M7824 in Combination With Chemotherapy in Stage IV Non-small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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The main purpose of the study was to evaluate the safety and tolerability of M7824 in combination with chemotherapy.

Official Title
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A Phase Ib/II, Open-Label Study of M7824 in Combination With Chemotherapy in Participants With Stage IV Non-small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Pemetrexed
* Drug: Nab-paclitaxel
* Drug: Gemcitabine
* Drug: Docetaxel
* Drug: M7824
* Drug: Carboplatin
* Drug: Carboplatin
* Drug: Bintrafusp alfa
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants greater than or equals to (>=) 18 years of age inclusive at the time of signing the informed consent Participants who have histologically confirmed diagnosis of Stage IV NSCLC: Participants in Cohort A, B, and C must not have received prior systemic therapy treatment for their Stage IV NSCLC Participants who had disease progression on previous treatment with Programmed death-ligand 1 (PD- L1) inhibitors in combination with platinum-based chemotherapy are enrolled in Cohort D, as long as therapy was completed at least 28 days of the first study intervention. Have measurable disease based on Response evaluation criteria in solid tumors (RECIST) 1.1 Have a life expectancy of at least 3 months Availability of archived tumor material (less than [<] 6 months old) adequate for biomarker analysis is mandatory at Screening, central laboratory confirmation is required. Fresh biopsies should be collected if archived tumor material is not available Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at study entry and date of first dose Exclusion Criteria: The participant's tumor harbors an epidermal growth factor receptor (EGFR) sensitizing (activating) mutation,ROS1 rearrangement, or BRAF V600E mutation or anaplastic lymphoma kinase (ALK) positive, if targeted therapy is locally approved Mixed small cell with NSCLC cancer histology Has received major surgery within 4 weeks prior to the first dose of study intervention; received thoracic radiation therapy (RT) of > 30 gray (Gy) within 6 months prior to the first dose of study intervention Previous malignant disease (other than the target malignancy to be investigated in this study) within the last 3 years Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are clinically stable for at least 2 weeks after the end of the RT and, have no evidence of new or enlarging brain metastases evaluated by imaging, preferably brain magnetic resonance imaging (MRI) Known severe hypersensitivity to study intervention or any components in their formulations For participants in Cohort A, B and C: Has received prior systemic therapy for Stage IV NSCLC, including anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) Unable to tolerate computed tomography (CT) or MRI in the opinion of the Investigator and/or allergy to contrast material.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Cisplatin or Carboplatin + Pemetrexed + Bintrafusp alfa<br>Participants received 2400 miligrams (mg) Bintrafusp alfa along with Cisplatin or Carboplatin, and Pemetrexed every 3 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death. | Drug: Cisplatin<br>* Cisplatin was administered intravenously at a dose of 75 milligrams per meter square (mg/m^2) over 60 minutes every 21 days for 4 cycles (each cycle is 21 days).<br>Drug: Carboplatin<br>* Carboplatin was administered at area under the concentration-time Curve (AUC) 5 when combined with pemetrexed over 30 to 60 minutes every 21 days for 4 cycles (each cycle is 21 days).<br>Drug: Pemetrexed<br>* Pemetrexed was administered intravenously at a dose of 500 mg/ m^2 over 10 minutes every 21 days.<br>Drug: M7824<br>* M7824 was administered intravenously at a dose of 2400 mg every 21 days in combination with chemotherapy for 4 cycles (each cycle is 21 days) followed by up to 31 cycles in maintenance with M7824 and pemetrexed.<br>|
| Experimental: Cohort B: Carboplatin + Paclitaxel or Nab-paclitaxel + Bintrafusp alfa<br>Participants received 2400 mg Bintrafusp alfa along with Carboplatin, and Paclitaxel or Nab-paclitaxel every 3 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death. | Drug: Nab-paclitaxel<br>* Nab-paclitaxel was administered intravenously at as dose of 100 mg/m^2 over 30 minutes in a 21 days cycle on Day 1, 8, and 15 in each cycle for 4 cycles (each cycle is 21 days).<br>Drug: Carboplatin<br>* Carboplatin was administered at area under the concentration-time Curve (AUC) 6 when combined with nab-paclitaxel over 30 to 60 minutes every 21 days for 4 cycles (each cycle is 21 days).<br>Drug: Bintrafusp alfa<br>* M7824 was administered intravenously at a dose of 2400 mg every 21 days in combination with chemotherapy for 4 cycles (each cycle is 21 days) followed by up to 31 cycles in maintenance with M7824 alone.<br>Drug: Paclitaxel<br>* Paclitaxel was administered intravenously at a dose of 200 mg/m2 over 3 hours every 3 weeks for 4 cycles (each cycle is 21 days).<br>|
| Experimental: Cohort C: Cisplatin or Carboplatin + Gemcitabine + Bintrafusp alfa<br>Participants received 2400 mg Bintrafusp alfa along with Cisplatin or Carboplatin, and Gemcitabine every 3 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death. | Drug: Cisplatin<br>* Cisplatin was administered intravenously at a dose of 75 milligrams per meter square (mg/m^2) over 60 minutes every 21 days for 4 cycles (each cycle is 21 days).<br>Drug: Gemcitabine<br>* Gemcitabine was administered intravenously at a dose of 1250 mg/m^2 over 30 minutes in a 21 days cycle on Day 1, and 8, in each cycle for 4 cycles (each cycle is 21 days).<br>Drug: Carboplatin<br>* Carboplatin was administered at area under the concentration-time Curve (AUC) 5 when combined with gemcitabine over 30 to 60 minutes every 21 days for 4 cycles (each cycle is 21 days).<br>Drug: Bintrafusp alfa<br>* M7824 was administered intravenously at a dose of 2400 mg every 21 days in combination with chemotherapy for 4 cycles (each cycle is 21 days) followed by up to 31 cycles in maintenance with M7824 alone.<br>|
