Phase 1/2 Study of Combination Immunotherapy and Messenger Ribonucleic Acid (mRNA) Vaccine in Subjects With NSCLC

Study Overview
=================
Brief Summary
-----------------
This is an open-label, multicenter, 2-arm study to evaluate the safety and preliminary efficacy of the addition of a vaccine therapy to 1 or 2 checkpoint inhibitors for NSCLC. Arm A: messenger ribonucleic acid (mRNA) Vaccine [BI 1361849 (formerly CV9202)] + anti-programmed death ligand 1 (PD-L1) antibody [durvalumab] Arm B: messenger ribonucleic acid (mRNA) Vaccine [BI 1361849] + anti-programmed death ligand 1 (PD-L1) [durvalumab] + anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody [tremelimumab] The run-in evaluation phase is followed by an expansion phase in which the cohort is expanded to 20 subjects (inclusive of subjects from the run-in).

Detailed Description
-----------------
This was a Phase 1/2, open-label, multicenter, 2-arm study to evaluate the safety and preliminary efficacy of the addition of a vaccine therapy to 1 or 2 checkpoint inhibitors in subjects with NSCLC. Up to 56 subjects were planned for enrollment from up to 8 clinical sites in 2 arms: Arm A: mRNA Vaccine [BI 1361849 (formerly CV9202)] + anti-PD-L1 antibody [durvalumab] Arm B: mRNA Vaccine [BI 1361849] + anti-PD-L1 [durvalumab] + anti-CTLA-4 antibody [tremelimumab] Subjects must have had histologically confirmed metastatic NSCLC. For subjects with known EGFR or ALK/ROS-1 mutations, prior therapy must have included an EGFR tyrosine kinase inhibitor or ALK/ROS-1 inhibitor, respectively. Subjects may have had 1 prior line of anti-PD-1/PD-L1 therapy and must not have had progression at or before 12 weeks after start of the prior anti-PD-1/PD-L1 treatment.

Official Title
-----------------
A Phase 1/2 Study of Combination Immunotherapy and mRNA Vaccine in Subjects With Non-small Cell Lung Cancer (NSCLC)

Conditions
-----------------
Metastatic Non-small Cell Lung Cancer, NSCLC

Intervention / Treatment
-----------------
* Drug: Durvalumab
* Drug: Tremelimumab
* Biological: BI 1361849
* Device: PharmaJet Tropis® device


