CTRI/2016/08/007204 [Registered on: 18/08/2016] Trial Registered Prospectively
Last Modified On:
28/04/2020
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Biological
Study Design
Randomized, Parallel Group Trial
Public Title of Study
A clinical trial to study the efficacy of MEDI4736 in combination with Tremelimumab Therapy Versus Standard of Care Platinum-Based Chemotherapy in First-Line Treatment of Patients with Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC)
Scientific Title of Study
A Phase III Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 in Combination with Tremelimumab Therapy Versus Standard of Care Platinum-Based Chemotherapy in First-Line Treatment of Patients with Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) (NEPTUNE)
Trial Acronym
NEPTUNE
Secondary IDs if Any
Secondary ID
Identifier
D419AC00003 Version 01, dated 21 March 2016
Protocol Number
NCT02542293
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
AstraZeneca Pharma India Limited
Block N1, 12th floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road
Bangalore KARNATAKA 560045 India
Phone
918067748006
Fax
918023622015
Email
tapankumar.shah@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB, 151 85 Södertälje, Sweden
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Södertälje, Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
Argentina Brazil Bulgaria Chile Denmark Finland Greece Hong Kong India Israel Japan Malaysia Mexico Peru Philippines Poland Portugal Qatar Republic of Korea Romania Saudi Arabia Singapore Sweden Turkey Ukraine United Arab Emirates United Kingdom United States of America
1. Age greater than or equal to 18 years at the time of screening
2. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
3. Histologically or cytologically documented Stage IV NSCLC not amendable to curative surgery or radiation (according to version 7 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology; IASLC Staging Manual in Thoracic Oncology).
4. Patients must have tumors that lack activating EGFR mutation (eg, exon 19 deletion or exon 21 L858R, exon 21 L861, exon 18 G719, or exon 20 S7681 mutation) and ALK rearrangement. (If a patient has squamous histology or is known to have a tumor with a KRAS mutation, then EGFR and ALK testing is not required).
5. No prior chemotherapy or any other systemic therapy for advanced or metastatic NSCLC. Patients who have received prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred >6 months from last therapy.
6. Tumor PD-L1 status, confirmed by a reference laboratory using the Ventana IHC assay, must be known prior to randomization. As such, all patients must be able to undergo a fresh tumor biopsy during screening or to provide an available tumor sample taken <3 months prior to screening. Tumor lesions used for fresh biopsies should not be target lesions, unless there are no other lesions suitable for biopsy. Fine needle aspirate specimens are not acceptable. Specimens from metastatic bone lesions are typically unacceptable unless there is a significant soft tissue component. The tumor specimen submitted to establish eligibility should be of sufficient quantity to allow for PD-L1 IHC and other exploratory biomarker analyses and is preferred in formalin-fixed paraffin embedded blocks.
7. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment.
8. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines.
9. No prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines.
10. Adequate organ and marrow function as defined below:
- Hemoglobin ≥9.0 g/dL
- Absolute neutrophil count ≥1.5 × 109 /L
- Platelet count ≥100 × 109/L
- Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician.
- ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN
- Calculated creatinine clearance (CL) >50 mL/min as determined by Cockcroft-Gault (using actual body weight)
11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
- Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
ExclusionCriteria
Details
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
2. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study
3. Mixed small-cell lung cancer and NSCLC histology or not otherwise specified (NSCLC NOS).
4. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
5. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of IP. Note: Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable.
6. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
7. History of allogenic organ transplantation
8. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis with the exception of diverticulosis, celiac disease or other serious GI chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
9. Any condition that, in the opinion of the Investigator, would interfere with the evaluation of IP or interpretation of patient safety or study results, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs from MEDI4736 or tremelimumab, or compromise the ability of the patient to give written informed consent.
10. Medical contraindication to platinum (cisplatin or carboplatin)-based doublet chemotherapy.
11. History of another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease (eg, cervical cancer in situ)
12. History of leptomeningeal carcinomatosis
13. Brain metastases or spinal cord compression unless asymptomatic or treated and stable off steroids and anti-convulsants for at least 1 month prior to study treatment. Patients with suspected brain metastases at screening should have a CT/MRI of the brain prior to study entry.
14. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms
15. History of active primary immunodeficiency
16. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
17. Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736 or tremelimumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection).
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
18. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP.
19. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of MEDI4736 + tremelimumab combination therapy or 90 days after the last dose of MEDI4736 monotherapy, whichever is the longer time period.
20. Known allergy or hypersensitivity to IP or any excipient or to other humanized mAbs
Method of Generating Random Sequence
Stratified randomization
Method of Concealment
Not Applicable
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
To assess the efficacy of MEDI4736 + tremelimumab combination therapy compared
to Standard of Care (SoC) in terms of OS in patients with Non Small Cell Lung Cancer (NSCLC)
To assess the efficacy of MEDI4736 plus tremelimumab combination therapy compared
to SoC in terms of Overall Survival in patients with PD-L1– negative NSCLC
OS in patients with PD-L1–negative NSCLC (Time frame-Approximately 4 years)
To further assess the efficacy of MEDI4736 plus tremelimumab combination therapy compared to SoC in terms of
- Progression-free survival
(PFS)
- Objective response rate
(ORR)
- Duration of response (DoR)
- Proportion of patients
alive at 18 months (OS18)
- Proportion of patients alive and progression free at 12 months (APF12)
- Progression-free survival after subsequent anticancer therapy (PFS2)
- PFS, and ORR in patients with PD-L1–negative NSCLC
- PFS, ORR, DoR, and APF12 using Investigator
assessments according to RECIST 1.1 PFS2 using local standard clinical practice
OS12 and OS18 (Time frame-Approximately 4 years)
To assess the Pharmacokinetics (PK) of MEDI4736 plus tremelimumab combination therapy
Concentration of MEDI4736 and tremelimumab in blood and non-compartmental PK parameters, such as peak concentration and trough (as data allow; sparse sampling)
(Time frame-Approximately 4 years)
To investigate the immunogenicity of MEDI4736 and tremelimumab
Presence of ADAs for MEDI4736 and tremelimumab
(confirmatory results: positive and negative; titers)
(Time frame-Approximately 4 years)
Target Sample Size
Total Sample Size="800" Sample Size from India="60" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of MEDI4736 + tremelimumab combination therapy versus platinum-based SoC chemotherapy in the first-line treatment of patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type advanced or metastatic NSCLC.Patients will provide a tumor tissue sample at screening to determine PD-L1 expression status (defined by an immunohistochemistry assay developed by Ventana in which ≥25% PD-L1 membrane–expression in tumoral tissue is considered positive and <25% is considered negative; referred to hereafter as patients with PD-L1-positive or -negative tumors, respectively). Patients will be randomized in a 1:1 ratio in a stratified manner according to PD-L1 tumor expression status (as described above), histology (squamous versus non-squamous), and smoking status (never smoker versus ever smoker) to receive treatment with MEDI4736 + tremelimumab combination therapy or SoC therapy. Tumor assessments will be performed every 6 weeks for the first 48 weeks and then every 8 weeks until confirmed disease progression, with categorization of objective tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The primary objective of this study is to assess the efficacy of MEDI4736 + tremelimumab combination therapy compared with SoC in terms of overall survival (OS) in patients with EGFR and ALK wild-type advanced or metastatic NSCLC. OS will be defined as the time from the date of randomization until death due to any cause. Secondary efficacy variables include OS in patients with PD-L1-negative tumors, as well as progression-free survival (PFS), PFS in patients with PD-L1-negative tumors, objective response rate (ORR), ORR in patients with PD-L1-negative tumors, duration of response (DoR), proportion of patients alive at 12 months from randomization (OS12), proportion of patients alive at 18 months from randomization (OS18), proportion of patients alive and progression free at 12 months from randomization (APF12), and time from randomization to second progression (PFS2).