Tomivosertib Combined With Pembrolizumab in Subjects With PD-L1 Positive NSCLC (KICKSTART)

Study Overview
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Brief Summary
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Tomivosertib combined with pembrolizumab in Subjects with PD-L1 positive NSCLC

Detailed Description
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A Randomized, Double-Blind, Placebo-Controlled Trial of Tomivosertib in Combination With Anti-PD-(L)1 Therapy in Subjects With Non-Small Cell Lung Cancer as First Line Therapy or When Progressing on Single-Agent First-Line Anti PD (L)1 Therapy

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Trial of Tomivosertib in Combination With Anti-PD-(L)1 Therapy in Subjects With NSCLC as First Line Therapy or When Progressing on Single-Agent First-Line Anti PD (L)1 Therapy

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Tomivosertib
* Biological: Pembrolizumab
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria for Cohort A: Subjects who meet all of the following criteria will be eligible to participate in Cohort A of the study: 1. Have initiated first-line therapy for NSCLC with pembrolizumab and satisfy the following: Have tumor PD-L1 ≥1% by 22C3 IHC; Are judged by the Principal Investigator as tolerating pembrolizumab monotherapy; and Have been on pembrolizumab for at least 3 months (measured from actual first dose date to first dose date of the current study) and the most recent scans are the first scans to objectively demonstrate Progressive Disease per RECIST 1.1 The first scan conducted a minimum of 21 days after first dose of anti-PD-(L)1 therapy must have shown either SD, PR, or CR (ie, not Progressive Disease) per RECIST 1.1; and The 2 most recent scans (including 1 demonstrating Progressive Disease) are available to be reviewed Inclusion Criterion for Cohort B Subjects who meet the following criterion will be eligible to participate in Cohort B of the study: 1. Are eligible for single-agent pembrolizumab for advanced/metastatic NSCLC in accordance with the package insert and have tumor PD-L1 ≥50% by 22C3 IHC • Must not have been treated previously with platinum-based chemotherapy in the advanced/metastatic setting. Note: Subjects may have received chemotherapy and/or anti PD (L)1 therapy in the neo/adjuvant setting, provided the last dose of therapy was >9 months prior to randomization. All cohorts require PD-L1 testing (TPS as determined by an FDA-approved test: subjects in Cohort B must specifically have PD-L1 testing using the PD-L1 IHC 22C3 pharmDx test kit). Subjects in Cohort B for whom PD-L1 testing was not performed with the required IHC 22C3 pharmDx test kit may be randomized if all other study criteria have been met, pending retest with the required IHC 22C3 pharmDx test kit. Subjects who meet the following criterion will be eligible to participate in Cohort C of the study: 1. Have initiated IL therapy for NSCLC and completed all planned (eg, 4 to 6 cycles) platinum-based chemotherapy with at least 2 cycles in combination with pembrolizumab; must not have had progressive disease on tumor staging imaging scans following completion of all planned platinum chemotherapy Are eligible for maintenance therapy with pembrolizumab ± pemetrexed in accordance with the package insert Have tumor PD-L1 ≥1% The last dose of platinum-based chemotherapy must be within 8 weeks of the first dose of the study drug in this study Inclusion Criterion for All Cohorts Subjects must also meet all of the following criteria to be eligible to participate in the study: Have histologically confirmed NSCLC that is inoperable, locally advanced or metastatic (Stage IIIb/IV) Have available at the site a representative formalin-fixed, paraffin-embedded tumor specimen that enabled diagnosis of NSCLC in a tissue block (preferred) or 10 unstained, serial slides, accompanied by an associated pathology report. Note: If the archival tissue is neither sufficient nor available, the subject may still be eligible, upon discussion with the Medical Monitor Have provided written informed consent and any authorizations required by local law Are ≥18 years of age Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Exclusion Criteria: Have NSCLC with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations Have gastrointestinal (GI) disease (eg, gastric or intestinal bypass surgery, pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic diarrheal illness, and/or bowel obstruction) that may interfere with drug absorption or with interpretation of GI AEs Have known symptomatic brain metastases requiring >10 mg/day of prednisone (or its equivalent). Subjects with previously diagnosed brain metastases are eligible if they have completed their treatment, have recovered from the acute effects of radiation therapy or surgery prior to randomization, fulfill the steroid requirement for these metastases, the 2 most recent serial magnetic resonance imaging (MRI) scans conducted >28 days apart show no central nervous system progression, and are neurologically stable and asymptomatic

