| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or Recurrent Non-Squamous Non-Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079440 |
| E.1.2 | Term | Non-squamous non-small cell lung cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate CT-P16 is similar to EU-Approved Avastin in terms of efficacy as determined by ORR up to Cycle 6 during the Induction Study Period |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate additional efficacy profiles including ORR during the Whole Study Period, response duration, time to progression (TTP), PFS, and OS
• To evaluate the PK of trough serum concentration (Ctrough)
• To evaluate safety profile including immunogenicity
• To evaluate quality of life (QoL) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient (male or female) must be ≥ 18 years of age.
2. Patient must have confirmed predominantly non-squamous non-small
cell lung cancer (nsNSCLC) by hematoxylin and eosin staining or
immunohistochemistry.
3. Patient must be diagnosed as recurrent disease or stage IV according
to the American Joint Committee on Cancer (AJCC) Lung Cancer Staging
8th edition. Stage IV is defined as below:
a. Separate tumor nodule(s) in a contralateral lobe, or
b. Tumor with pleural or pericardial nodules, or
c. Malignant pleural or pericardial effusion related to tumor, or
d. Single or multiple extrathoracic metastases in a single organ or in
multiple organs
4. Patient must have at least 1 measurable lesion by Response
Evaluation Criteria In Solid Tumors (RECIST) Version 1.1. Target lesions
situated in a previously irradiated area are considered measurable if
recurrence has been demonstrated in such lesions.
a. Tumor lesions: ≥ 10 mm in long axis by computerized tomography
(CT) scan, or
b. Malignant lymph nodes: ≥ 15 mm in short axis by CT scan
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1
6. Life expectancy > 6 months based on clinical judgement
7. Negative result in both epidermal growth factor receptor (EGFR)
mutation and anaplastic lymphoma kinase (ALK) rearrangement which is
confirmed by biopsy or cytology specimens.
8. Patient must have adequate organ function as follows. These tests
must be performed within 14 days prior to Day 1 of Cycle 1.
Bone marrow reserve:
a. Hemoglobin ≥ 9.0 g/dL, and
b. Absolute neutrophil count ≥ 1,500/mm3, and
c. Platelet count ≥ 100,000/mm3
Hepatic:
a. Alkaline phosphatase, aspartate aminotransferase and alanine
aminotransferase ≤ 3.0 × upper limit of normal (ULN) (≤ 5.0 × ULN with
liver metastasis), and
b. Total bilirubin ≤ 1.5 × ULN
Renal:
a. Serum creatinine ≤ 1.5 × ULN, and
b. Creatinine clearance (CrCl) rate ≥ 45 mL/min, and
c. Urine dipstick for proteinuria < 1+ (i.e., either 0 or trace); if urine
dipstick is ≥ 1+ then < 1.0 g of protein in 24 hours urine collection must
be confirmed to allow participation in the study
9. Patient and their partner of childbearing potential must agree to use
acceptable birth control methods throughout the study and for 6 months
after the last dose of assigned treatment
A man or woman is of childbearing potential if, in the opinion of the
investigator, he or she is biologically capable of having children and is
sexually active. Male and female patients and their partners who have
been surgically sterilized for less than 24 weeks prior to the date of
informed consent must agree to use any medically acceptable methods
of contraception. Menopausal females must have experienced their last
period more than 1 year prior to the date of informed consent to be
classified as not of childbearing potential
10. Patient has the ability to comprehend the full nature and purpose of
the study, including possible risks and side effects, to cooperate with the
investigator, to understand verbal and/or written instructions, and to
comply with the requirements of the entire study.
11. Patient and/or their legally authorized representative must be
informed and given ample time and opportunity to read and/or
understand the nature and purpose of this study and must sign the
informed consent form before any study specific procedures |
|
| E.4 | Principal exclusion criteria |
1. Patient who has predominantly squamous cell histology non-small cell
lung cancer (NSCLC). If small cell elements are present, the patient is
ineligible.
2. Patient who has clinically significant third-space fluid; for example,
ascites or pleural effusions that cannot be controlled by drainage or
other procedures prior to Day 1 of Cycle 1.
3. Patient who has untreated central nervous system (CNS) metastases
or CNS metastasis with bleeding risk at investigator's discretion and/or
leptomeningeal disease. However, treated and clinically stable
(asymptomatic; off steroids) brain metastases are allowed.
4. Patient who has invasion of major blood vessels. Patient with a tumor
cavitation in the opinion of the investigator is likely to bleed will be
excluded as well.
5. Patient who has received previous anti-cancer systemic therapy:
Cytotoxic chemotherapy for metastatic nsNSCLC, Cytotoxic
chemotherapy for non-metastatic nsNSCLC within 12 months prior to
Day 1 of Cycle 1, Anti-neoplastic biological therapy, immunotherapy or
targeted therapy, Bevacizumab (or a bevacizumab proposed biosimilar
product).
6. Patient who has received previous surgical procedure including:
Surgery for metastatic nsNSCLC, Surgery for non-metastatic nsNSCLC
within 6 months prior to Day 1 of Cycle 1, Open biopsy or open
pleurodesis within 28 days prior to Day 1 of Cycle 1, Core biopsy or other
minor surgical procedure (e.g. placement of vascular access device,
closed pleurodesis, thoracentesis, and mediastinoscopy) within 14 days
prior to Day 1 of Cycle 1.
