A Study of Safety and Efficacy of KFA115 Alone and KFA115 in Combination With Tislelizumab in Patients With Select Advanced Cancers

Study Overview
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Brief Summary
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The purpose of this study is to characterize the safety and tolerability of KFA115 and KFA115 in combination with tislelizumab in patients with select advanced cancers, and to identify the maximum tolerated dose and/or recommended dose.

Detailed Description
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This is a phase I, open-label, multi-center study of KFA115 as a single agent and in combination with tislelizumab. The study consists of a dose escalation part, followed by dose expansion part(s) for single-agent KFA115 and KFA115 in combination with tislelizumab. The escalation parts will characterize safety and tolerability. After the determination of the maximum tolerated dose (MTD) / recommended dose (RD), the dose expansion parts will assess the preliminary anti-tumor activity in defined patient populations and further assess the safety and tolerability at MTD/RD.

Official Title
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A Phase I, Open-label, Multi-center Study of KFA115 as a Single Agent and in Combination With Tislelizumab in Patients With Select Advanced Cancers

Conditions
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Carcinoma, Non-Small-Cell Lung, Cutaneous Melanoma, Carcinoma, Renal Cell, Carcinoma, Ovarian Epithelial, Nasopharyngeal Carcinoma, Carcinoma, Thymic, Anal Cancer, Mesothelioma, Esophagogastric Cancer, High Microsatellite Instability Colorectal Carcinoma, Squamous Cell Carcinoma of Head and Neck

Intervention / Treatment
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* Drug: KFA115
* Drug: tislelizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-small cell lung cancer with historic PD-L1 ≥ 1%, as determined locally using a clinically accepted assay. Patients must have experienced benefit from previous anti-PD(L)1-containing therapy for at least 4 months based on investigator-assessed disease stability or response prior to developing documented disease progression. Patients must have also received prior platinum-based chemotherapy, either in combination or in sequence with anti-PD-(L)1, unless patient was ineligible to receive such treatment. Renal cell carcinoma, clear cell histology, previously treated with anti-PD(L)1-containing therapy and a VEGF targeted therapy as monotherapy or in combination. Patients should have documented disease progression following anti-PD(L)1-containing therapy. Cutaneous melanoma, previously treated with anti-PD(L)1-containing therapy. Patients should have documented disease progression following anti-PD(L)1-containing therapy. Patients with BRAF V600-mutant melanoma must have also received prior therapy with a BRAF V600 inhibitor, with or without a MEK inhibitor. Ovarian cancer, high-grade serous histology, naive to anti-PD(L)1 therapy, and must have received one prior systemic therapy in platinum-resistant setting. Nasopharyngeal carcinoma, non-keratinizing locally advanced recurrent or metastatic, naive to anti-PD(L)1 therapy. Locally advanced unresectable or metastatic anal cancer (squamous), thymic carcinoma, MSI-H CRC, esophagogastric cancer, mesothelioma, and HNSCC, all naive to anti-PD(L)1 therapy and for whom anti-PD(L)1 therapy is not available. Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening, and during therapy on the study, if medically feasible. Exceptions may be considered after documented discussion with Novartis. Patients with archival tumor tissue obtained ≤ 6 months prior to study treatment initiation do not need to undergo a new tumor biopsy at screening, if the patient has not received any anti-cancer therapy since the biopsy was taken, and if adequate tissue is available. Patients must have body weight > 36 kg. Exclusion Criteria: Impaired cardiac function or clinically significant cardiac disease. Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of study. History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients. Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur may be considered. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded. Any evidence of interstitial lung disease (ILD) or pneumonitis, or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids. Patients who discontinued prior anti-PD-(L)1 therapy due to an anti-PD-(L)1-related toxicity (applicable to the KFA115 in combination with tislelizumab treatment arms). Patients with symptomatic peripheral neuropathy limiting instrumental activities of daily living. Other protocol-defined inclusion/exclusion criteria may apply

