Study of Safety and Efficacy of DKY709 Alone or in Combination With PDR001 in Patients With Advanced Solid Tumors.

Study Overview
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Brief Summary
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This is a phase I/Ib, open label study. The escalation portion will characterize the safety and tolerability of DKY709 and DKY709 in combination with PDR001 in subjects with NSCLC or melanoma who have received prior anti-PD-1/PD-L1 therapy, or subjects with NPC. After the determination of the MTD/RD for a particular treatment arm, dose expansion will further assess safety, tolerability, PK/PD, and anti-tumor activity of each regimen at the MTD/RD.

Official Title
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A Phase I/Ib, Open-label, Multi-center, Study of DKY709 as a Single Agent and in Combination With PDR001 in Patients With Advanced Solid Tumors

Conditions
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Melanoma, Nasopharyngeal Carcinoma, Carcinoma, Non-Small-Cell Lung, Microsatellite Stable Colorectal Cancer, Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: DKY709
* Drug: PDR001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Patients must be ≥18 years of age at the time of informed consent form (ICF) signature. Patients with advanced/metastatic cancer who have progressed despite having received standard therapy in the metastatic setting or are intolerant to standard therapy, and for whom no effective standard therapy is available In expansion: patient with measurable disease as determined by RECIST version 1.1, Dose escalation, patients must fit into one of the following groups: NSCLC, previously treated with an anti-PD-1/PD-L1 therapy Cutaneous Melanoma, previously treated with an anti-PD-1/PD-L1 therapy NPC Dose expansion part, patients must fit into one of the following groups: NSCLC with historic documentation of PD-L1 ≥ 1%. Patients must have progressive disease after having experienced at least 4 months of investigator-assessed disease stability or response on prior anti-PD-L1-containing therapy Cutaneous Melanoma, previously treated with anit-PD-1/PD-L1 therapy. Patients should have documented progression following anti-PD-1/PD-L1 therapy. NPC, naive to anti-PD-1/PD-L1 therapy mssCRC, naive to anti-PD-1/PD-L1 therapy TNBC, naive to anti-PD-1/PD-L1 therapy ECOG Performance Status ≤ 1 Patients must have a site of disease amenable to core needle biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy at baseline, and during therapy on the study. Exceptions may be considered after documented discussion with Novartis. Exclusion Criteria: Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids within 2 weeks prior to study entry. Patients with treated brain metastases should be neurologically stable for at least 4 weeks prior to study entry and off steroids for at least 2 weeks before administration of any study treatment. History of severe hypersensitivity reactions to any ingredient of study drug(s) or other mAbs and/or their excipients. Patient with out of range laboratory values defined as: Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 40 mL/min Total bilirubin > 1.5 x ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN Alanine aminotransferase (ALT) > 3 x ULN, except for patients that have tumor involvement of the liver, who are excluded if ALT > 5 x ULN Aspartate aminotransferase (AST) > 3 x ULN, except for patients that have tumor involvement of the liver, who are excluded if AST > 5 x ULN Absolute neutrophil count (ANC) < 1.0 x 109/L Platelet count < 75 x 109/L (growth factor or transfusion support may not be used to meet entry criterion) Hemoglobin (Hgb) < 8 g/dL (growth factor or transfusion support may not be used to meet entry criterion) Magnesium, calcium or phosphate abnormality CTCAE > grade 1 Potassium abnormality CTCAE ≥ grade 1; supplementation to meet eligibility criteria is acceptable Clinically significant cardiac disease or impaired cardiac function, including any of the following: Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA grade ≥ 2), uncontrolled hypertension or clinically significant arrhythmia On screening: QTcF > 450 msec (male), or > 460 msec (female) QTc not assessable Congenital long QT syndrome History of familial long QT syndrome or known family history of as Torsades de Pointes Acute myocardial infarction or unstable angina pectoris < 3 months prior to study entry

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: DKY709<br>DKY709 monotherapy | Drug: DKY709<br>* Novel immunomodulatory agent<br>|
| Experimental: DKY709 + PDR001<br>Combination therapy with DKY709 and PDR001 | Drug: DKY709<br>* Novel immunomodulatory agent<br>Drug: PDR001<br>* PDR001 is a high-affinity, ligand-blocking, humanized IgG4 monoclonal antibody directed against PD-1 that blocks the binding of PD-L1 and PD-L2<br>* Other names: Spartalizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of DKY709 single agent treatment or DKY709 in combination with PDR001. | Incidence and severity of AEs and SAEs | 24 months | 
| incidence of Dose Limiting Toxicities (DLTs) | The incidence of DLTs during the first cycle of treatment with single agent DKY709 or the combination of DKY709 with PDR001. | 1 Month | 
| Tolerability of DKY709 single agent treatment or DKY709 in combination with PDR001. | Incidence and severity of AEs and SAEs | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC of DKY709 and PDR001 | AUC | 24 months | 
| Cmax of DKY709 and PDR001 | Cmax | 24 months | 
| Tmax of DKY709 and PDR001 | Tmax | 24 months | 
| Half-life of DKY709 and PDR001 | Half-life | 24 months | 
| Progression Free Survival (PFS) | Determine PFS in each part of the study | 24 months | 
| Best Overall Response (BOR) | Determine BOR in each part of the study | 24 months | 
| Duration of Response (DOR) | Determine DOR in each part of the study | 24 months | 
| Time to Progression (TTP) | Determine TTP in each part of the study | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small Cell Lung Cancer, Melanoma, Nasopharyngeal Carcinoma, Microsatellite Stable Colorectal Cancer, Triple Negative Breast Cancer