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: In each Cohort approximately 60 eligible Subjects will be randomized to receive tomivosertib or matching placebo in combination with pembrolizumab. Cohorts A and C are not currently enrolling. In Cohort B, subjects will receive blinded IP (tomivosertib or matching placebo) in combination with pembrolizumab as first line therapy.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A1 Tomi + Current Pembro<br>Subjects who have initiated pembrolizumab as a single agent and in accordance with the package insert will receive tomivosertib in addition to pembrolizumab. | Drug: Tomivosertib<br>* Tomivosertib (eFT508) will be taken at 100 mg twice daily (bid) with meals<br>* Other names: eFT508;Biological: Pembrolizumab<br>* Subjects will initiate or continue to receive pembrolizumab at either 200 mg intravenously (IV) at a frequency of every 3 weeks or 400 mg IV at a frequency of every 6 weeks.<br>* Other names: Keytruda®;|
| Placebo Comparator: Pbo + Current Pembro<br>Subjects who have initiated pembrolizumab as a single agent and in accordance with the package insert, will receive matching placebo in addition to pembrolizumab. | Biological: Pembrolizumab<br>* Subjects will initiate or continue to receive pembrolizumab at either 200 mg intravenously (IV) at a frequency of every 3 weeks or 400 mg IV at a frequency of every 6 weeks.<br>* Other names: Keytruda®;|
| Experimental: B1 Tomi + Pembro<br>Subjects will initiate pembrolizumab as first-line therapy and receive tomivosertib. | Drug: Tomivosertib<br>* Tomivosertib (eFT508) will be taken at 100 mg twice daily (bid) with meals<br>* Other names: eFT508;Biological: Pembrolizumab<br>* Subjects will initiate or continue to receive pembrolizumab at either 200 mg intravenously (IV) at a frequency of every 3 weeks or 400 mg IV at a frequency of every 6 weeks.<br>* Other names: Keytruda®;|
| Placebo Comparator: Pbo + Pembro<br>Subjects will initiate pembrolizumab as first-line therapy and receive matching placebo. | Biological: Pembrolizumab<br>* Subjects will initiate or continue to receive pembrolizumab at either 200 mg intravenously (IV) at a frequency of every 3 weeks or 400 mg IV at a frequency of every 6 weeks.<br>* Other names: Keytruda®;|
| Experimental: C1 Tomi + Pembro + Pemetrexed (Non-sqamous) or Tomi + Pembro (Squamous)<br>Subjects who have completed 4 to 6 cycles of platinum-based chemotherapy doublet will receive tomi plus pembrolizumab and pemetrexed (non-squamous NSCLC) or tomi plus pembro as a single agent (squamous) in accordance with the package insert. | Drug: Tomivosertib<br>* Tomivosertib (eFT508) will be taken at 100 mg twice daily (bid) with meals<br>* Other names: eFT508;Biological: Pembrolizumab<br>* Subjects will initiate or continue to receive pembrolizumab at either 200 mg intravenously (IV) at a frequency of every 3 weeks or 400 mg IV at a frequency of every 6 weeks.<br>* Other names: Keytruda®;Drug: Pemetrexed<br>* Subjects will initiate pemetrexed at 500 mg/m2 intravenously (IV) at a frequency of every 3 weeks.<br>* Other names: Alimta®;|
| Placebo Comparator: Pbo + Pembro + Pemetrexed (Non-sqamous) or Pbo + Pembro (Squamous)<br>Subjects who have completed 4 to 6 cycles of platinum-based chemotherapy doublet will receive placebo plus pembrolizumab and pemetrexed (non-squamous NSCLC) or placebo plus pembro as a single agent (squamous) in accordance with the package insert. | Biological: Pembrolizumab<br>* Subjects will initiate or continue to receive pembrolizumab at either 200 mg intravenously (IV) at a frequency of every 3 weeks or 400 mg IV at a frequency of every 6 weeks.<br>* Other names: Keytruda®;Drug: Pemetrexed<br>* Subjects will initiate pemetrexed at 500 mg/m2 intravenously (IV) at a frequency of every 3 weeks.<br>* Other names: Alimta®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the progression-free survival (PFS) of tomivosertib when added to pembrolizumab as a first-line treatment; and | Defined as the time from randomization to the first occurrence of disease progression as assessed by the Investigator using RECIST 1.1 or death from any cause, whichever occurs earlier. | 2 years | 
| To characterize the PFS of tomivosertib when added to pembrolizumab as first line therapy. | Defined as the time from randomization to the first occurrence of disease progression as assessed by the Investigator using RECIST 1.1 or death from any cause, whichever occurs earlier. | 2 years | 
| To characterize the PFS of tomivosertib when added to pembrolizumab and pemetrexed in non-squamous NSCLC, and pembrolizumab in squamous NSCLC as first line maintenance therapy. | Defined as the time from randomization to the first occurrence of disease progression as assessed by the Investigator using RECIST 1.1 or death from any cause, whichever occurs earlier. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the PFS of tomivosertib when added to pembrolizumab in Cohorts A, B, and B C individually and combined | Defined as the time from randomization to the first occurrence of disease progression as assessed by the Investigator using RECIST 1.1 or death from any cause, whichever occurs earlier. | 2 years | 
| To characterize the PFS of tomivosertib when added to pembrolizumab as a first-line treatment in subjects with NSCLC | Defined as the time from randomization to the first occurrence of disease progression as assessed by the Investigator using RECIST 1.1 or death from any cause, whichever occurs earlier. Objective response per RECIST 1.1, as assessed by the BIRC. | 2 years | 
| To characterize the PFS of tomivosertib when added to pembrolizumab and pemetrexed in non-squamous NSCLC, and pembrolizumab in squamous NSCLC as a first-line maintenance treatment in subjects with NSCLC. | Defined as the time from randomization to the first occurrence of disease progression as assessed by the Investigator using RECIST 1.1 or death from any cause, whichever occurs earlier. Objective response per RECIST 1.1, as assessed by the BIRC. | 2 years | 
| To characterize the PFS of tomivosertib when added to pembrolizumab after first radiographic progression on pembrolizumab monotherapy | Defined as the time from randomization to the first occurrence of disease progression as assessed by the Investigator using RECIST 1.1 or death from any cause, whichever occurs earlier. Objective response per RECIST 1.1, as assessed by the BIRC | 2 years |