneous melanoma in which radiological progression has been demonstrated during therapy with a PD-(L)1 immune CPI and for which no existing options are considered to provide clinical benefit (only one line of PD-(L)1 therapy is permitted). Progression on ipilimumab is not required. BRAF V600 mutation patients must have progressed on, or are intolerant to, BRAF +/- MEK inhibitor therapy. Patients with BRAF V600-positive tumor(s) should have received prior treatment with a BRAF inhibitor (alone or in combination with a MEK inhibitor) in addition to treatment with pembrolizumab or nivolumab with or without ipilimumab or to have declined targeted therapy. NOTE: Patients with BRAF V600-positive tumors with no clinically significant tumor-related symptoms or evidence of rapidly progressive disease are not required to be treated with a BRAF inhibitor (alone or in combination with a MEK inhibitor) based on investigator's decision. Colorectal Cohort: histologically confirmed diagnosis of advanced and/or metastatic colorectal adenocarcinoma. Patients must have had recurrence, progression or intolerance to standard therapy consisting of at least 2 prior standard regimens (containing a fluoropyrimidine plus a platinum analogue and/or irinotecan) for metastatic disease. Patients who are inappropriate candidates for or have refused treatment with these regimens are also eligible. Patients should have received no more than 4 prior regimens. Luminal B or Triple-Negative Breast Cancer: histologically confirmed diagnosis of advanced and/or metastatic luminal B or triple-negative breast cancer. Patient must have had recurrence, progression or intolerance to standard therapy for metastatic disease consisting of at least 2 prior regimens, but no more than 3 standard chemotherapy regimens. Hormonal treatment regimens without concomitant non-hormonal therapy will not be counted as lines of therapy. Basket Cohort: patients with histologically diagnosed unresectable, locally advanced, or metastatic tumor types eligible in Dose Escalation not listed in tumor specific expansion cohorts. Patients must have experienced progressive disease on an established standard systemic anti-cancer therapy for a given tumor type or have been intolerant to such therapy, or in the opinion of the Investigator have been considered ineligible for a particular form of standard therapy on medical grounds. Patients must have no available proven curative or life prolonging therapies. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Life expectancy ≥12 weeks. Measurable disease as per RECIST 1.1 criteria and documented by CT and/or MRI. Note: lesions treated previously with radiation must demonstrate clear evidence of radiographic progression since the completion of prior radiotherapy and prior to study enrollment. Acceptable laboratory parameters: Albumin ≥ 2.8 g/dL. Platelet count ≥ 75,000. Hemoglobin ≥ 8.0 g/dL. Absolute neutrophil count ≥ 1,500/µL. ALT/AST ≤ 3.0 times ULN. ALT/AST ≤ 5 × ULN for patients with liver metastases. Total bilirubin ≤ 1.5 ULN or ≤ 3 x ULN for patients with Gilbert's disease. Direct bilirubin ≤ ULN for patients with total bilirubin > 1.5 ULN. Creatinine ≤ 1.8 mg/dL. Or calculated/measured creatinine clearance > 30 mL/minute. Identification of an archival tumor sample (i.e., tissue block (formalin-fixed paraffin-embedded [FFPE]) or a series of approximately 10-15 slides). Consent to pre- and on- treatment fresh tumor biopsy for all patients enrolled as back fill in Dose Escalation or for at least 6 additional patients per expansion cohort in Cohort Expansion in Simon Stage 2. Women of childbearing potential (WOCBP) not surgically sterilized and between menarche and 1 year post menopause must: Have a negative serum or urine pregnancy test performed within 72 hours prior to the initiation of study drug administration. Be willing to use 2 forms of effective contraception throughout the study, starting with the screening and through 90 days after the last dose of JK08. Abstinence is considered a highly effective method if this is the established and preferred contraception method for the patient and is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female and male condoms should not be used together. Male patients with partners of childbearing potential, even if surgically sterilized (i.e., status post-vasectomy) must agree to: Use effective barrier contraception from the time of consent through 90 days after discontinuation; or Agree to practice true abstinence, if this is the established and preferred contraception method by the patient and is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. Periodic abstinence [e.g., calendar, symptothermal, post-ovulation methods], withdrawal, spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female and male condoms should not be used together. In addition, male patients should also have their partners use contraception for the same period of time. Central nervous system (CNS) metastases must have been treated, be asymptomatic for ≥14 days, and meet the following at the time of enrollment: No concurrent treatment for CNS disease (e.g., surgery, radiation, corticosteroids ≥ 10 mg prednisone/day or equivalent). No concurrent or past history of leptomeningeal disease or cord compression. Must