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Submitted by: Ranelle Lou Dorado 2016-01-08 00:00:00 Last Updated by: Ranelle Lou Dorado 2020-05-18 16:14:54


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)

PHRR160112-001142

Protocol No. D419AC00003

2015-CT0317

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)

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

Regime Classification Priority
2010 - 2016 Health Technology Development Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2016-03-16 41 2019-08-16 2019-08-06

Completed

Institution Classification Region LTO #
AstraZeneca Pharmaceuticals (Philippines) Inc. Private Business NCR CDRR-NCR-S-17
Institution Classification Region LTO #
AstraZeneca Pharmaceuticals (Philippines) Inc. Private Business NCR CDRR-NCR-S-17
Institution Region
AstraZeneca Pharmaceuticals (Philippines) Inc. NCR
Name E-Mail Institution and Institution Address
Samia T. Necesito samia.necesito@astrazeneca.com 16F, Inoza Tower, 40th Street, Bonifacio Global City,Taguig, Metro Manila
Name E-Mail Institution and Institution Address
Samia T. Necesito samia.necesito@astrazeneca.com 16F, Inoza Tower, 40th Street, Bonifacio Global City,Taguig, Metro Manila
Name Expertise Affiliation
Annielyn Beryl Ong-Cornel, MD Oncology University of Perpetual Help DALTA Medical Center
Ellie May Villegas, MD Oncology Perpetual Succour Hospital
Gerardo Cornelio, MD Oncology San Juan de Dios Hospital
Jasmin Igama, MD Oncology Baguio General Hospital and Medical Center
Jorge Ignacio, MD Oncology Philippine General Hospital
Maria Karen Luisa Villanueva-Timbol, MD Oncology Manila Doctors Hospital
Priscilla B. Caguioa, MD Oncology St. Luke's Medical Center - Quezon City
Solidad Lim-Balete, MD Oncology Jose R. Reyes Memorial Medical Center
Project Location Institutional Ethics Review Board
University of Perpetual Help DALTA Medical Center University of Perpetual Help DALTA Medical Center Ethics Review Committee
Perpetual Succour Hospital Perpetual Succour Hospital Institutional Ethics and Review Board
San Juan de Dios Hospital San Juan de Dios Educational Foundation Inc., Hospital Ethics Review Committee
Baguio General Hospital and Medical Center Baguio General Hospital and Medical Center Ethics Review Committee
Philippine General Hospital Philippine General Hospital Ethics Review Board
Manila Doctors Hospital Manila Doctors Hospital Institutional Review Board
St. Luke's Medical Center - Quezon City St. Luke's Medical Center Institutional Ethics Review Board
Jose R. Reyes Memorial Medical Center Jose R. Reyes Memorial Medical Center Ethics Review Committee

epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type advanced or metastatic NSCLC

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). All tumor-assessment-related endpoints as assessed by site Investigator.

Completed

  • Argentina
  • Brazil
  • Bulgaria
  • Chile
  • Finland
  • Greece
  • Israel
  • Japan
  • Malaysia
  • Mexico
  • Philippines
  • Poland
  • Singapore
  • South Korea
  • Sweden
  • Turkey
  • Ukraine
  • United Kingdom
  • United States

Clinical Trial

Protocol No. D419AC00003

20150918091244

2015-12-10

0000-00-00

30

11

Unspecified

16 Mar 2016

For inclusion in the study, patients should fulfill the following criteria:

1. Age ≥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. For patients aged < 20 years and enrolling in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.

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 folliclestimulating 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).

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

Interventional

MEDI4736 + tremelimumab

Patients in the MEDI4736 + tremelimumab combination therapy group will receive 20-mg/kg MEDI4736 via IV infusion q4w for up to 4 doses/cycles and 1-mg/kg tremelimumab via IV infusion q4w for up to 4 doses/cycles, and then continue 20-mg/kg MEDI4736 q4w starting on Week 16 for up to 8 months (9 doses). Dosing outside the window should be discussed with the Study Physician. Tremelimumab will be administered first. MEDI4736 infusion will start approximately 1 hour after the end of tremelimumab infusion. The duration will be approximately 1 hour for each infusion. A 1-hour observation period is recommended after the first infusion of MEDI4736 and tremelimumab. If no clinically significant infusion reactions are observed during or after the first cycle, subsequent infusion observation periods can be at the Investigator’s discretion (suggested 30 minutes after each MEDI4736 and tremelimumab infusion).

None

Randomized

Open Label

Unspecified

Crossover

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

Phase III

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