Ph2 Study NKT2152 With Palbociclib & Sasanlimab in Subjects With Advanced Clear Cell Renal Cell Carcinoma (ccRcc)

Study Overview
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Brief Summary
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The goal of the Lead-in phase of the study is to evaluate the safety, efficacy, pharmacokinetics (PK) and determine recommended dose for expansion (RDE) of NKT2152 in combination with palbociclib (Doublet) and with palbociclib and sasanlimab (Triplet) in subjects with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who received prior therapy. The goal of the Expansion phase of the study is to evaluate the safety, efficacy, PK at the selected RDE and identify the RP2D for NKT2152 in combination with palbociclib (Doublet) and with palbociclib and sasanlimab (Triplet) in subjects with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who received prior therapy.

Detailed Description
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This is a Phase 2 open-label, multicenter, global study of NKT2152. This study is designed as two phases: a Lead-in phase and an Expansion phase. Patients must be 18 years or older, with advanced or metastatic clear cell renal cell carcinoma (ccRCC). Eligible patients must have progressed or relapsed after at least 1 prior anti-vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) systemic therapy and 1 immune checkpoint inhibitor (ICI) for advanced or metastatic ccRCC alone or in combination. The Lead-in phase is designed as a dose escalation phase to evaluate the safety, efficacy, pharmacokinetics (PK) and determine recommended dose for expansion (RDE) of NKT2152 in combination with palbociclib and sasanlimab in advanced or metastatic ccRCC patients who received prior therapy. The subsequent Expansion phase will evaluate the safety, efficacy, PK at the selected RDE and identify the RP2D for NKT2152 in combination with palbociclib and sasanlimab in advanced or metastatic ccRCC patients who received prior therapy.

Official Title
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A Phase 2 Trial to Evaluate the Safety and Efficacy of NKT2152 in Combination With Palbociclib (Doublet) and With Palbociclib and Sasanlimab (Triplet) in Subjects With Advanced or Metastatic Clear Cell Renal Cell Carcinoma

Conditions
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Urologic Neoplasms, ccRCC, Clear Cell Renal Cell Carcinoma, Kidney Cancer, Kidney Neoplasms, Renal Cancer, Renal Neoplasms, Recurrent Renal Cell Carcinoma, Metastatic Renal Cell Carcinoma, Refractory Renal Cell Carcinoma, Advanced Renal Cell Carcinoma, Carcinoma, Neoplasms, Carcinoma, Renal Cell, Neoplasms, Glandular and Epithelial, Neoplasm by Histology, Adenocarcinoma, Urogenital Neoplasms, Neoplasms by Site, Kidney Diseases, Urologic Diseases

Intervention / Treatment
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* Drug: NKT2152
* Drug: palbociclib
* Other: sasanlimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have locally advanced or metastatic ccRCC and have progressed or relapsed after at least 1 prior anti-VEGF/VEGFR systemic therapy and 1 ICI. Measurable disease per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) KPS score of at least 70% Able to swallow oral medications. Exclusion Criteria: Active CNS metastases and/or carcinomatous meningitis Has had any major cardiovascular event within 6 months or clinically significant cardiovascular disease Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 3 months before administration of study drug. Has known HIV History of hepatitis B or known active hepatitis C infection Has received prior treatment with NKT2152, other HIF2α inhibitors, other CDK 4/6 inhibitors, palbociclib, or sasanlimab Radiation therapy for bone metastasis within 2 weeks, or any other external radiation therapy within 4 weeks before administration of the first dose of study treatment Corrected QT interval calculated by Fridericia formula (QTcF) > 480 ms within 28 days prior to first dose Hypoxia or requires intermittent or chronic supplemental oxygen or any chronic lung condition which has required supplemental oxygen in the past Has a history of interstitial lung disease Has any active or recent history of a known or suspected autoimmune disease

