Study of Immunotherapy (Sasanlimab) in Combination With Targeted Therapies in People With Advanced Non-small Cell Lung Cancer (NSCLC) (Landscape 1011 Study)

Study Overview
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Brief Summary
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Phase 1b/Phase 2 Umbrella Study; open-label, multi-center, parallel group study. Sasanlimab (a PD-1 antagonist monoclonal antibody) will be combined with a different targeted therapy in each sub-study. Phase1b of each sub-study will evaluate the safety of the combination and select the dose for the Phase 2 portion. Phase 2 of each sub-study will evaluate the anti-tumor activity of the combination. Sub-Study A is active, not recruiting, ongoing participants are still receiving treatment in Phase 1, Phase 2 will not be initiated. Sub-study B is complete. All participants have discontinued treatment and any additional follow up required by protocol.

Detailed Description
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Landscape 1011 is a clinical research study for people with advanced (stage 3b or 4) non-small cell lung cancer (NSCLC). The purpose of this study is to learn if the study medicine (sasanlimab, a type of immunotherapy) along with other study medicines is safe and effective in people with non-small cell lung cancer that has spread outside of the lungs. There are currently two sub-studies using different types of medicines. People in the first sub-study will receive sasanlimab as a subcutaneous (under the skin) injection at the study clinic every 4 weeks. Additionally, they will take targeted cancer therapies encorafenib by mouth once a day and binimetinib by mouth twice a day at home. People in the second sub-study will receive the study medicine sasanlimab as a subcutaneous (under the skin) injection at the study clinic every 3 weeks and will also receive SEA-TGT (an immunotherapy) by infusion every three weeks. Additionally, they will take axitinib (a targeted therapy) by mouth twice a day at home. In addition to taking the study drugs, participants in the sub-studies will be asked to visit the clinic for health checks. These include health questions, physical examinations, blood and urine samples, and imaging scans. These assessments help the study doctor and team to monitor the participants' safety and well-being, and to see how their cancer is responding to the treatment. Participants will continue in the study until the cancer is no longer responding to the study medicine.

Official Title
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A Phase 1b/2 Open Label Umbrella Study of Sasanlimab Combined With Anti-Cancer Therapies Targeting Multiple Molecular Mechanisms in Participants With Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Sasanlimab Prefilled syringe
* Drug: Encorafenib
* Drug: Binimetinib
* Drug: Sasanlimab
* Drug: Axitinib
* Drug: SEA-TGT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Umbrella Phase 1b & 2: Histologically or cytologically confirmed locally advanced/metastatic (Stage IIIB-IV) NSCLC. At least one measurable lesion per RECIST v1.1 at Screening. ECOG Performance Status 0 or 1. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1. Adequate hepatic, renal, and bone marrow function. Additional Inclusion Criteria for Sub-Study A Phase 1b &2: -BRAFV600E mutation in tumor tissue or plasma as determined by a local laboratory PCR or NGS assay and documented in a local pathology report. Additional Inclusion Criteria for Sub-Study A Phase 1b only: -Any line of therapy for locally advanced/metastatic NSCLC. Additional Inclusion Criteria for Sub-Study A Phase 2 only: -Previously untreated for locally advanced/metastatic NSCLC Additional Inclusion Criteria for Sub-Study B Phase 1b only:: -Any line of therapy for locally advanced/metastatic NSCLC. Additional Inclusion Criteria for Sub-Study B Phase 2 only: Previously untreated for locally advanced/metastatic NSCLC (Arms B1 & B2), or One or 2 prior lines of therapy for advanced/metastatic NSCLC (Arm B3), including immune checkpoint inhibitor treatment + chemotherapy, and have progressed during or after that therapy. PD-L1 TPS ≥1% Exclusion Criteria Umbrella Phase 1b &2: Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Active non-infectious pneumonitis, pulmonary fibrosis, or known history of immune-mediated pneumonitis. Active infection requiring systemic therapy. Clinically significant cardiovascular disease. Other malignancy within 2 years of first dose, with exceptions. Symptomatic brain metastasis, with exceptions. Additional Exclusion Criteria for Sub-Study A Phase 1b&2: EGFR mutation, ALK fusion oncogene, or ROS1 rearrangement. Prior treatment with any BRAF inhibitor or MEK inhibitor. Additional Exclusion Criteria for Sub-Study A Phase 2 only: -Prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents. Additional Exclusion Criteria for Sub-Study B Phase 1b&2: -Documentation of any tumor-driving molecular alteration (eg, BRAF, EGFR, ALK) Additional Exclusion Criteria for Sub-Study B Phase 2 only: Prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents.(Arms B1 & B2) Confirmed progressive disease on 1st or 2nd imaging tumor assessment after initiation of therapy for advanced/metastatic NSCLC.