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Histologic confirmation of metastatic NSCLC. For subjects with known EGFR or ALK/ROS-1 mutations, prior therapy must have included an EGFR tyrosine kinase inhibitor or ALK/ROS-1 inhibitor, respectively. Subjects may have had 1 prior line of anti-PD-1/PD-L1 therapy. Subjects who received prior anti-PD-1/PD-L1 therapy must have progressed during or after the prior anti-PD-1/PD-L1 therapy treatment, but not prior to Week 12 of treatment. Measurable disease according to RECIST 1.1. Availability of archival (diagnostic) specimens or willing to undergo a pre-treatment biopsy. Subjects with treated brain metastases must have been treated with surgery and/or radiation therapy ≥ 21 days pre-study and must be clinically stable with no requirement for steroids. Laboratory parameters for vital functions should be in the normal range. ECOG Performance Status ≤ 2. Body weight > 30 kg. Exclusion Criteria Subjects may not enter the study if they fulfill any of the following criteria: Treatment with an investigational agent within 4 weeks of starting treatment or prior treatment with anti-CTLA-4 therapy. Active, suspected or prior documented autoimmune disease, clinically significant cardiovascular disease, or clinically uncontrolled hypertension. History of pneumonitis or interstitial lung disease, or any unresolved immune-related adverse events following prior therapy. Major surgery within 4 weeks of starting treatment (or scheduled for surgery during the projected course of the study) or prior cancer vaccine treatment or allogeneic bone marrow transplantation. Subjects who are immunosuppressed, including those with known immunodeficiency or have active infection or other serious illnesses. Active infection including tuberculosis (TB), hepatitis B (HBV), hepatitis C, or human immunodeficiency virus (HIV). Subjects with a past or resolved HBV infection were eligible. Subjects positive for hepatitis C (HCV) antibody were eligible only if polymerase chain reaction was negative for HCV RNA. History of severe allergic reactions to any unknown allergens or components of the study drugs. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, bleeding disorders, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or serious chronic gastrointestinal conditions associated with diarrhea. Subjects must not have donated blood while on study and for at least 90 days following the last durvalumab treatment or for 6 months after the last dose of tremelimumab (whichever was longer). History of allogeneic organ transplant. History of leptomeningeal carcinomatosis. Active or prior malignancy except for history of other prior malignancy treated with curative intent which, in the opinion of the treating Investigator and the Sponsor, had minimal risk of interfering with safety or efficacy endpoints of the study. Women of childbearing potential who were pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) or nursing. Skin disease (e.g., psoriasis) that may prevent intradermal administration of the vaccine into the target areas.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: Arm A: BI 1361849 mRNA Vaccine + durvalumab<br>The BI 1361849 mRNA vaccine comprises 6 drug product components (F2408 coding for MUC1, F2409 coding for survivin, F2410 coding for NY-ESO-1, F2624 coding for 5T4, F2625 coding for MAGE-C2, and F2626 coding for MAGE-C1), which were provided and administered separately; each component was administered twice, thus there were 12 intradermal administrations of 100 µL (80 µg) each for each dose. The PharmaJet Tropis® device was used for the administration of the BI 1361849 components. Durvalumab 1500 mg was to be administered as an intravenous (IV) infusion every 4 weeks for 12 cycles; BI 1361849 was to be administered as 14 doses over the 12 cycles. | Drug: Durvalumab<br>* anti-PD-L1<br>* Other names: MEDI4736;Biological: BI 1361849<br>* mRNA Vaccine<br>* Other names: CV9202;Device: PharmaJet Tropis® device<br>* The PharmaJet Tropis® device was used for the intradermal administration of the BI 1361849 vaccine components.<br>|
| Experimental: Arm B: BI 1361849 mRNA Vaccine + durvalumab + tremelimumab<br>The BI 1361849 mRNA vaccine comprises 6 drug product components (F2408 coding for MUC1, F2409 coding for survivin, F2410 coding for NY-ESO-1, F2624 coding for 5T4, F2625 coding for MAGE-C2, and F2626 coding for MAGE-C1), which were provided and administered separately; each component was administered twice, thus there were 12 intradermal administrations of 100 µL (80 µg) each for each dose. The PharmaJet Tropis® device was used for the administration of the BI 1361849 components. Durvalumab 1500 mg was to be administered as an intravenous (IV) infusion every 4 weeks for 12 cycles; tremelimumab 75 mg was to be administered as an intravenous (IV) infusion every 4 weeks for the first 4 cycles (Arm B only); BI 1361849 was to be administered as 14 doses over the 12 cycles. | Drug: Durvalumab<br>* anti-PD-L1<br>* Other names: MEDI4736;Drug: Tremelimumab<br>* anti-CTLA-4<br>Biological: BI 1361849<br>* mRNA Vaccine<br>* Other names: CV9202;Device: PharmaJet Tropis® device<br>* The PharmaJet Tropis® device was used for the intradermal administration of the BI 1361849 vaccine components.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) | Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0 and classified by MedDRA system organ class (SOC) and preferred term. The severity was assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03. AEs were reported based on clinical laboratory tests, vital signs, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent was signed through 90 days after the last dose of study treatment. TEAEs are AEs that occurred or worsened in severity after administration of the first dose of study treatment. For each arm, the first 6 subjects were evaluated for dose limiting toxicities (DLTs). Deaths within the AE Reporting Period included all deaths that occurred during the study treatment period, or up to 90 days after the administration of the last dose of study drug or initiation of a new treatment. | up to 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median PFS by RECIST 1.1 as Estimated Using the Kaplan-Meier Method | Progression Free Survival (PFS) was measured from the date of the first dose of study treatment to the date of earliest disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) or to the date of death, if disease progression did not occur. Per RECIST 1.1, progressive disease (PD) is defined as a ≥ 20% increase in the sum of the longest diameter of target lesions or the presence of new lesions. | up to 15 months | 
