RILVEGOSTOMIG for Non-small cell lung cancer | Advanced non-small cell lung cancer | Metastatic non-small cell lung cancer

Inclusion criteria

• {"criterion_text":"- Capable of giving signed informed consent as described in Appendix A 3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.\n- Predicted life expectancy of ≥ 12 weeks.\n- Must have at least one measurable lesion according to RECIST v1.1. (a) For participants who undergo biopsies at screening and/or on treatment, the biopsied lesion must be distinct from any lesion used in the RECIST v1.1 evaluation. See Section 8.5.2.1 for further details.\n- Adequate organ and bone marrow function measured during the screening period (ie, Day -28 to Day -1) as defined in Table 7. Table 7 Criteria for Adequate Organ and Marrow FunctionType Parameter Value Hematological Hemoglobin ≥ 9.0 g/dL (5.59 mmol/L) with no blood transfusions (packed red blood cells) during the screening period (ie, Day -28 to Day -1) Absolute neutrophil count ≥ 1.5 × 109/L (1,500 per mm3) Platelet count ≥ 100 × 109/L (100,000 per mm3) with no platelet transfusions during the screening period (ie, Day 28 to Day -1) Hepatic Total bilirubin ≤ 1.5 × ULN in the absence of Gilbert’s syndrome ≤ 3 × ULN if the participant has Gilbert’s syndrome Alanine transaminase and aspartate transaminase ≤ 3 × ULN ≤ 5 × ULN in the case of liver metastasis Renal Calculated creatinine clearance by modified Cockcroft Gault (Rostoker et al, 2007) ≥ 45 mL/minute ULN = upper limit normal. Reproduction and Contraception Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Refer to Appendix B for definitions of women of childbearing potential and highly effective methods of contraception.\n- Female participants of childbearing potential: (a) Must have negative pregnancy test at screening and prior to each administration of investigational product. (b) If sexually active with a non-sterilized male partner, must use at least one highly effective method of birth control (see Appendix B) from screening to 60 days after the last dose of investigational product. (c) Non-sterilized male partners of female participants of childbearing potential must use a male condom plus spermicide from screening to 60 days after the last dose of investigational product. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. (d) Must not breastfeed and must not donate, or retrieve for their own use, ova from screening to 60 days after the last dose of investigational product.\n- Non-sterilized male participants who are sexually active with a female partner of childbearing potential: (a) Non-sterilized male participants who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom plus spermicide from screening to 60 days after the last dose of investigational product. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. (b) Female partners (of childbearing potential) of a male participant also must use at least one highly effective method of contraception (see Appendix B) throughout this period. (c) Male participants must refrain from fathering a child or donating sperm during the study and for 60 days after the last dose of investigational product.\n- Written informed consent and any locally required authorization obtained from the participant prior to performing any protocol-related procedures.\n- Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative (Section 8.6 and Appendix F). Participants not giving consent for Optional Genetic Research will still be eligible.\n- Must be 18 years of age or over at the time of signing the ICF.