A Phase III, Study to Investigate the Efficacy, Safety, and Pharmacokinetics of ZRC-3276 Versus Opdivo® (Nivolumab) in Subjects with locally advanced or Metastatic Non-Small Cell Lung Cancer

Phase 3

Completed

• Conditions: Malignant neoplasm of unspecifiedpart of bronchus or lung,

• Registration Number: CTRI/2022/12/047923
• Lead Sponsor: Zydus Lifesciences Ltd Formerly Cadila Healthcare Limited

Brief Summary

Lung cancer is the most common cancer and the leading cause of cancer-related deaths globally. Non–small-cell lung cancer accounts for 85% to 90% of lung cancers . Based on the national cancer registry data, incidence of lung cancer is highest amongst all approved indication of Nivolumab in India. Therefore, the selection of target patient population for current study was based on data in Indian population.



Nivolumab is a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, that binds with high affinity to PD-1 receptors expressed on T cells and disrupts negative signaling induced by PD-ligand 1 (PD-L1) and PD-ligand 2 to restore T-cell effector function. In one of the Phase I study in patients with advanced NSCLC, Nivolumab monotherapy demonstrated a mean ORR of 17% and 18% in pateints with squamous and nonsquamous histologies, respectiely. The survival rates were 42% (95% CI, 33 to 50) at 1 year, 24% (95% CI, 17 to 33) at 2 year, and 18% (95% CI, 11 to 25) at 3 year in the total population across all dose levels. [13]. These initial signals of efficacy and tolerability prompted two phase

III trials that demonstrated a survival benefit for salvage Nivolumab over docetaxel in patients with advanced pretreated NSCLC leading to its approval in the United States for treatment of patients with metastatic NSCLC whose disease has progressed on or after platinum based chemotherapy and after an approved TKI therapy (if expressing EGFR or ALK genomic tumor aberrations). Also, Nivolumab is approved in the European Union for locally

advanced or metastatic NSCLC after prior chemotherapy.

Detailed Description

Not available

Study Timeline

• Study Start: 2022-12-30
• Last Update Posted: 2024-04-13
• Study Completion: 2024-07-02

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 248

Inclusion Criteria

• 1.Male or female with≥ 18 years of age 2.Subjects with histologically or cytologically-documented locally advanced or metastatic NSCLC who present with Stage IIIB/IIIC/Stage IV or recurrent or progressive disease following multi-modality therapy (radiation therapy, surgical resection or definitive chemo radiation therapy for locally advanced disease). Note: Subjects eligible for study therapy after acceptable prior therapy are as specified below: o Subjects must have experienced disease recurrence or progression during or after one first line therapy for advanced or metastatic disease. o A switch of an agent within a regimen in order to manage toxicity does not define the start of a new line of therapy. Subjects must have received at least 2 cycles of platinum doublet based chemotherapy before discontinuation for toxicity. o Maintenance therapy following first line chemotherapy is not considered as a separate regimen of therapy and could comprise continuation of one or more of the agents used in the first-line therapy regimen or switch to another non cross-resistant agent. The initiation of maintenance therapy requires the lack of progressive disease with front-line therapy. Subjects who showed disease progression during or after maintenance therapy will be eligible. o Treatment given for locally advanced disease is not considered as a line of therapy for advanced disease. Participants with recurrent disease >6 months after platinum containing adjuvant, neoadjuvant or definitive chemo-radiation therapy given for locally advanced disease, who also subsequently progressed during or after a platinum doublet-based regimen given to treat the recurrence, are eligible. o Experimental therapies when given as separate regimen are considered as separate line of therapy. Subject who received experimental therapies for disease progression after fist line therapy will not be eligible.
• Participants who received adjuvant, neoadjuvant chemotherapy or definitive chemo-radiation therapy given for locally advanced disease, and developed recurrent disease within 6 months of completing therapy are eligible. o Adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery and/or radiation therapy) followed by recurrent or metastatic disease within 6 months of completing therapy is considered as first line therapy for advanced disease. 3.With at least one measurable target lesion (based on response evaluation criteria in solid tumors [RECIST] criteria, version 1.1) performed within 28 days of randomization a. Target Lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site 4.Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1. 5. Subjects who meets following laboratory values (assessed within 28 days prior to randomization): a. WBCs ≥2000/μL b. Neutrophils ≥1500/μL c. Platelets ≥100 X 10³/μL d. Hemoglobin ≥9.0 g/dL e. Serum creatinine of ≤1.5 X ULN or creatinine clearance >40 mL/minute (using Cockcroft/Gault formula) f. AST & ALT ≤1.5 X ULN g. Total bilirubin ≤ 1.5 X ULN 6. Female subjects who are not pregnant or breastfeeding and at least one of the following conditions applies: -Are postmenopausal for at least 24 months before the screening visit, OR -Are surgically sterile by bilateral tubal ligation, hysterectomy, or bilateral oophorectomy, OR -If they are of childbearing potential, agree to practice highly effective methodsof contraception (failure rate of less than 1% per year) with low user dependency when used consistently and correctly, from at least 28 days before starting study drug through 5 months after the last dose of study treatment, OR agree to completely abstain from heterosexual intercourse.
• A woman of child bearing potential must have a negative highly sensitive serum beta-human chorionic gonadotropin (beta-hCG) test at Screening and urine beta-hCG test at Baseline 7.Male subjects, even if surgically sterilized (i.e., status post vasectomy), who: -Agree to completely abstain from heterosexual intercourse, OR -Agree to practice effective barrier contraception during the entire study treatment period and through 5 months after the last dose of study treatment if their partner is of childbearing potential, even if they have had a successful vasectomy. 8.No clinically significant findings on clinical and/or physical examination, 12 lead ECG, or laboratory tests after signing the ICF but before receiving the first dose study drug. The Investigator will determine if a particular finding is clinically significant. 9. Subjects must have signed and dated an Institutional Review Board (IRB)/ Independent Ethics committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. 10. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.