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: Sub-Study A<br>Sasanlimab will be administered subcutaneously. Encorafenib & binimetinib will be administered orally. Treatments will be administered until progressive disease, unacceptable AE, participant withdraws, or study is terminated. | Drug: Sasanlimab Prefilled syringe<br>* prefilled syringe<br>Drug: Encorafenib<br>* capsules<br>Drug: Binimetinib<br>* tablets<br>|
| Experimental: Sub-Study B<br>Sasanlimab will be administered subcutaneously. Axitinib will be administered orally. SEA-TGT will be administered intravenously. Treatments will be administered until progressive disease, unacceptable AE, patient withdraws, or study is terminated. | Drug: Sasanlimab<br>* solution supplied in vials<br>Drug: Axitinib<br>* tablets<br>Drug: SEA-TGT<br>* solution in vials<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b of Sub-Study A: Percentage of Participants With Dose-Limiting Toxicities (DLT) | DLT=AEs in DLT observation period (OP) related to any study intervention:Grade (G)4 neutropenia;thrombocytopenia or anemia;febrile neutropenia;neutropenic infection;G3 thrombocytopenia with bleeding. Any G>=3 toxicity (except transient G3 fatigue, local reactions/headache that resolved to G<=1/baseline; G3 nausea, vomiting controlled within 72 hrs, G3 hypertension controlled by medical therapy (MT), G3 diarrhea that improved to G<=2 within 72 hrs, G3 skin toxicity that resolved to G<=1 in <7 days after MT, G3 endocrinopathies controlled by MT and tumors flare); Non-hematologic G3 lab abnormality [LA](medical intervention or hospitalization), or any G4 LA;ALT/AST>3*ULN (normal at baseline) or >3*ULN and doubling baseline (>ULN at baseline) and associated with total bilirubin(TB) >2*ULN;or ALT/AST>5*ULN; or TB>3*ULN. Missing 75% of planned doses during DLT OP due to treatment-related toxicities. AE not listed/DLT criteria outside DLT OP was DLT at discretion of sponsor and investigator. | Day 1 up to Day 28 of Cycle 1 | 
| Phase 2 of Sub-Study A: Durable Objective Response Rate (ORR) | Durable ORR was defined as percentage of participants with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 based on investigator assessment, lasting for at least 10 months from the date of first CR or PR until the date of the first documentation of disease progression (PD), death, or start of new anticancer therapy. CR was defined as complete disappearance of all target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10 millimeter [mm]). PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 mm. | From the date of first CR or PR until the date of the first documentation of PD, death, or start of new anticancer therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b of Sub-Study A: Number of Participants With Adverse Events (AEs) Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs will be graded by the investigator according to NCI CTCAE version 5.0; where Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening and Grade 5=death. | From the start of study treatment (Cycle1 Day1) up to 30 days after last dose of study treatment (approximately 44 months) | 
| Phase 2 of Sub-Study A: Number of Participants With Adverse Events Graded According to NCI-CTCAE Version 5.0 | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. AEs were planned to be graded by the investigator according to NCI CTCAE version 5.0; where Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening and Grade 5=death. | From the start of study treatment (Cycle1 Day1) up to 30 days after last dose of study treatment | 
| Phase 1b of Sub-Study A: Number of Participants With Laboratory Abnormalities | Following assessments will be performed: hematology: hemoglobin, platelet count, white blood cell (WBC) count, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, absolute basophils. Chemistry: alanine aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate or carbon dioxide (CO2), C-reactive protein (CRP), alkaline phosphatase, sodium, potassium, magnesium chloride, total calcium, total bilirubin, total protein, blood urea nitrogen (BUN) or urea, creatinine, creatinine clearance, uric acid, glucose (random), lactate dehydrogenase, albumin, phosphorus or phosphate, amylase, lipase. | From the start of study treatment (Cycle1 Day1) up to 30 days after last dose of study treatment (approximately 44 months) | 
| Phase 2 of Sub-Study A: Number of Participants With Laboratory Abnormalities | Hematology and clinical chemistry parameters were planned to be assessed. | From the start of study treatment (Cycle1 Day1) up to 30 days after last dose of study treatment | 
