Study of Navtemadlin Plus Pembrolizumab as Maintenance Therapy in Locally Advanced and Metastatic Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This study evaluates Navtemadlin (KRT-232) in combination with Pembrolizumab as a maintenance therapy in patients with locally advanced and metastatic non small cell lung cancer.

Detailed Description
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This is a 2 part, phase 1b/2, maintenance study for patients who have achieved a partial response (PR) or complete response (CR) after completion of up to 4 cycles of a combination platinum-based chemotherapy plus CPI regimen. Phase 1b is a 3+3 dose escalation design that will be used to determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of navtemadlin in combination with pembrolizumab. A Safety Review Committee (SRC) will review the safety data during the dose escalation to decide on dose escalation and/or exploration of intermediate doses. Phase 2 will evaluate the efficacy and safety of the RP2D of navtemadlin plus pembrolizumab compared to navtemadlin placebo plus pembrolizumab. Each Arm will have approximately 40 subjects enrolled for a total of approximately 80 subjects. Eligible subjects will be randomized 1:1. This part of the study has a randomized, controlled, double-blind design. A stratified, permuted-block randomization scheme will be used for treatment allocation.

Official Title
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A Two-Part, Phase 1b/2, Multicenter, Open-Label, Dose Escalation and Double-Blind, Randomized, Placebo-Controlled, Dose Expansion Study of the Safety, Efficacy and Pharmacokinetics of Navtemadlin Plus Pembrolizumab as Maintenance Therapy in Subjects With Locally Advanced and Metastatic Non-Small Cell Lung Cancer

Conditions
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Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Navtemadlin
* Drug: Navtemadlin Placebo
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ECOG 0-1 Histologically or cytologically confirmed diagnosis of NSCLC documented as TP53WT Locally advanced or metastatic disease; must have completed up to 4 cycles of platinum-based chemo plus CPI and achieved a CR or PR per RECIST V1.1 Adequate hematologic, hepatic and renal function (within 14 days) Exclusion Criteria: Symptomatic or uncontrolled central nervous system (CNS) metastases Prior treatment with a MDM2 inhibitor Grade 2 or higher QTc prolongation (>480 msec per NCI-CTCAE criteria version 5.0) History of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 24 weeks History of major organ transplant Active pneumonitis or known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis Prior radiotherapy, cytoreductive therapy, cytokine therapy or any investigational therapy within 28 days Medical condition, serious intercurrent illness, psychiatric condition or other circumstance that, in the Investigator's judgment could jeopardize the subject's safety, or that could interfere with study objectives

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Navtemadlin in combination with pembrolizumab<br>Navtemadlin will be administered orally, once daily (QD), on days 1-7 in a 21-day cycle. Pembrolizumab will be administered intravenously on Day 1 of a 21-day cycle. | Drug: Navtemadlin<br>* Navtemadlin is an experimental MDM2 anticancer drug taken by mouth.<br>* Other names: KRT-232;Drug: Pembrolizumab<br>* Pembrolizumab is a humanized antibody used in cancer immunotherapy that will be administered intravenously<br>* Other names: Keytruda;|
| Placebo Comparator: Navtemadlin placebo in combination with pembrolizumab<br>Navtemadlin placebo will be administered orally, once daily (QD), on days 1-7 in a 21-day cycle. Pembrolizumab will be administered intravenously on Day 1 of a 21-day cycle. | Drug: Navtemadlin Placebo<br>* Navtemadlin placebo is a placebo that is the same in appearance to navtemadlin drug taken by mouth.<br>Drug: Pembrolizumab<br>* Pembrolizumab is a humanized antibody used in cancer immunotherapy that will be administered intravenously<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b- To determine the recommended Phase 2 dose (RP2D) | The Safety Review Committee will determine the RP2D based on safety data of the combination of navtemadlin and pembrolizumab. | 21 days | 
| Phase 2- To assess the treatment effect of navtemadlin plus pembrolizumab treatment on PFS compared with the treatment effect of navtemadlin placebo plus pembrolizumab treatment. | PFS is defined as the time from randomization date to disease progression (assessed by the Independent Review Committee [IRC] per RECIST v1.1) or death, whichever occurs first | 64 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b- To characterize the pharmacokinetic (PK) profile of navtemadlin | Will determine the Maximum observed concentration (Cmax) on Cycle 1 Day 1 | 1 day | 
| Phase 1b- To characterize the pharmacokinetic (PK) profile of navtemadlin | Will determine the area under the plasma concentration versus time curve (AUC) on Cycle 1 Day 1 | 1 day | 
| Phase 1b- To characterize the pharmacokinetic (PK) profile of navtemadlin | Will determine the time of maximum plasma concentration (Tmax) on Cycle 1 Day 1 | 1 day | 
| Phase 1b- To assess the treatment effect on progression-free survival (PFS) | PFS is defined as the time from first dose date to disease progression (assessed by the IRC and Investigator per RECIST v1.1) or death, whichever occurs first | 64 Months | 
| Phase 2- To assess the treatment effect of navtemadlin plus pembrolizumab treatment on PFS compared with the treatment effect of navtemadlin placebo plus pembrolizumab treatment. | PFS is defined as the time from randomization date to disease progression (assessed by the Investigator per RECIST v1.1) or death, whichever occurs first | 64 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Navtemadlin