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Lead-in/Dose Escalation (doublet & triplet combination) and Dose Expansion (doublet & triplet combination)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lead-in Doublet combination<br>Lead-in Doublet assesses safety of oral dosing NKT2152 at increasing dosage levels in combination with palbociclib to determine a recommended dose for expansion (RDE). | Drug: NKT2152<br>* Oral HIF2a inhibitor<br>Drug: palbociclib<br>* a cyclin-dependent kinases (CDK) 4 and 6 inhibitor<br>* Other names: IBRANCE®;|
| Experimental: Lead-in Triplet combination<br>Lead-in Triplet assesses the safety of two doses of NKT2152 identified in the Doublet arm (RDE and RDE-1) by orally dosing ccRCC patients with NKT2152 in combination with palbociclib and sasanlimab | Drug: NKT2152<br>* Oral HIF2a inhibitor<br>Drug: palbociclib<br>* a cyclin-dependent kinases (CDK) 4 and 6 inhibitor<br>* Other names: IBRANCE®;Other: sasanlimab<br>* an immunoglobulin G4 (IgG4) monoclonal antibody that blocks PD-1; a solution for injection for subcutaneous administration<br>|
| Experimental: Expansion Doublet combination<br>Subjects randomized to Arm 1 will receive the Doublet combination (NKT2152 in combination with palbociclib) to provide an assessment of anti-tumor activity and to determine the RP2D. | Drug: NKT2152<br>* Oral HIF2a inhibitor<br>Drug: palbociclib<br>* a cyclin-dependent kinases (CDK) 4 and 6 inhibitor<br>* Other names: IBRANCE®;|
| Experimental: Expansion Triplet combination<br>Subjects randomized to Arm 2 will receive the Triplet therapy (NKT2152 in combination with palbociclib and sasanlimab) to provide an assessment of anti-tumor activity and to determine the RP2D. | Drug: NKT2152<br>* Oral HIF2a inhibitor<br>Drug: palbociclib<br>* a cyclin-dependent kinases (CDK) 4 and 6 inhibitor<br>* Other names: IBRANCE®;Other: sasanlimab<br>* an immunoglobulin G4 (IgG4) monoclonal antibody that blocks PD-1; a solution for injection for subcutaneous administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose Limiting Toxicity (DLT) events during the DLT monitoring period (first 28 days of dosing) in the Lead-in Phase | DLTs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5 .0. | 28 days | 
| Objective Response Rate (ORR) determined by the Investigator | ORR defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | 1 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS defined as the time from the date the participant started study drug to the date the participant experiences an event of disease progression or death. | 2 years | 
| Duration of Response (DOR) | Duration of overall response is defined as the time from the date of first documented CR or PR, assessed by investigator and based on RECIST v. 1.1, to the documented date of progressive disease (PD) or death, whichever occurred first. | 1 years | 
| Time to Response (TTR) | TTR is defined as the time from first dose to the first documented CR or PR which is subsequently confirmed. | 1 years | 
| Overall Survival (OS) | OS defined as the time from the date the participant started study drug to death for any reason. | 2 years | 
| Clinical Benefit Rate (CBR) | CBR defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) or a stable disease (SD) of 8 weeks or longer based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | 1 years | 
| Number of Participants with Adverse Events | An adverse event (AE) is defined as any untoward medical occurrence in a patient and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. | 2 years | 
| Maximum observed plasma concentration (Cmax) of NKT2152 | Maximum observed plasma concentration (Cmax) of NKT2152 | 1 years | 
| Time to maximum observed plasma concentration of NKT2152 (Tmax) | Time to maximum observed plasma concentration of NKT2152 (Tmax) | 1 years | 
| Observed trough concentration of NKT2152 (Ctrough) | Observed trough concentration of NKT2152 (Ctrough) | 1 years | 
| Area under the plasma concentration time curve (AUC0-t) of NKT2152, and accumulation ratio (RAC) | Area under the plasma concentration time curve (AUC0-t) of NKT2152, and accumulation ratio (RAC) | 1 years | 
| Maximum observed plasma concentration (Cmax) of palbociclib | Maximum observed plasma concentration (Cmax) of palbociclib | 1 years | 
| Time to maximum observed plasma concentration of palbociclib (Tmax) | Time to maximum observed plasma concentration of palbociclib (Tmax) | 1 years | 
| Observed trough concentration of palbociclib (Ctrough) | Observed trough concentration of palbociclib (Ctrough) | 1 years | 
| Area under the plasma concentration time curve (AUC0-t) of palbociclib, and accumulation ratio (RAC) | Area under the plasma concentration time curve (AUC0-t) of palbociclib, and accumulation ratio (RAC) | 1 years | 
| Observed trough concentration of sasanlimab (Ctrough) | Observed trough concentration of sasanlimab (Ctrough) | 1 years | 
| Maximum observed plasma concentration (Cmax) of sasanlimab | Maximum observed plasma concentration (Cmax) of sasanlimab | 1 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIF2a, Hypoxia-inducible factor 2alpha, CDK4 inhibitor, CDK6 inhibitor, PD-1, immune checkpoint inhibitors