| Phase 1b of Sub-Study A: Durable Objective Response Rate | Durable ORR was defined as percentage of participants with confirmed CR or PR according to RECIST v1.1 based on investigator assessment, lasting for at least 10 months from the date of first CR or PR until the date of the first documentation of PD, death, or start of new anticancer therapy. CR was defined as complete disappearance of all target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above smallest sum observed (over baseline if no decrease in the sum is observed during therapy) with a minimum absolute increase of 5 mm. | From the date of first CR or PR until the date of the first documentation of PD, death, or start of new anticancer therapy (approximately 44 months) | 
| Phase 1b of Sub-Study A: Objective Response Rate | Objective response rate is defined as percentage of participants with confirmed best overall response of CR or PR according to RECIST v1.1 from the date of first dose of study treatment until the date of the first documentation of PD. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. | From the date of first dose of study treatment until the date of the first documentation of PD (approximately 44 months) | 
| Phase 2 of Sub-Study A: Objective Response Rate | Objective response rate is defined as percentage of participants with confirmed best overall response of CR or PR according to RECIST v1.1 from the date of first dose of study treatment until the date of the first documentation of PD. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. | From the date of first dose of study treatment until the date of the first documentation of PD | 
| Phase 2 of Sub-Study A: Duration of Response (DR) | DR was defined for participants with confirmed objective response (OR) as time from date of first documentation of OR to the date of first documentation of PD or death (any cause), whichever occurred first. OR=CR or PR according to RECIST v1.1 based on investigator assessment. CR and PR must be confirmed by repeat assessments performed no <4 weeks after criteria for response were first met. CR=complete disappearance of all target lesions (TLs) with exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). PR=greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions (TMLs). PD=20% increase in sum of diameters of TMLs above smallest sum observed (over baseline if no decrease in sum was observed during therapy), with a minimum absolute increase of 5 mm. | From the date of first documentation of OR to the date of the first documentation of PD or death due to any cause, whichever occurred first | 
| Phase 2 of Sub-Study A: Time to Tumor Response (TTR) | TTR is defined for participants with confirmed objective response as the time from the date of first dose of study treatment to the date of first documentation of objective response (CR or PR) which was subsequently confirmed. CR=complete disappearance of all target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). PR=greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. | From the date of first dose of study treatment to the date of first documentation of objective response | 
| Phase 2 of Sub-Study A: Progression-Free Survival (PFS) | PFS is defined as the time from the date of first dose of study treatment to the date of first documentation of PD or death due to any cause, whichever occurred first. PD=20% increase in sum of diameters of target measurable lesions above smallest sum observed (over baseline if no decrease in sum was observed during therapy), with a minimum absolute increase of 5 mm. | From the date of first dose of study treatment to the date of first documentation of PD or death due to any cause, whichever occurred first | 
| Phase 2 of Sub-Study A: Overall Survival (OS) | OS is defined as the time from the date of first dose of study treatment to the date of death due to any cause. Participants last known to be alive were planned to be censored at the date of last contact. | From the date of first dose of study treatment to the date of death due to any cause or censoring date | 
| Phase 1b of Sub-Study A: Area Under the Concentration Verses Time Curve Over the Dosing Interval (AUCtau) After Single Dose of Sasanlimab | AUCtau was defined as area under the plasma concentration time curve from time zero to the next dose. | Cycle 1 (pre-dose on Day 1, 168 hours [Day 8] and 336 hours [Day 15] and Day 28 post-dose) | 
| Phase 2 of Sub-Study A: Area Under the Concentration Verses Time Curve Over the Dosing Interval (AUCtau) After Single Dose of Sasanlimab |  | Cycle 1 (pre-dose on Day 1, 336 hours [Day 15] and Day 28 post-dose) | 
| Phase 1b of Sub-Study A: Maximum Observed Plasma Concentration (Cmax) of Sasanlimab |  | Cycle 1 (pre-dose on Day 1, 168 hours [Day 8],336 hours [Day 15] and Day 28 post-dose) and Cycle 5 (pre-dose on Day 1 and 168 hours [Day 8] post dose) | 