be willing and able to comply with clinic visits and procedures outlined in the study protocol. Concurrent use of hormones for breast cancer or for non cancer related conditions (e.g., insulin for diabetes, hormone replacement therapy) is acceptable. Bisphosphonates or RANK-L inhibitor or analogues are permitted for supportive care of patients with bone metastases. Exclusion Criteria: Patients with symptomatic or unstable CNS primary tumor or metastases and/or carcinomatous meningitis. Patients with documented treated CNS metastases stable for at least 4 weeks may be enrolled at the discretion of the investigator. Patients with active, or history of, severe autoimmune disease who in the opinion of the investigator and/or the Sponsor or Sponsor's designee would be exposed to unacceptable risk by participating in the study. Major surgery within 6 weeks from treatment initiation. Clinically significant cardiovascular/vascular disease ≤ 6 months before first dose: Myocardial infarction or unstable angina. Clinically significant cardiac arrhythmias. Uncontrolled hypertension: systolic blood pressure (SBP) > 180 mmHg, diastolic blood pressure (DBP) > 100 mmHg. Pulmonary embolism, symptomatic cerebrovascular events or any other serious cardiac condition (e.g., pericardial effusion or restrictive cardiomyopathy). QTcF prolongation > 480 msec. Congestive heart failure (New York Heart Association class III-IV). Myocarditis/clinically significant pericarditis. Clinically significant gastrointestinal disorders including: Gastrointestinal perforation or unhealed ulcerations < 6 months prior to study drug administration. Patients must have documented evidence (e.g., upper endoscopy, colonoscopy) of completely healed area of prior perforation. Clinically significant gastrointestinal bleeding < 3 months prior to study drug administration. Pancreatitis < 6 months prior to study drug administration. History of Crohn's disease or ulcerative colitis. Clinically significant pulmonary compromise requiring supplemental oxygen use. History of Grade 3 or greater drug-related immune-mediated AE during treatment with CPIs such as anti-PD-(L)1 or anti-CTLA-4 antibodies. Vaccination with any live virus vaccine within 4 weeks prior to the initiation of study drug administration. Inactivated annual influenza vaccination is allowed. At least 2 doses of COVID-19 vaccination must have been completed prior to enrollment (see Section 8.2 for further details). Known hypersensitivity to JK08 or any excipient (histidine/histidine-HCl, sucrose, glycine, PS-80). Second primary invasive malignancy not in remission for ≥ 1 year. Exceptions include non melanoma skin cancer, cervical carcinoma in situ, resected melanoma in situ, or any malignancy considered to be indolent and never required therapy. Any serious underlying medical or psychiatric condition that would preclude understanding and rendering of informed consent or impair the ability of the patient to receive or tolerate the planned treatment. Recent or ongoing serious infection including the following: Any uncontrolled Grade 3 or higher (per CTCAE v5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of JK08. Routine antimicrobial prophylaxis is allowed. Uncontrolled infection with human immunodeficiency virus (HIV). Patients on stable highly active antiretroviral therapy (HAART) therapy with undetectable viral load and normal CD4 counts for at least 6 months prior to study entry are eligible. Serological testing for HIV at screening is not required. Known to be positive for hepatitis B (HBV) surface antigen, or any other positive test for hepatitis B indicating acute or chronic infection. Patients who are or have received anti-HBV therapy and have undetectable HBV DNA for at least 6 months prior to study entry are eligible. Serological testing for hepatitis B at screening is not required. Known active hepatitis C (HCV) as determined by positive serology and confirmed by polymerase chain reaction (PCR). Patients on or having received antiviral therapy are eligible provided they are virus-free by PCR for at least 6 months prior to study entry. Serological testing for hepatitis C at screening is not required. Known active or latent tuberculosis (testing at screening not required). Use of systemic corticosteroids within 15 days or other immunosuppressive drugs within 30 days prior to start of the study, with the exception of corticosteroids as replacement therapy up to an equivalent of prednisone 10 mg/day which is allowed. Inhaled, topical, or intraarticular steroids are allowed. Prior systemic anti-cancer treatment as follows: For cytotoxic chemotherapy, small molecule inhibitors, radiation, or similar investigational treatments, ≤ 2 weeks or 5 half lives, whichever is shorter. For monoclonal antibodies or similar experimental therapies: ≤ 3 weeks or 5 half-lives, whichever is shorter. Antibody drug conjugates and radioimmunoconjugates or other similar experimental therapies ≤ 6 weeks or 5 half-lives, whichever is shorter. Ascites or pleural effusions requiring large volume para- or pleurocentesis within 4 weeks of treatment initiation. Pregnant or nursing. Therapeutic anticoagulation for a thromboembolic event that occurred within 3 months of dosing; prophylactic anticoagulation is permitted.