\n- Histologically or cytologically documented squamous/non squamous NSCLC not amenable to curative surgery or radiation as defined below (according to the 8th Edition of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology): (a) Part A (Dose Escalation) and B (Dose Expansion): stage III unresectable and stage IV squamous/non squamous NSCLC. (b) Parts C and D (Dose Expansion): stage IV squamous/non squamous NSCLC only (c) Parts E (Dose Expansion): stage IV squamous NSCLC only\n- Documented PD-L1 by PD L1 IHC meeting the criteria below (Note: in countries where PD-L1 testing is not standard of care, this testing may be conducted after informed consent as a study procedure during the screening window): (a) Part A (Dose Escalation): PD-L1 TPS ≥ 1% per local report. (b) Part B (Dose Expansion): PD-L1 TPS ≥ 1% per local report. (c) Part C (Dose Expansion): PD-L1 TPS ≥ 1% per local report. For Part C, 22C3 antibody results will be preferred. (d) Part D (Dose Expansion): PD-L1 TPS ≥ 50% per local report. For Part D, 22C3 antibody results will be preferred. (e) Part E (Dose Expansion): PD-L1 TPS ≥ 1% per local report. For Part E, 22C3 antibody results will be preferred. (f) All Parts: provision of archival tumor tissue (or fresh tumor tissue biopsy if archival tumor tissue is not available and if clinically feasible) is mandatory at screening for all study parts (A-E). See Section 8.5.2.1 for details.\n- Prior anticancer therapy as detailed below: (a) Parts Aand Part B: Must have received both a prior CPI and prior platinum-based chemotherapy (either in combination or as part of separate lines of treatment) as follows and be deemed not amenable for available standard of care options: \t(i) Primary CPI resistance with a CPI exposure of ≥ 6 weeks and at least two full cycles and with best overall response (BOR) of either PD or complete response (CR), PR, or SD (per immune RECIST [iRECIST]/RECIST v1.1) for < 6 months duration with anti PD 1/L1 monotherapy with or without chemotherapy according to the principles of Society for Immunotherapy of Cancer (SITC) consensus definition (Kluger et al, 2020) or \t(ii) Secondary CPI resistance defined as previous CPI exposure of ≥ 6 months with BOR of CR, PR, or SD (per iRECIST v1.1) for ≥ 6 months duration with anti PD 1/L1 monotherapy with or without chemotherapy according to the principles of SITC consensus definition (Kluger et al, 2020). \t(iii) CPI-experienced participants are eligible only if they have received a minimum number of 2 cycles of a locally approved CPI regimen regardless of the approved schedule (Q3W, every 4 weeks [Q4W], or every 6 weeks [Q6W]); participants having received a regimen including a combination of CPIs are eligible if this regimen was administered at the same time and not sequentially. \t(iv) Participants must have confirmed progression during or after completing treatment with a CPI including regimen, irrespective of whether this is the most recent regimen (NOTE: Participants progressing after discontinuation of a CPI including regimen for non-medical reasons may still be eligible). Confirmed progression is defined as radiologic progression confirmed by a second scan at approximately 4 to 8 weeks after the initial scan showing PD, or a single scan showing radiological progression accompanied by correlative symptoms suggestive of PD (NOTE: A single scan showing PD may be sufficient if, per clinical judgment, the participant is considered to have progressed on the CPI containing regimen). (b) Part C: Must meet one of: \t(i) No prior treatment for metastatic NSCLC, eligible for CPI-monotherapy because of high PD-L1 expression (TPS ≥ 50%), and not in need of rapid disease control via chemotherapy-containing regimen, or \t(ii) No prior treatment for metastatic NSCLC and not eligible for or not consenting to a platinum-based chemotherapy or combination regimen, or \t(iii) Prior treatment for metastatic NSCLC with one regimen consisting of chemotherapy only. (c) Part D: Must meet one of: \t(i) No prior treatment for metastatic NSCLC, and not in need of rapid disease control via chemotherapy-containing regimen, or \t(ii) Prior treatment for metastatic NSCLC with one regimen consisting of chemotherapy only. (d) Part E (i) No prior treatment for metastatic NSCLC, and not in need of rapid disease control via chemotherapy-containing regimen.\n- Body mass index ≥ 17.\n- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment."}

