Phase 1b DV281 With an Anti-PD-1 Inhibitor in NSCLC

Study Overview
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Brief Summary
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This open-label, multicenter, dose-escalation and expansion trial is designed to evaluate the safety and preliminary efficacy of inhaled DV281 in combination with nivolumabfor the treatment of NSCLC and to select a recommended phase 2 dose (RP2D).

Detailed Description
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Pre-clinical studies support the proposed dosing schema to be tested and a potential benefit of the combination of inhaled DV281 with nivolumab for subjects with advanced NSCLC. This study (DV9-NSC-01) is designed for establishing an immunologically optimal RP2D for inhaled DV281 in combination with an approved anti-PD-1 inhibitor. This trial, studying the potential to enhance the efficacy of an approved anti-PD-1 inhibitor in subjects with advanced NSCLC, addresses an unmet need for NSCLC patients having tumors that do not respond or do not respond adequately to anti-PD-1 inhibitor monotherapy.

Official Title
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Phase 1b Dose Escalation and Dose Expansion Trial of DV281 in Combination With an Approved Anti-PD-1 Inhibitor in Subjects With Advanced Non-Small Cell Lung Cancer

Conditions
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Advanced Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: DV281
* Device: Breath Actuated Nebulizer
* Drug: DV281 (RP2D)
* Drug: Approved Anti-PD-1 Inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have documented histologically or cytologically confirmed advanced NSCLC as the dominant histology. If confirmed EGFR or ALK directed testing warrants actionable targeted therapy, must have confirmed disease progression on targeted therapy or cannot tolerate targeted therapy. Aged 18 years and older on the day of signing informed consent Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2 for Dose Escalation phase and ECOG PS 0 to 1 for Dose Expansion phase Adequate organ function as indicated by laboratory values Life expectancy, in the opinion of the investigator, of at least 3 months Exclusion Criteria Condition of the subjects lung anatomy is such that proper delivery of inhaled DV281 to the specific location of intra-thoracic tumor(s) could be compromised Any known additional malignancy that is progressing or required active treatment in the last 3 years Current or history of clinically significant non-infectious pneumonitis History of clinically severe lung disease, asthma, or chronic obstructive pulmonary disease (COPD) requiring emergency management and/or hospitalization in the last year Received more than 30 Gy of conventional radiation therapy in the thoracic region within 26 weeks prior to study enrollment Is expected to require any other form of anti-cancer therapy while in the trial. Zoledronic acid or denosumab as supportive care for bone metastases will be allowed if started prior to study enrollment Diagnosis of immunodeficiency or is receiving systemic steroid therapy (>10 mg of prednisone or equivalent) or any other form of immunosuppressive therapy (including immune modulators or systemic corticosteroids) that cannot be discontinued safely within 14 days prior to study enrollment Has a medical condition that requires immunosuppression Active autoimmune disease requiring systemic treatment in the past 2 years or a disease that requires immunosuppressive medication including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, or autoimmune thrombocytopenia. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. Known central nervous system metastases, brain metastases, or carcinomatous meningitis

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: Sequential Assignment
Interventional Model Description: In the Dose Escalation phase of the study, 5 DV281 dose cohorts will be evaluated in combination with an approved anti-PD-1 Inhibitor. The Dose Expansion phase of the study will establish the Recommended Phase 2 Dose of DV281 in combination with an approved anti-PD-1 inhibitor.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Cohort 1-5<br>Cohort 1-4 DV281 - Dose Level 1-5 DV281 in combination with nivolumab DV281 is administered via a breath actuated nebulizer | Drug: DV281<br>* - Dose Escalation will be the preliminary dose finding phase of the study. Subjects will be enrolled to available Dosing Cohorts.<br>Device: Breath Actuated Nebulizer<br>* Breath-actuated, electronic system designed to aerosolize liquid medication.<br>* Other names: Nebulizer;Drug: Approved Anti-PD-1 Inhibitor<br>* FDA approved Anti-PD-1 Inhibitor<br>* Other names: nivolumab;|
| Experimental: Dose Expansion (RP2D)<br>4 Cohorts Preliminary Recommended Phase 2 dosing of DV281 in combination with nivolumab Cohort 1: Non-squamous and non-EGFR/ ALK mutation and progressed on anti-PD-1/L1 therapy Cohort 2: Non-squamous and EGFR/ ALK mutation and progressed on targeted therapy Cohort 3: Squamous and anti-PD-1/ L1 therapy experienced Cohort 4: Squamous and anti-PD-1/L1 therapy naive DV281 is administered via a breath actuated nebulizer. | Device: Breath Actuated Nebulizer<br>* Breath-actuated, electronic system designed to aerosolize liquid medication.<br>* Other names: Nebulizer;Drug: DV281 (RP2D)<br>* - Dose Expansion will be enrolled into 4 groups based on NSCLC characteristics.<br>Drug: Approved Anti-PD-1 Inhibitor<br>* FDA approved Anti-PD-1 Inhibitor<br>* Other names: nivolumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation | Incidence of dose-limiting toxicities (DLTs) | DLT assessment period - Day 1 through Day 28. | 
| Dose Expansion | Objective response rate (ORR) of dosing regimen established during the Dose Escalation | 1 year after last subject is enrolled in the Dose Expansion phase of study | 
| Dose Expansion | Duration of Response (DOR) and time to response. | 1 year after last subject is enrolled in the Dose Expansion phase of the Study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation | Assess IFN-a induced gene expression in blood when DV281 is administered as a monotherapy and in combination with an approved anti-PD-1 inhibitor | IFN response assessment period - Day 1 through Day 21 | 
| Dose Expansion | Incidence of treatment related AE's as assessed by CTCAE Version 4.03 | 1 year after last subject is enrolled in the Dose Expansion phase of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Lung Cancer, NSCLC, Anti-PD-1 inhibitor, Immuno-oncology, Toll-Like Receptor (TLR) agonist