| Phase 2 of Sub-Study A: Maximum Observed Plasma Concentration (Cmax) of Sasanlimab |  | Cycle 1 (pre-dose on Day 1, 336 hours [Day 15] and Day 28 post-dose) and Cycle 5 Day 1 (pre-dose) | 
| Phase 1b of Sub-Study A: Time for Cmax (Tmax) of Sasanlimab |  | Cycle 1 (pre-dose on Day 1, 168 hours [Day 8], 336 hours [Day 15] and Day 28 post-dose) and Cycle 5 (pre-dose on Day 1 and 168 hours [Day 8] post dose) | 
| Phase 2 of Sub-Study A: Time for Cmax (Tmax) of Sasanlimab |  | Cycle 1 (pre-dose on Day 1, 336 hours [Day 15] and Day 28 post-dose) and Cycle 5 Day 1 (pre-dose) | 
| Phase 1b of Sub-Study A: Pre-dose Concentration During Multiple Dosing (Ctrough) of Sasanlimab |  | Cycle 5 Day 1 (pre-dose) | 
| Phase 2 of Sub-Study A: Pre-dose Concentration During Multiple Dosing (Ctrough) of Sasanlimab |  | Cycle 5 Day 1 (pre-dose) | 
| Phase 1b of Sub-Study A: Ctrough of Encorafenib |  | Cycle 5 Day 1 (pre-dose) | 
| Phase 2 of Sub-Study A: Ctrough of Encorafenib |  | Cycle 5 Day 1 (pre-dose) | 
| Phase 1b of Sub-Study A: Ctrough of Binimetinib |  | Cycle 5 Day 1 (pre-dose) | 
| Phase 2 of Sub-Study A: Ctrough of Binimetinib |  | Cycle 5 Day 1 (pre-dose) | 
| Phase 1b of Sub-Study A: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibody (NAb) Against Sasanlimab | In this outcome measure, number of ADA-positive and NAb-positive participants has been presented. A participant was considered ADA (or NAb) positive if (1) baseline titer was missing or negative and participant had >= 1 post-treatment positive titer (treatment-induced), or (2) positive titer at baseline and had a >= [4-fold dilution increase] in titer (equivalent to 0.602 unit increase in logarithm to base 10 (log10) titer from baseline in >= 1 post-treatment sample (treatment-boosted). | Pre-dose on Cycle 1 Day 1 until end of treatment (up to approximately 255 days); each cycle is about 28 days | 
| Phase 2 of Sub-Study A: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibody (NAb) Against Sasanlimab |  | Pre-dose on Cycle 1 Day 1 until end of treatment; each cycle is about 28 days | 
| Phase 2 of Sub-Study A: Objective Response (OR) Rate by Programmed Death Ligand-1 (PD-L1) Expression at Baseline | OR rate is defined as percentage of participants with CR or PR according to RECIST v1.1 based on investigator assessment. CR=complete disappearance of all target lesions with exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). PR=greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. OR by PD-L1 expression at baseline was planned to be assessed. | From the date of first dose of study treatment until the date of the first documentation of PD | 
| Phase 2 of Sub-Study A: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30) Score | EORTC QLQ-C30: consisted of 30 questions grouped into 5 functional scales (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale; 3 symptom scales (fatigue, pain, nausea and vomiting); and 6 single items that assessed additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea), and financial impact. All scales and single item measures ranged in score from 0 to 100. Higher scores on the global health status/quality of life scale represent higher health status/quality of life. Higher scores on the functional scales represent higher levels of functioning. Higher scores on the symptom scales and single items represent a greater presence of symptoms or financial impact. | Baseline up to end of treatment | 
| Phase 2 of Sub-Study A: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC), Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13) Score | The EORTC QLQ-LC13 is the lung cancer specific module of the EORTC Quality of Life Questionnaire. The EORTC QLQ-LC13 consisted of 13 questions which included 1 multi-item scale and 9 single items assessing symptoms (dyspnea, cough, hemoptysis, and site specific pain), side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and pain medication use. The item scale ranged from 1 to 4 (1 = Not at all; 4 = Very Much) where the EORTC-QLQ-LC13 scoring algorithm was applied to convert to a 0 to 100 point scale where 100 is best quality of life (QOL), for comparability. Higher scores are reflective of a greater presence of symptoms. | Baseline up to end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Small-Cell Lung Carcinoma, NSCLC, non small cell lung cancer, non-small cell lung cancer, BRAF mutation, BRAF V600e, BRAF, B-RAF NSCLC, lung cancer, immunotherapy, sasanlimab, encorafenib, binimetinib, axitinib, SEA-TGT, TIGIT, locally advanced, metastatic, ECOG 0, ECOG 1, Stage 3B, Stage IV, previously untreated, second-line therapy, first-line therapy