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single-agent KFA115<br>KFA115 monotherapy | Drug: KFA115<br>* Immunomodulatory agent<br>* Other names: NVP-KFA115;|
| Experimental: KFA115 run-in (1 cycle) + tislelizumab<br>1-cycle KFA115 run-in followed by addition of tislelizumab | Drug: KFA115<br>* Immunomodulatory agent<br>* Other names: NVP-KFA115;Drug: tislelizumab<br>* Anti-PD-1 antibody<br>* Other names: BGB-A317;|
| Experimental: KFA115 + tislelizumab<br>KFA115 + tislelizumab combination given concurrently | Drug: KFA115<br>* Immunomodulatory agent<br>* Other names: NVP-KFA115;Drug: tislelizumab<br>* Anti-PD-1 antibody<br>* Other names: BGB-A317;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of dose limiting toxicities (DLTs) during the DLT evaluation period of single-agent KFA115 (dose escalation only) | A DLT is defined as an adverse event or abnormal laboratory value that occurs during the DLT evaluation period where the relationship to study treatment cannot be ruled out, and is not primarily related to disease, disease progression, intercurrent illness, or concomitant medications and meets the criteria defined in the study protocol | 28 days | 
| Incidence and severity of dose limiting toxicities (DLTs) during the DLT evaluation period of KFA115 in combination with tislelizumab (dose escalation only) | A DLT is defined as an adverse event or abnormal laboratory value that occurs during the DLT evaluation period where the relationship to study treatment cannot be ruled out, and is not primarily related to disease, disease progression, intercurrent illness, or concomitant medications and meets the criteria defined in the study protocol | 56 days | 
| Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) | Incidence and severity of adverse events and serious adverse events, including changes in laboratory values, vital signs, and electrocardiograms qualifying and reported as AEs | 35 months | 
| Frequency of dose interruptions, reductions | Number of dose interruptions of KFA115 and tislelizumab, and number of dose reductions of KFA115 | 35 months | 
| Dose intensity | Dose intensity of KFA115 and tislelizumab is defined as the ratio of actual cumulative dose received and actual duration of exposure | 35 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response (BOR) per RECIST v1.1 | BOR is defined as the best response recorded from the start of the treatment until disease progression/recurrence | 35 months | 
| Progression free survival (PFS) per RECIST v1.1 | PFS is defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause | 35 months | 
| Duration of response (DOR) per RECIST v1.1 | DOR is defined as the time from the date of the first documented response (CR or PR) to the date of the first documented progression as per RECIST v1.1 or death due to underlying cancer | 35 months | 
| Time to progression (TTP) per RECIST v1.1 | TTP is defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to underlying cancer | 35 months | 
| Area under the concentration time curve (AUC) of KFA115 or tislelizumab | Area under the concentration time curve | During the first 168 days of treatment for single-agent KFA115 and 35 months for KFA115 in combination with tislelizumab | 
| Peak plasma or serum concentration (Cmax) of KFA115 or tislelizumab | The maximum (peak) observed plasma or serum drug concentration after single dose administration | During the first 168 days of treatment for single-agent KFA115 and 35 months for KFA115 in combination with tislelizumab | 
| Minimum plasma or serum concentration (Cmin) of KFA115 or tislelizumab | The minimum observed plasma or serum drug concentration reached during the time interval between two dose administrations | During the first 168 days of treatment for single-agent KFA115 and 35 months for KFA115 in combination with tislelizumab | 
| Time to reach peak plasma or serum concentration (Tmax) of KFA115 or tislelizumab | The time to reach maximum (peak) plasma or serum drug concentration after single dose administration | During the first 168 days of treatment for single-agent KFA115 and 35 months for KFA115 in combination with tislelizumab | 
| Elimination half-life (T1/2) of KFA115 or tislelizumab | The elimination half-life associated with the terminal slope of a semi logarithmic concentration-time curve | During the first 168 days of treatment for single-agent KFA115 and 35 months for KFA115 in combination with tislelizumab | 
| The number of participants with anti-drug antibodies (ADA) | Immunogenicity of tislelizumab when dosed in combination with KFA115 | 35 months for KFA115 in combination with tislelizumab | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung cancer, Non-small cell lung cancer, NSCLC, Malignant Skin Cancer, Skin Cancer, Cutaneous melanoma, Renal cell carcinoma, RCC, Kidney cancer, Renal cancer, Clear cell carcinoma, Cancer of the ovaries, Female reproductive cancer, Ovarian carcinoma, Epithelial ovarian cancer, Nasopharyngeal Neoplasms, NPC, Thymic carcinoma, Thymic tumor, Rectal cancer, Rectal neoplasms, Esophageal cancer, Cancer of throat, Colon cancer, Colorectal cancer, Bowel cancer, Cancer of the colon and rectum, High microsatellite instability colorectal carcinoma, CRC, MSI-H CRC, Advanced solid malignancies, Head and neck cancer, HNSCC, SCCHN, Squamous cell carcinoma of the head and neck, Cancer, Advanced cancer, NVP-KFA115