| Experimental: Cohort D: Docetaxel + Bintrafusp alfa<br>Participants received 2400 mg Bintrafusp alfa along with Docetaxel every 3 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death. | Drug: Docetaxel<br>* Docetaxel was administered intravenously at a dose of 75 mg/m^2 over 60 minutes every 21 days for 4 cycles (each cycle is 21 days).<br>Drug: Bintrafusp alfa<br>* M7824 was administered intravenously at a dose of 2400 mg every 21 days in combination with chemotherapy for 4 cycles (each cycle is 21 days) followed by up to 31 cycles in maintenance with M7824 alone.<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 Toxicities (DLTs) | DLT was defined as Adverse Events(AEs) with any of following toxicities: Grade 4 nonhematologic toxicity or hematologic toxicity lasting more than equal to(>=) 7 days despite medical intervention; Grade 3 nausea, vomiting, and diarrhea lasting >= 3 days despite supportive care; Any Grade 3 or Grade 4 nonhematologic lab value leading to hospitalization or persisting for >= 7 days; Grade 3 or Grade 4: grade 3 is defined as absolute neutrophil count (ANC) less than (<) 1,000/Cubic Millimeter(mm3) with a temperature of > 38.3 degree Celsius (°C); grade 4 is defined as ANC < 1,000/mm3 with a temperature of > 38.3°C, with life-threatening consequences; Thrombocytopenia < 25,000/mm3 associated with bleeding not resulting in hemodynamic instability or a life-threatening bleeding resulting in urgent intervention; Bleeding events >= Grade 3 occurring within 5 days of bintrafusp alfa treatment; Prolonged delay(> 3 weeks) in initiating Cycle 2 due to treatment-related toxicity; Grade 5 toxicity. | Day 1 Week 1 up to Week 3 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether considered related to the medicinal product or protocol-specified procedure. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious TEAEs and non-serious TEAEs. | Time from first treatment assessed up to approximately 26 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Investigator (IRC) | Percentage of participants with confirmed objective response that is at least one overall assessment of complete response (CR) or partial response (PR) reported here. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). Confirmed objective response was determined according to RECIST v1.1 and as adjudicated by Investigator. | Time from first treatment assessed up to approximately 26 months | 
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Investigator | PFS was defined as the time from first administration of study intervention until date of the first documentation of disease progression (PD) or death due to any cause, whichever occurred first. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Kaplan-Meier estimates was used to calculate PFS. | Time from first administration of study drug until the first documentation of PD or death, assessed up to approximately 26 months | 
| Overall Survival (OS) | OS was defined as the time from first administration of study intervention to the date of death due to any cause. The OS was analyzed by using the Kaplan-Meier method. | Time from first treatment assessed up to approximately 26 months | 
| Duration of Response (DOR) | DOR was defined for participants with confirmed response, as the time from first documentation of confirmed objective response (Complete Response [CR] or Partial Response [PR]) according to RECIST 1.1 to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Results were calculated based on Kaplan-Meier estimates. | Time from first documentation of a confirmed objective response to PD or death due to any cause (assessed up to approximately 26 months) | 
| Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Bintrafusp Alfa | Ceoi was the observed concentration at the end of the infusion period. This was taken directly from the observed Bintrafusp Alfa concentration-time data. | Predose, Day 22, Day 43, Day 64 and Day 85 | 
| Serum Trough Concentration Levels (Ctrough) of Bintrafusp Alfa | Ctrough was the serum concentration observed immediately before next dosing. | Predose, Day 22, Day 43, Day 64 and Day 85 | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Bintrafusp Alfa | The area under the concentration-time curve (AUC) from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down). | Predose, Day 22, Day 43, Day 64 and Day 85 | 
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Bintrafusp Alfa | The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from terminal first order (elimination) rate constant determination. AUC0-inf= AUC0-tlast +Clast pred/ terminal first order (elimination) rate constant. | Predose, Day 22, Day 43, Day 64 and Day 85 | 
| Maximum Observed Plasma Concentration (Cmax) of Bintrafusp Alfa | Cmax was obtained directly from the concentration versus time curve. | Predose, Day 22, Day 43, Day 64 and Day 85 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Bintrafusp Alfa | The time to reach the maximum observed concentration collected during a dosing interval. Tmax was obtained directly from the concentration versus time curve. | Predose, Day 22, Day 43, Day 64 and Day 85 | 
| Terminal Elimination Half-Life (T1/2) of Bintrafusp Alfa | Elimination half-life determined as 0.693/terminal first order (elimination) rate constant. | Predose, Day 22, Day 43, Day 64 and Day 85 | 
| Number of Participants With Positive Antidrug Antibodies (ADA) | Serum samples were analyzed by a validated assay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported. | Time from first treatment assessed up to approximately 26 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small Cell Lung Cancer, Bintrafusp alfa (proposed INN), M7824, Stage IV, INTR@PID LUNG 024