Exclusion criteria

• {"criterion_text":"- Participants with either of the following are excluded: a) Sensitizing epidermal growth factor receptor mutations or anaplastic lymphoma kinase fusions (documented test result is mandatory for participants with non squamous histology). For participants with squamous histology mutation, testing is mandatory only if participant is a never smoker or in the presence of a mixed histology. b) Documented test result for any other known genomic alteration for which a targeted therapy is approved in first line per local standard of care (eg, ROS1, NTRK fusions, BRAF, V600E mutation, etc).\n- Other invasive malignancy within 2 years prior to screening.\n- Psychiatric illness/social situations/substance abuse disorders that would limit compliance with study requirements, substantially increase risk of incurring AEs, or compromise the ability of the participant to give written informed consent.\n- Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product is excluded. The following are exceptions to this criterion: a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intraarticular injection). b) Systemic corticosteroids at physiological doses not to exceed 10 mg/day of prednisone or equivalent. c) Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication).\n- Any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for noncancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable.\n- Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants should not receive live vaccine while receiving study intervention and up to 30 days after the last dose of study intervention. COVID 19 vaccination should not be given for 72 hours prior to administration of the first dose of investigational product or during the DLT period.\n- Concurrent enrollment into another interventional clinical trial, unless it is an observational (non interventional) clinical study or during the follow up period of an interventional study.\n- Known allergy or hypersensitivity to rilvegostomig or any of the excipients of rilvegostomig.\n- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).\n- Pregnant or lactating female, or intend to become pregnant during the study.\n- Judgment by the investigator that the individual should not participate in the study.\n- Part A (Dose Escalation) and Part B (Dose Expansion): a) Previous treatment with an anti-TIGIT therapy. b) Primary or secondary resistance after treatment with 2 or more regimens including a CPI. c) Unresolved toxicities of ≥ Grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] v5.0) from prior therapy (excluding vitiligo, alopecia, endocrine disorders that are controlled with replacement hormone therapy, asymptomatic laboratory abnormalities). d) Experienced a toxicity that led to permanent discontinuation of prior immunotherapy.\n- Parts C, D, and E (Dose Expansion): (a) Parts C and D (i) Any prior systemic treatment with an immune oncology agent, including but not limited to anti PD 1, anti PD L1, anti CTLA 4. Treatment with one previous systemic chemotherapy will be allowed. Note: Prior administration of immune oncology agent for curative intent to treat other invasive malignancy is permitted. (ii) Unresolved toxicities of ≥◦Grade◦2 (CTCAE v5.0) from prior therapy (excluding vitiligo, alopecia, endocrine disorders that are controlled with replacement hormone therapy, asymptomatic laboratory abnormalities). (b) Part E (Dose Expansion): (i) Any prior systemic treatment for metastatic NSCLC, including but not limited to chemotherapy, anti PD 1, anti PD L1, anti CTLA 4. (ii) Unresolved toxicities of ≥ Grade 2 (CTCAE v5.0) from prior therapy (excluding vitiligo, alopecia, endocrine disorders that are controlled with replacement hormone therapy, asymptomatic laboratory abnormalities).\n- Symptomatic central nervous system (CNS) metastasis. a) Note: potentially eligible are: participants with known asymptomatic CNS lesions that do not require treatment according to principal investigator judgment, or asymptomatic, adequately treated with stereotactic radiation therapy, craniotomy, gamma knife therapy, or whole brain radiotherapy, with no subsequent evidence of CNS progression (documented with magnetic resonance imaging [MRI] scans showing the absence of brain metastasis progression after radiotherapeutic intervention); participants must not require steroid exceeding 10 mg prednisone or 2 mg/day of dexamethasone or equivalent; participants with a history of CNS metastases must have MRI of the brain at screening. Participants with CNS metastases who are receiving steroids must be on a stable dose of steroids for ≥ 7 days prior to study entry and prior to baseline imaging.\n- Thromboembolic event within 3 months before the first dose of investigational product.\n- History of organ transplant.\n- Active primary immunodeficiency/active infectious disease(s): a) Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination, and radiographic findings and TB testing in line with local practice). b) Human immunodeficiency virus (HIV) (positive for HIV-1 or HIV-2 antibodies). c) Chronic or active hepatitis B, chronic or active hepatitis C; however, participants who have chronic hepatitis B and are receiving suppressive antiviral therapy are allowed to be enrolled if ALT is normal and viral load is controlled. Controlled hepatitis B viral load is defined as serum hepatitis B virus deoxyribonucleic acid (DNA) < 100 U/mL by polymerase chain reaction (PCR). Participants with controlled hepatitis B viral load must remain on antiviral therapy, per institutional practice, during the study treatment and follow up period to ensure adequate viral suppression. Participants who have chronic hepatitis C are allowed to be enrolled if ALT is normal and hepatitis C virus (HCV) ribonucleic acid (RNA) undetectable by PCR, either spontaneously or in response to a successful prior course of anti hepatitis C therapy (Regev et al, 2020). Controlled hepatitis C viral load is defined as undetectable hepatitis C RNA by PCR either spontaneously or in response to a successful prior course of anti hepatitis C therapy. d) Acute hepatitis A. e) For all participants in the study, all local institutional standards for coronavirus disease 2019 (COVID 19) must be followed for testing. For participants with a known previous COVID-19 infection, either negative PCR test must be documented prior to the first dose or a minimum of 10 days must have elapsed since the last positive COVID-19 test.\n- History of arrhythmia (such as multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (National Cancer Institute [NCI] CTCAE v5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.\n- Uncontrolled intercurrent illness including, but not limited to, ongoing or active known infection, cardiomyopathy of any etiology, symptomatic congestive heart failure (as defined by New York Heart Association class ≥ 3), ILD, uncontrolled hypertension, uncontrolled diabetes mellitus, unstable angina pectoris, history of myocardial infarction within the past 6 months, serious chronic gastrointestinal conditions associated with diarrhea (eg, active inflammatory bowel disease), active non infectious skin disease (including any grade rash, urticarial, dermatitis, ulceration, or psoriasis, but excluding stable plaque psoriasis from the definition of active disease), active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment."}

Primary endpoints

• {"endpoint_text":"- The ORR is defined as The percentage of participants with a confirmed CR or PR, with The denominator defined as The number of participants in The response evaluable set. Objective response rate and its CIs will be summarized by dose regimen. Percentage of participants with AEs and imAEs, SAEs, DLTs, vital signs, and abnormal laboratory parameters Rate of rilvegostomig discontinuation due to toxicity","definition_or_measurement_approach":"ORR defined as percentage of participants with a confirmed complete response (CR) or partial response (PR); denominator = number of participants in the response-evaluable set. ORR and CIs summarized by dose regimen. Safety summaries include percentages with AEs, immune-mediated AEs (imAEs), SAEs, DLTs, vital signs, abnormal labs and discontinuation rate due to toxicity."}

