Study of Treatment With Sacituzumab and Zimberelimab for Patients With Lung Cancer Confined to the Chest and Previously Operated on Who Were Not Disease-free.

Carcinoma, Non-Small-Cell Lung Clinical Trial

— ARIAN  

Official title:

A Phase III Clinical Trial of Adjuvant Treatment With Sacituzumab and Zimberelimab for Stage IB-IIIA-IIIB(N2) Previously Resected (R0) Non-small Cell Lung Cancer Patients That Did Not Achieve Pathological Complete Response After Neoadjuvant treatment_ARIAN

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06431633
• Other study ID #: GECP 23/03_ARIAN
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: June 16, 2024
• Est. completion date: June 15, 2031

Study information

• Verified date: May 2024
• Source: Fundación GECP
• Contact: Eva Pereira
• Phone: +34 934302006
• Email: gecp[@]gecp.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Open-label, phase III, randomized, stratified (PDL1- vs PDL1+), 3 arms, multicenter clinical trial.

129 resected patients (43 per arm) with stage from IB to IIIA and IIIB (N2) non-small cell lung cancer that do not achieve pathologic complete response (pCR) after neoadjuvant treatment.

This clinical trial has 3 arms of treatment. ARM 1: Observation 10 months, ARM 2: treatment with immunotherapy (Zimberelimab) for 13 cycles and ARM 3: treatment with Sacituzumab Govitecan and Zimberelimab for 8 cycles and Zimberelimab monotherapy for 5 cycles.

The primary objective is to evaluate the disease-free survival (DFS): defined as the length of time from randomization to the earliest event defined as disease recurrence, any new lung cancer (even in the opposite lung), or death from any cause at any known point in time.

Patient accrual is expected to be completed within 2 years, treatment is planned to extend during 1 years and the patients will be followed up for 2 years. The study will end once survival follow-up has concluded.

Description:

This is an open-label, phase II, randomized, stratified (PDL1- vs PDL1+), 3 arms, multicenter clinical trial.

Patients stage IB to IIIA-IIIB (T3N2) after surgical resection if they did not achieve a pathological com-plete response (pCR) will be randomized 1:1:1 to:

• ARM 1: Observational Arm for 10 months

• ARM 2: Immunotherapy (Zimberelimab) treatment for 13 cycles, Q3W

• ARM 3: Sacituzumab Govitecan + Zimberelimab Q3W for 8 cycles + Zimberelimab Q3W for 5 cycles. Patients will receive 8 cycles of the combination and 5 cycles of Zimberelimab monotherapy.

The primary objective is to evaluate the disease-free survival (DFS): defined as the length of time from randomization to the earliest event defined as disease recurrence, any new lung cancer (even in the opposite lung), or death from any cause at any known point in time.

Disease Free survival (DFS): The time from random assignment to cancer recurrence or death from any cause.

Secondary objectives:

• Overall survival (OS): at 12, 24 and 36 months after the start of adjuvant treatment

• Safety and tolerability of the combination of Sacituzumab Govitecan + Zimberelimab according to CTCAE v5.0.

Exploratory objectives

• To evaluate whether there is a significant association between change in levels of ctDNA between baseline and after adjuvant treatment and OS and DFS.

The total trial duration will be 7 years approximately. Approval-start up: 4-6 months. Patient accrual is expected to be completed within 2 years. One year of treatment and 3 years of follow up, and close-out: 4-6 months. The study will end once survival follow-up has concluded

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 129
• Est. completion date: June 15, 2031
• Est. primary completion date: June 15, 2031
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 1. Patients diagnosed of primary non-small cell lung cancer, histologically confirmed.

• 2. Patients should be classified postoperatively in stage IB, IIA, IIB, IIIA or IIIB (N2) according to pathological criteria (pTNM) and according to 8th version of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology

• 3. Complete surgical resection (R0) of the primary NSCLC is also essential. Surgeons are strongly advised to dissect or obtain samples of all accessible lymph node levels, as established in the European Society of Thoracic Surgeons guide. Consequently, at the end of the surgical intervention it is recommended to have obtained samples of a minimum of 3 specific mediastinal ganglionic lobe stations (N2), one of which should include station 7, and at least one N1 station

• 4. The surgical intervention may consist of a lobectomy, sleeve resection, bilobectomy or pneumonectomy, as determined by the responsible surgeon based on intraoperative findings. Patients who have had only segmentectomies or wedge resections are not considered eligible for participation in this study except if R0 resection can be confirmed.

• 5. Only patients that do not achieve pathological complete response (pCR) seen in the surgical piece after neoadjuvant therapy are eligible.