Exclusion Criteria

• Subjects with CNS metastases, except for treated asymptomatic CNS metastases, provided all of the following criteria are met: a.
• Only supra-tentorial metastases allowed (i.e., no metastases to midbrain, pons, medulla, or spinal cord) b.
• No evidence of interim progression or hemorrhage after completion of CNS-directed therapy c.
• No ongoing requirement for corticosteroids as therapy for CNS disease (anticonvulsants at a stable dose are allowed at least two weeks prior to screening) d.
• No stereotactic radiation within 14 days or whole-brain radiation within 28 days prior to randomization e.
• Leptomeningeal disease (i.e. carcinomatous meningitis) 2.History of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease, or tests positive for HBsAg or anti- HCV at Screening.
• History of human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV at Screening.
• Other active malignancy requiring concurrent intervention.
• Subject with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, endometrial, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to screening AND no additional therapy is required or anticipated to be required during the study period.
• Subject with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization.
• Corticosteroids with minimal systemic absorption and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease 7.
• Subject with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue not resolved to grade 1 (NCI CTCAE version 5) or baseline before administration of study drug.
• Prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents.
• Prior radiotherapy or radiosurgery received within 2 weeks prior to screening.
• Prior treatment with Nivolumab or any other anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CD-137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) 12.
• Subject with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
• Subject not recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment.
• History of severe hypersensitivity reactions to other monoclonal antibodies.
• Allergy or intolerance (unacceptable adverse event) to study drug components, or Polysorbate-80-containing infusions.
• Ongoing or planned administration of anti-cancer therapies other than those specified in this study or use of strong CYP3A4 inhibitors.
• Have received treatment with any other investigational drug in the last 30 days before study entry, or within less than five half-lives after receiving the previous investigational drug.
• Receipt of IV antibiotics for infection within 14 days of randomization.
• 18.Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment.
• Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures).
• Have a history or suspicion of unreliability, poor cooperation or non-compliance with medical treatment or any other medical or psychiatric condition that could compromise study participation.
• History of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-V) criteria within 1 year before Screening or positive test result(s) for alcohol or drugs of abuse (including barbiturates, opiates, cocaine, cannabinoids, amphetamines and benzodiazepines) at Screening if required as per medical history.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Compare the efficacy of	Baseline and Cycle 12
ZRC-3276 IV infusion versus	Baseline and Cycle 12
Opdivo IV infusion in subjects	Baseline and Cycle 12
with locally advanced or	Baseline and Cycle 12
metastatic non-small cell lung	Baseline and Cycle 12
cancer.	Baseline and Cycle 12

Secondary Outcome Measures

Name	Time	Method
To assess the pharmacokinetics	of ZRC-3276 IV infusion
To assess the immunogenicity	of ZRC-3276 IV infusion
To compare the safety and	tolerability in subjects exposed

Trial Locations

Locations (46)

Aakash Healthcare Pvt. Ltd.; 🇮🇳 Delhi, DELHI, India

All Institute of Medical Sciences; 🇮🇳 Delhi, DELHI, India

BAPS Pramukh Swami Hospital; 🇮🇳 Surat, GUJARAT, India

Basavatarakam Indo- American cancer hospital & research institute; 🇮🇳 Hyderabad, TELANGANA, India

Charnock Hospital; 🇮🇳 Kolkata, WEST BENGAL, India

Deenanath Mangeshkar Hospital & Research Center; 🇮🇳 Pune, MAHARASHTRA, India

HCG Curie City Cancer Center; 🇮🇳 Krishna, ANDHRA PRADESH, India

HCG Manavata Cancer Center; 🇮🇳 Nashik, MAHARASHTRA, India

HCG- Cancer Centre; 🇮🇳 Visakhapatnam, ANDHRA PRADESH, India

HealthCare Global Enterprises Limited; 🇮🇳 Bangalore, KARNATAKA, India

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Aakash Healthcare Pvt. Ltd.

🇮🇳Delhi, DELHI, India

Dr Parveen Jain

Principal investigator

8800015976

anjusha.singh@aakashhealthcare.com