7. Patient who has received previous anti-cancer radiotherapy including
one or more of the following(s):
a. Radiotherapy for metastatic nsNSCLC, but radiotherapy as part of the
palliative therapy and/or treatment for CNS metastases completed at
least 14 days prior to Day 1 of Cycle 1 is allowed,
b. Radiotherapy for non-metastatic nsNSCLC within 6 months prior to
Day 1 of Cycle 1,
c. Any toxicity related with radiotherapy prior to Day 1 of Cycle 1.
8. Patient who has a medical history of disease including one or more of
the following(s):
a. Clinically significant allergic reactions such as asthma, urticaria,
angio-oedema, and eczematous dermatitis, hypersensitivity to any
component of carboplatin, paclitaxel, bevacizumab and Chinese Hamster
Ovary (CHO) cell products or other recombinant human or humanized
antibodies.
b. Cardiac, gastrointestinal, renal, hepatic, hematological (including
pancytopenia, aplastic anemia or blood dyscrasia), metabolic (including
known diabetes mellitus), autoimmune disease, or pulmonary diseases
classed as significant in the opinion of the investigator.
c. A known infection with hepatitis B (active or carrier of hepatitis B),
hepatitis C, or infection with human immunodeficiency virus (HIV).
However, a patient with past hepatitis B virus is allowed if resolved.
d. New York Heart Association (NYHA) class 2, severe uncontrolled
cardiac disease (unstable angina, clinically significant electrocardiogram
[ECG] abnormalities, etc.), or myocardial infarction, within 6 months
prior to Day 1 of Cycle 1.
e. Malignancy or history of malignancy other than NSCLC in the past 5
years except adequately treated squamous or basal cell carcinoma of the
skin or carcinoma in situ of the cervix.
f. Any recent infection requiring a course of systemic anti-infectives or a
serious infection (associated with hospitalization and/or which required
intravenous antibiotics) within 14 days prior to Day 1 of Cycle 1.
g. Use of oral or parenteral anticoagulants or thrombolytic agent for
therapeutic purposes, or evidence of bleeding diathesis or coagulopathy.
However, a patient who can discontinue regular use of aspirin (> 325
mg/day) administration at least 10 days prior to the Day 1 of Cycle 1 or
a patient who continues with low dose aspirin (≤ 325 mg/day) are
allowed for enrollment.
h. Hemoptysis (> 2.5 mL of red blood), thrombotic or hemorrhagic event
within the past 6 months prior to Day 1 of Cycle 1.
i. Vascular disease history such as cerebrovascular accident, transient
ischemic attack, or thromboembolic reactions including pulmonary
embolism.
j. Abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within the past 6 months prior to Day 1 of Cycle 1.
k. Unhealed wound following surgery, significant traumatic injury within
28 days prior to Day 1 of Cycle 1, or an anticipated need for major
surgery during the study.
l. Uncontrolled hypertension (defined as either systolic blood pressure ≥
140 mmHg or diastolic blood pressure ≥ 90 mmHg), even after
treatment.
m. Uncontrolled diabetes mellitus, even after insulin treatment.
9. Female patient who is currently pregnant, breastfeeding, or planning
to become pregnant or breastfeed and male patient who is planning to
have child within 6 months of the last dose of study drug administration. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the ORR based on BOR during the Induction Study Period by RECIST v.1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be eavluated up to Cycle 6 during the induction study period |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
• ORR based on BOR during the Whole Study Period by RECIST v.1.1
• Response duration: the time between initial response (CR or PR) and PD/recurrence
• TTP: the time from randomization until PD/recurrence
• PFS: the time from randomization until PD/recurrence or death due to any cause, whichever occurs first
• OS: the time from randomization until death due to any cause
Secondary PK Endpoints:
• Ctrough: Trough serum concentration
Secondary Safety Endpoints:
• Safety assessments will be performed on immunogenicity, hypersensitivity monitoring (via vital sign and ECG), vital sign measurements (blood pressure, heart rates, respiratory rates and body temperature), weight, viral assessment, physical examination, clinical laboratory analyses, ECG, ECOG, Adverse Events (AEs) (including serious adverse events [SAEs]), adverse events of special interest (AESIs) (hypersensitivity/infusion-related reactions, gastrointestinal perforations and fistulae, wound healing complications, hypertension, posterior reversible encephalopathy syndrome (PRES), proteinuria, arterial thromboembolism (ATE), venous thromboembolism (VTE), hemorrhages, congestive heart failure (CHF) and ovarian failure/fertility), pregnancy testing, prior and concomitant medications throughout the study. Adverse events will be reported for term and grade according to the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.
Secondary QoL Endpoints:
• Quality of Life will be assessed using the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ). The QLQ core 30 (QLQ-C30) and QLQ lung cancer-specific module (QLQ-LC13) will be used. Patients will complete the questionnaires at Screening, end of Cycle 2, Cycle 4, and Cycle 6 of the Induction Study Period, and every 3 cycles (end of Cycle 3, Cycle 6, Cycle 9…) of the Maintenance Study Period and EOT. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoint evaluations will be conducted druing induction study period, maintenance study period and follow-up period. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belarus |
| Brazil |
| Bulgaria |
| Chile |
| Croatia |
| Czech Republic |
| Georgia |
| Hungary |
| India |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Peru |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Thailand |
| Ukraine |
| Vietnam |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Study will be completed 36 months from Day 1 of Cycle 1 of the induction study period for the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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