• 6. Preoperative (neoadjuvant) use of platinum-based chemotherapy + immunotherapy (anti PD-1) is mandatory.

• 7. Preoperative, postoperative, or scheduled radiation therapy is not accepted for a later time. Patients with only N2 disease, who have to receive post-operative adjuvant radiotherapy will not be eligible.

• 8. A minimum of 3 weeks must have elapsed between the surgical intervention performed for the NSCLC and the randomization. Adjuvant treatment must start between the 3rd and the 10th week from surgery.

• 9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• 10. Patients aged = 18 years.

• 11. PDL1 value analysed locally (hospital must be able to provide this value before randomization)

• 12. PET-CT and brain CT before randomization to confirm the absence of distant disease.

• 13. Adequate hematologic and organ function

• 14.All patients are notified of the investigational nature of this study and signed a written in-formed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention.

• 15.For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception

• 16. For male patients with female partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception

• 17. Oral contraception should always be combined with an additional contraceptive method because of a potential interaction with the study drugs.

• 18.Women who are not postmenopausal or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug.

• 19.Patient capable of proper therapeutic compliance and accessible for correct follow-up

• 20. Patients with a life expectancy of at least more than 12 weeks

Exclusion Criteria:

• 1. Patients with a history of other malignant diseases, with the exception of the following:

• properly treated non-melanotic skin cancer

• cancer in situ treated with curative intent or other malignancies treated with curative intent and without signs of disease for a period of> 3 years after the end of the treatment and which, in the opinion of the doctor in charge of their treatment, do not present a substantial risk of relapse of the previous malignant disease.

• 2.T4 patients with invasion of heart, great vessels, carina, trachea, oesophagus or spine

• 3. Patients with ALK translocation, STK11 o KEAP1 known mutations before inclusion in this trial.

• 4. Patients with adenocarcinoma NSCLC must be tested for the common EGFR mutations before inclusion. Patients with any known EGFR mutation cannot be enrolled in the study.

• 5. Patients with a combination of microcytic and non-small cell lung cancer, a carcinoid lung tumor or large cell neuroendocrine carcinoma

• 6. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or GI perforation within 6 months of randomization.

• 7. Patients that received live attenuated vaccines within 30 days prior to randomization

• 8. History of a primary immunodeficiency, history of organ allogeneic transplantation, use of immunosuppressive drugs within 28 days before randomization or previous history of toxicity of severe immune mechanism (grade 3 or 4) with other immunological treatments

• 9. Patients with active or uncontrolled infections or with serious medical conditions or disorders that may not allow patient management as established in the protocol.

• 10. Patients who have suffered untreated and / or uncontrolled cardiovascular disorders and / or who have symptomatic cardiac dysfunction

• 11. Pregnant or breastfeeding women

• 12. Patients in whom R0 resection cannot be confirmed.

• 13. Patients with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

• 14.Patients with a condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

• 15. Have active hepatitis B virus (HBV) or hepatitis C virus (HCV). In patients with a history of HBV or HCV, patients with detectable viral loads will be excluded.

• 16. History of allergy or hypersensitivity to any of the study drug components

• 17. Pleural or pericardial effusion, both will be considered indicative of metastatic disease unless proven otherwise. Patients with pleural effusion not visible on chest-X-ray or too small to perform diagnostic puncture safely may be included.

• 18. Have known history of HIV-1 or 2 with detectable viral load OR taking medications that may interfere with SN-38 metabolism.

• 19.Severe infections within 4 weeks prior to be included in the study, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.

• 20.Patients with medical, mental, neurological or psychological condition which in the opinion of the investigator would not permit the patient to understand the patient information sheet or comply with study procedures.

• 21. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder; any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement; or prior pneumonectomy.

• 22. Treatment with systemic immunosuppressive medications

• 23.Patients with uncontrolled comorbidities that may affect the clinical trial compliance.

• 24.Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Non-Small-Cell Lung
• Lung Diseases
• Resectable Lung Non-Small Cell Carcinoma

Intervention

Drug:
• Zimberelimab
Zimberelimab is a fully human IgG4 monoclonal antibody targeting human PD-1. PD-1 is a type I transmembrane protein that is part of the immunoglobulin gene superfamily and the CD28 family of cell surface receptors. PD-1 is an inhibitory immune checkpoint protein that is expressed on activated B cells, T cells, and myeloid cells, and it plays a key role in limiting the activity of effector T cells. Zimberelimab is formulated at 30 mg/mL in a buffer solution containing histidine/histidine-HCl buffer solution, sucrose, sodium chloride, and polysorbate 80, at pH 5.5. The investigational product is supplied as a vial contains 120 mg of active Zimberelimab at a concentration of 30mg/mL. No premedication nor profilaxis is needed before Zimberelimab administration. Zimberelimab doses are administered by IV infusion over 60 minutes, followed by a 30- to 60-minute observation period, on D1 of each 21-day cycle.
• Sacituzumab govitecan
Sacituzumab govitecan (SG) is an ADC composed of the following 3 components: o The humanized monoclonal antibody hRS7 IgG1?, which binds to Trop-2, a transmembrane calcium signal transducer that is overexpressed in many epithelial cancers. o The camptothecin-derived agent SN-38, a topoisomerase I inhibitor. o A hydrolyzable linker, with the company designation as CL2A that links the humanized monoclonal antibody to SN-38. Sacituzumab govitecan is approved globally for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) and HR+ breast cancer.
• Cisplatin
Cisplatin-based adjuvant chemotherapy Cisplatin - CAS 15663-27-1, is a platinum coordination complex with potent anti-neoplastic activity. Induces apoptosis in cancer cells, possibly via caspase-3 activation.
• Carboplatin
Cisplatin-based adjuvant chemotherapy Structure: The cis-diamino (cyclobutane-1, 1 dicarboxylate) plating. Stability: 24 hours at ambient temperature in 5% glucose, glucosamine or physiologic saline. It is recommended not to dilute with chlorinated solutions for this could affect the carboplatin. Route of administration: Intravenous infusion. Guidelines of Carboplatin administration: According to the standard of each center. Other Name: ATC code: L01XA02

Locations

Country	Name	City	State
Spain	Hospitalario Universitario A Coruña	A Coruña	La Coruña
Spain	Hospital General Universitario de Alicante	Alicante
Spain	ICO Badalona, Hospital Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clínic De Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Parc Taulí	Barcelona
Spain	Hospital Universitari Vall d' Hebron	Barcelona
Spain	Hospital De Basurto	Bilbao
Spain	Hospital General de Elche	Elche	Alicante
Spain	ICO Hospitalet	Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitario Jerez De La Frontera	Jerez De La Frontera	Cádiz
Spain	Hospital Universitari de Gran Canària Doctor Negrín	Las Palmas De Gran Canaria	Las Palmas
Spain	Hospital Universitario de León	León
Spain	Hospital Universitario Lucus Augusti	Lugo
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Universitario Fundación Jiménez Díaz	Madrid
Spain	Hospital Universitario la Paz	Madrid
Spain	Hospital Universitario Puerta de Hierro	Majadahonda	Madrid
Spain	Hospital Santa María Nai	Ourense
Spain	Hospital de Son Espases	Palma De Mallorca	Mallorca
Spain	Hospital Universitari Son Llatzer	Palma De Mallorca
Spain	Hospital Universitari Sant Joan de Reus	Reus	Tarragona
Spain	Hospital Universitario Salamanca	Salamanca
Spain	Hospital Universitario Nuestra Señora La Candelaria	Santa Cruz De Tenerife
Spain	Hospital Virgen del Rocío	Sevilla
Spain	Consorci Sanitari de Terrassa	Terrassa
Spain	Hospital Clínico de Valencia	Valencia
Spain	Hospital Universitario La Fe	Valencia
Spain	Hospital Clínico Universitario de Valladolid	Valladolid
Spain	Complejo Hospitalario Universitario de Vigo	Vigo	Pontevedra

Sponsors (1)

Lead Sponsor	Collaborator
Fundación GECP

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in levels of ctDNA during treatment	Analyze plasma samples and quantifying the amount of circulating tumor DNA (ctDNA) by NGS.	To analyze at pretreatment, after 6 months of treatment, and at disease relapse, assessed up to 36 months
Primary	Disease free survival	Defined as the length of time from randomization to the earliest event defined as disease recurrence, any new lung cancer (even in the opposite lung), or death from any cause at any known point in time.	The time from random assignment to cancer recurrence or death from any cause, assessed up to 36 months
Secondary	Overall survival	defined as the length of time from either the date of diagnosis or the start of the treatment that patients diagnosed with the disease are still alive.	To evaluate at 12, 24 and 36 months after the start of adjuvant treatment
Secondary	Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)	Occurrence and severity of adverse events, with severity determined by NCI CTCAE v5.0 criteria.	From the subject's written consent to participate in the study through 180 days after the final administration of the drug

External Links

•   Web page of the sponsor where users can find more information about Fundación GECP studies