Secondary endpoints

• {"endpoint_text":"- Best Overall Response is defined as the best response a subject has had following start of dosing, but prior to starting any subsequent cancer therapy and up to and including RECIST progression or the last evaluable assessment in the absence of RECIST progression. Categorization of BOR is based on RECIST using the following response categories: CR, PR, SD, PD, and not evaluable (NE).","definition_or_measurement_approach":"BOR: best response after dosing but before subsequent therapy, up to RECIST progression or last evaluable assessment. Categorized per RECIST v1.1 as CR, PR, SD, PD, NE."}
• {"endpoint_text":"- The DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression. Only participants who have achieved confirmed CR or PR will be included in the summaries of DoR. The DoR will be summarized using descriptive statistics and Kaplan Meier plots, where there are sufficient numbers of responders.","definition_or_measurement_approach":"Duration of Response: time from first documented response to progression or death; analyses limited to confirmed CR/PR; summarized with descriptive stats and Kaplan-Meier where sufficient responders."}
• {"endpoint_text":"- Disease control rate at time point of interest is defined as the percentage of participants who have a best objective response of confirmed CR or PR or who have SD lasting for at least a certain time of period after start of treatment. The DCR and its exact CIs will be summarized by dose regimen.","definition_or_measurement_approach":"DCR: percent with confirmed CR or PR or SD lasting at least a prespecified duration after treatment start; summarized with exact CIs by dose regimen."}
• {"endpoint_text":"- The DRR is defined as the percentage of participants who have a confirmed CR or PR with duration of response lasting ≥ 6 months. The DRR and its exact CIs will be summarized by dose regimen.","definition_or_measurement_approach":"DRR: percent with confirmed CR/PR with DoR ≥ 6 months; summarized with exact CIs by dose regimen."}
• {"endpoint_text":"- Time to response (TTR) is defined as the time from the first dose until the first documentation of a subsequently confirmed objective response. Only participants who have achieved confirmed CR or PR will be included in the summaries of TTR. The TTR will be summarized using the Kaplan-Meier method, where there are sufficient numbers of responders.","definition_or_measurement_approach":"TTR: time from first dose to first documentation of a subsequently confirmed objective response; analyses among confirmed CR/PR; summarized by Kaplan-Meier where feasible."}
• {"endpoint_text":"- The best percentage change from baseline in tumor size is the largest decrease (or smallest increase) for a participant, using RECIST assessments.","definition_or_measurement_approach":"Best percent change from baseline in tumor size per RECIST assessments (largest decrease or smallest increase)."}
• {"endpoint_text":"- Progression-free survival is defined as the time from the start of treatment until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the participant withdraws from study therapy or receives another anti-cancer therapy prior to progression.","definition_or_measurement_approach":"PFS: time from treatment start to objective progression or death; analyzed irrespective of withdrawal or subsequent therapy."}
• {"endpoint_text":"- Measure the RO of TIGIT and PD 1 on peripheral blood T cells for parts A and B","definition_or_measurement_approach":"Receptor occupancy (RO) measurement of TIGIT and PD-1 on peripheral blood T cells for Parts A and B (assay/methodology referenced in protocol)."}
• {"endpoint_text":"- Incidence of ADAs against rilvegostomig in serum","definition_or_measurement_approach":"Incidence (frequency) of anti-drug antibodies (ADAs) to rilvegostomig measured in serum samples."}
• {"endpoint_text":"- Serum concentrations and PK parameters (where applicable) of rilvegostomig; PK parameters to be evaluated include but not limited to Cmax, AUC, clearance, and t1/2","definition_or_measurement_approach":"Pharmacokinetic endpoints: serum concentrations and PK parameters including Cmax, AUC, clearance, t1/2, etc., per PK sampling schedule."}

Belgium

Earliest CTIS Part Ii Submission Date

2024-03-21

Latest Decision Or Authorization Date

15-04-2024

Processing Time Days

25

Number Of Sites

2

Number Of Participants

20

Denmark

Earliest CTIS Part Ii Submission Date

2024-03-21

Latest Decision Or Authorization Date

03-04-2024

Processing Time Days

13

Number Of Sites

1

Number Of Participants

10

France

Earliest CTIS Part Ii Submission Date

2024-03-21

Latest Decision Or Authorization Date

05-04-2024

Processing Time Days

15

Number Of Sites

2

Number Of Participants

3

Spain

Earliest CTIS Part Ii Submission Date

2024-03-21

Latest Decision Or Authorization Date

05-04-2024

Processing Time Days

15

Number Of Sites

3

Number Of Participants

11

Netherlands

Earliest CTIS Part Ii Submission Date

2024-03-21

Latest Decision Or Authorization Date

04-04-2024

Processing Time Days

14

Number Of Sites

3

Number Of Participants

17

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden