| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-squamous Non-small Cell Lung Cancer (nsNSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-squamous Non-small Cell Lung Cancer (nsNSCLC) |
|
| 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 clinical equivalence of the bevacizumab biosimilar (HD204) to reference bevacizumab (EU-Avastin®) given with chemotherapy by comparing the best overall response rate (ORR) at Week 12 in Patients with Metastatic or Recurrent Non-squamous Non-small Cell Lung Cancer. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare ORR at Week 6 and Week 18 between the bevacizumab biosimilar (HD204) and reference bevacizumab (EU-Avastin®).
2. To compare ORR at Week 12 adjusted on dose intensity.
3. To compare the efficacy of bevacizumab biosimilar (HD204) to reference bevacizumab (EU-Avastin®) in terms of duration of response (DoR), progression-free survival (PFS) and overall survival (OS).
4.To compare the safety and immunogenicity of bevacizumab biosimilar (HD204) and reference bevacizumab (EU-Avastin®).
5. To compare bevacizumab PK parameters after administration of bevacizumab biosimilar (HD204) and reference bevacizumab (EU-Avastin®). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able and willing to give written informed consent.
2. Aged ≥ 18 years of age.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and life expectancy >3 months based on Investigator’s judgement.
4. Histologically confirmed metastatic Stage IV or recurrent non squamous non-small cell lung cancer (NSCLC) that is no longer amendable to curative surgery or local therapy.
5. At least one measurable lesion according to RECIST v.1.1. as confirmed by CIR; bone-only and brain-only metastases are not allowed. Lesions previously treated with radiotherapy are non-target lesions unless clear progression was documented. Previous results are acceptable if performed within 4 weeks prior to screening.
6. No first line treatment for metastatic or recurrent disease. Prior systemic therapy and/or radiotherapy for locally advanced disease is permitted if completed ≥ 6 months prior to the diagnosis of relapsing disease.
7. Tumors without EGFR mutation or ALK receptor alteration. Patients with unknown mutation status or known EGFR mutation or ALK receptor alteration may be included provided the corresponding targeted agent is not available and chemotherapy is the standard of care of the study center.
8. Adequate hematological function, defined as:
a. Platelet count: ≥ 100,000/μL without the need for transfusion in the 2 weeks prior to Screening.
b. Prothrombin time (PT), International normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤1.5 x the upper limit of normal (ULN).
c. Absolute neutrophil count: ≥ 1,500/μL without any medical interventionaltreatment (ie, granulocyte-colony stimulating factors [G-CSFs] and/or herbal remedies).
d. Hemoglobin: ≥ 9 g/dL, without the need for transfusion in the 2 weeks prior to Screening.
9. Adequate hepatic function as evidenced by meeting all of the following requirements:
a. Total bilirubin: ≤ 1.5 x ULN.
b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP): ≤ 3 x ULN.
c. If liver metastases are present, ALT and AST <5 x ULN; if liver and/or bone metastases are present ALP ≤ 5 x ULN.
10. Adequate renal function, as evidenced by meeting all of the following requirements:
a. Serum creatinine ≤ 1.5 x ULN and creatinine clearance > 50 mL/minute or estimated glomerular filtration rate (GFR) >50 mL/minute.
b. Urine dipstick for proteinuria of less than 2+ (other ways of urinalysis are also acceptable); if urine dip stick is ≥ 2+, proteinuria must be < 2 g in 24 hours or an equivalent protein/creatinine ratio of <2000 mg/g creatinine (or < 226.0 mg/mmoL creatinine).
11. Female patients with childbearing potential (excluding women who have undergone surgical sterilization or menopause. Menopause is defined as the status where no menstrual periods continue for 1 year or more without any other medical reasons), are eligible if they have negative serum pregnancy testing within 7 days
prior to first dosing and are willing to use an effective method of birth
control/contraception to prevent pregnancy until 6 months after the end of study. Male patients must consent using effective method of contraception until 6 months after the end of study. |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of small cell carcinoma of the lung or mixed tumors including small cell
carcinoma.
2. Known ROS-1 positive tumor, except in scenarios where the corresponding target agent is not available, and chemotherapy is the standard of care at the study center. Patients with ROS-1 status not known at all can be considered as eligible for the study.
3. Tumor cavitation, tumor invading into large blood vessels or close to large vessels
with high risk of bleeding, according to Investigator's judgment.
4. Prior therapy with monoclonal antibodies or small molecule inhibitors against VEGF
or VEGFR.