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: Dose Escalation<br>Escalating repeated doses of JK08 administered as a subcutaneous injection. A cycle of treatment is defined as 21 days, in which three doses of JK08 will be planned for administration. | Drug: JK08<br>* Recombinant fusion protein consisting of two functional elements, which are a fully human monoclonal antibody, directed against CTLA-4 and a protein complex formed by the human IL-15 and the Sushi domain of human IL-15Rα.<br>|
| Experimental: Dose Expansion - Melanoma Cohort<br>JK08 administered at the maximum-tolerated dose/recommended Phase 2 dose as a subcutaneous injection in patients with melanoma. | Drug: JK08<br>* Recombinant fusion protein consisting of two functional elements, which are a fully human monoclonal antibody, directed against CTLA-4 and a protein complex formed by the human IL-15 and the Sushi domain of human IL-15Rα.<br>|
| Experimental: Dose Expansion - Colorectal Cancer Cohort<br>JK08 administered at the maximum-tolerated dose/recommended Phase 2 dose as a subcutaneous injection in patients with colorectal cancer. | Drug: JK08<br>* Recombinant fusion protein consisting of two functional elements, which are a fully human monoclonal antibody, directed against CTLA-4 and a protein complex formed by the human IL-15 and the Sushi domain of human IL-15Rα.<br>|
| Experimental: Dose Expansion - Breast Cancer Cohort<br>JK08 administered at the maximum-tolerated dose/recommended Phase 2 dose as a subcutaneous injection in patients with breast cancer. | Drug: JK08<br>* Recombinant fusion protein consisting of two functional elements, which are a fully human monoclonal antibody, directed against CTLA-4 and a protein complex formed by the human IL-15 and the Sushi domain of human IL-15Rα.<br>|
| Experimental: Dose Expansion - Mixed Solid Tumors Cohort<br>JK08 administered at the maximum-tolerated dose/recommended Phase 2 dose as a subcutaneous injection in patients with a mix of solid tumors. | Drug: JK08<br>* Recombinant fusion protein consisting of two functional elements, which are a fully human monoclonal antibody, directed against CTLA-4 and a protein complex formed by the human IL-15 and the Sushi domain of human IL-15Rα.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicity (DLT) | The incidence of DLTs during the DLT assessment period. | First 21 days of treatment. | 
| Dose-Finding | Determination of the maximum-tolerated dose/recommended Phase 2 dose. | Screening to 90 days from last dose. | 
| Safety and Tolerability | Incidence, nature, and severity of treatment-emergent adverse events [TEAEs]. Defined as any AE that occurs during the treatment period (i.e., after any treatment) and up to 28 days after the last dose of study treatment. | First treatment through 28 days after last dose of treatment or End of Treatment [EOT] visit, whichever is later. | 
| Safety and Tolerability | Incidence, nature, and severity of Serious Adverse Events [SAEs]. | Screening date through 30 days after last dose of treatment or End of Treatment [EOT] visit, whichever is later. | 
| Safety and Tolerability | Incidence, nature, and severity of adverse events [AEs]. | Screening date through 30 days after last dose of treatment or End of Treatment [EOT] visit, whichever is later. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of JK08 | Maximum Plasma Concentration (Cmax) | Day 1 of dosing through 21 days post last dose. | 
| Pharmacokinetics of JK08 | Area Under the Curve (AUC) | Day 1 of dosing through 21 days post last dose. | 
| Objective Response Rate (ORR) | ORR according to RECIST v1.1. | Day 1 of dosing through every 90 after the last dose. | 
| Disease Control Rate (DCR) | The percentage of patients with a complete response, partial response, or stable disease for at least 2 consecutive tumor assessments. | ay 1 of dosing through every 90 after the last dose. | 
| Progression Free Survival (PFS) | Time from the date of initiation of study therapy to the date measurement criteria are first met for progressive disease or death from any cause, whichever occurs first. | Day 1 of dosing through every 90 after the last dose. | 
| Overall Survival (OS) | Time from the date of initiation of study therapy to the date of death from any cause. | Day 1 of dosing through every 90 after the last dose. |