| Number of Subjects Without Progression at 8 and 24 Weeks by RECIST 1.1 | Progression-free Survival (PFS) was measured from the date of the first dose of study treatment to the date of earliest disease progression or to the date of death, if disease progression did not occur. Per RECIST 1.1, progressive disease (PD) is defined as a ≥ 20% increase in the sum of the longest diameter of target lesions or the presence of new lesions. | up to 24 weeks | 
| Median PFS by irRECIST as Estimated Using the Kaplan-Meier Method | Progression-free Survival (PFS) was measured from the date of the first dose of study treatment to the date of earliest disease progression according to immune related Response Evaluation Criteria in Solid Tumors (irRECIST) or to the date of death, if disease progression did not occur. Per irRECIST, progressive disease (irPD) is defined as a ≥ 20% increase from nadir in the total measurable tumor burden (TMTB). | up to 15 months | 
| Number of Subjects Without Progression at 8 and 24 Weeks by irRECIST | Progression-free Survival (PFS) was measured from the date of the first dose of study treatment to the date of earliest disease progression or to the date of death, if disease progression did not occur. Per irRECIST, progressive disease (irPD) is defined as a ≥ 20% increase from nadir in the total measurable tumor burden (TMTB). | up to 24 weeks | 
| Number of Subjects With Best Overall Tumor Response By RECIST 1.1 | Tumor responses were evaluated using appropriate imaging and categorized according to RECIST 1.1 at Screening (up to 28 days before the first dose of study treatment), at cycles 3, 5, 7, 9, and 11 during study treatment, and during on-study follow-up every 8 weeks starting 8 weeks after the last disease assessment. Per RECIST 1.1, target lesions are categorized as follows: complete response (CR): disappearance of all target lesions; partial response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; PD: ≥ 20% increase in the sum of the longest diameter of target lesions or the presence of new lesions; stable disease (SD): small changes that do not meet above criteria. | up to 15 months | 
| Number of Subjects With Objective Responses at 8 and 24 Weeks By RECIST 1.1 | Tumor responses were evaluated using appropriate imaging and categorized according to RECIST 1.1 at Screening (up to 28 days before the first dose of study treatment), at cycles 3, 5, 7, 9, and 11 during study treatment, and during on-study follow-up every 8 weeks starting 8 weeks after the last disease assessment. Per RECIST 1.1, target lesions are categorized as follows: complete response (CR): disappearance of all target lesions; partial response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; PD: ≥ 20% increase in the sum of the longest diameter of target lesions or presence of new lesions; stable disease (SD): small changes that do not meet above criteria. An Objective Response is defined as a CR or PR over a period of at least 4 weeks. | up to 24 weeks | 
| Duration of Response (DoR) By RECIST 1.1 | Duration of Response (DoR) was defined as the interval between the date of earliest determination of CR or PR to the date of earliest determination of progressive disease (PD), clinical progression or death, whatever occurred first. | up to 15 months | 
| Number of Subjects With Best Overall Tumor Response By irRECIST | Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), at cycles 3, 5, 7, 9, and 11 during study treatment, and during on-study follow-up every 8 weeks starting 8 weeks after the last disease assessment. Per irRECIST, responses are categorized as follows: Complete Response (irCR): Complete disappearance of all target lesions; Partial Response (irPR): ≥ 30% decrease from baseline in the total measurable tumor burden (TMTB); Progressive Disease (irPD): ≥ 20% increase from nadir in TMTB; Stable Disease (irSD): not meeting above criteria. | up to 15 months | 
| Number of Subjects With Objective Responses at 8 and 24 Weeks By irRECIST | Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), at cycles 3, 5, 7, 9, and 11 during study treatment, and during on-study follow-up every 8 weeks starting 8 weeks after the last disease assessment. Per irRECIST, responses are categorized as follows: irCR: Complete disappearance of all target lesions; irPR: ≥ 30% decrease from baseline in the total measurable tumor burden (TMTB); irPD: ≥ 20% increase from nadir in TMTB; irSD: not meeting above criteria. An Objective Response is defined as an irCR or irPR over a period of at least 4 weeks. | up to 24 weeks | 
| Duration of Response (DoR) by irRECIST | Duration of Response (DoR) was defined as the interval between the date of earliest determination of irCR or irPR to the date of earliest determination of progressive disease (irPD), clinical progression or death, whatever occurred first. | Up tp 15 months | 
| Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method | After completion of treatment, all subjects were followed for survival every 6 months following initiation of study treatment until October 29, 2021 when all post-study follow-up was completed. OS was measured from the date of the first dose of study treatment to the date of death or last follow-up. Subjects lost to follow-up were censored on the date when they were last known to be alive. | up to October 29, 2021 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
mRNA Vaccine, durvalumab, MEDI4736, anti-PD-L1, tremelimumab, anti-CTLA-4, BI 1361849, PharmaJet Tropis® device