5. Prior systemic anticancer therapy, or radiotherapy for locally advanced nsNSCLC if
completed <6 months prior to the diagnosis of relapsing disease.
6. Previous malignancy other than NSCLC in the last 5 years except for basal cell carcinoma
of the skin or pre-invasive cancer of the cervix.
7. Known brain metastasis or other CNS metastasis that is either symptomatic or
untreated. Metastases that have been treated by complete resection and/or
radiotherapy demonstrating stability or improvement are not an exclusion criterion
provided they are stable as shown by computed tomography (CT) or magnetic
resonance imaging (MRI) scan for at least 4 weeks before Screening without evidence
of cerebral edema. Patients on stable dose of corticosteroids or anticonvulsants are
permitted.
8. Any unresolved toxicity > Grade I (except alopecia) from previous anticancer therapy
(including radiotherapy).
9. History of hemoptysis (> 1/2 teaspoon per event over the past 6 months) or evidence
of inherited bleeding diathesis or coagulopathy with the risk of bleeding. Clinically
non-significant minor bleeding is acceptable.
10. A significant thrombotic or hemorrhagic event ≤ 6 months prior to Screening (includes
hemoptysis [> 2.5 mL of red blood], gastrointestinal bleeding, hematemesis, CNS
hemorrhage, severe epistaxis or vaginal bleeding, cerebral infarction, transient
ischemic attacks, myocardial infarction, unstable angina, and uncontrolled coronary artery
disease).
11. Clinically serious non-healing wounds, or incompletely healed bone fracture at
screening.
12. Known hypersensitivity to any of the study drugs or their excipients, or history of
clinically significant atopic allergy (eg, asthma including childhood asthma, urticarial).
13. Live/attenuated vaccine within 12 weeks prior to the Screening Visit.
14. History of myocardial infarction (≤ 6 months prior to Screening), unstable angina, New
York Heart Association Grade II or greater, congestive heart failure, or serious cardiac
arrhythmia requiring medication.
15. History of poorly controlled hypertension or resting blood pressure >150/100 mmHg
in the presence of a stable regimen of antihypertensive therapy.
16. Any major surgical procedure (risk of bleeding or wound healing complications) within
28 days prior to the screening.
17. History of active gastroduodenal ulcer, abdominal fistula as well as nongastrointestinal
fistula, gastrointestinal perforation or intra-abdominal abscess within
6 months prior to Screening. However, patient with history of ulcer which had been treated could be considered as eligible for the study.
18. Clinically significant active infection requiring systemic therapy.
19. Known active Hepatitis B infection (according to local site standards) or active
Hepatitis C infection (Hepatitis C virus [HCV] antibody positive); the patient could be
included in the study if he/she is HCV RNA negative. Patient with unknown Hep B/C status, could be considered as eligible for the study.
20. Known human immunodeficiency virus (HIV) infection (positive results from patient
history are accepted), syphilis, or active tuberculosis infection. In cases where HIV/Syphilis/Tuberculosis status is not known at all, patient could be considered as eligible for the study.
21. Patient considered unsuitable for inclusion by the Investigator (eg, inability to
understand and/or comply with study requirements or presence of any condition,
which, in the opinion of the Investigator, would not allow safe participation in the
study).
22. Pregnant or lactating women.
23. Any planned dental surgical intervention during the study.
24. Patients who require permanent oral anticoagulation (eg, warfarin, rivaroxaban,
dabigatran, acenocumarol, etc.) treatment. However, administration of low molecular anticoagulants is permitted for prophylaxis purpose. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall response rate (ORR12) at Week 12. The response is evaluated according to RECIST
version 1.1, as assessed by the central, independent, blinded radiologist. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
-ORR at Week 6 and Week 18 of the bevacizumab biosimilar (HD204) and reference
bevacizumab (EU-Avastin®).
- ORR at Week 12 adjusted on dose intensity.
- Progression free Survival rate (PFS) at 12 months.
- Progression free Survival time (time from randomization to date of documented clinical or
radiological progression or death due to any cause).
- Overall survival rate at 12 months.
- Overall survival time.
- Duration of Response (DOR) (from first documentation of a response
(CP or PR) and first documentation of progression according to RECIST 1.1).
Safety:
Safety assessments will include monitoring for vital sign abnormalities, clinical laboratory
abnormalities, physical examination, electrocardiogram parameters, adverse events (AEs; graded
as mild, moderate, or severe), serious AEs, and treatment-emergent AEs (TEAEs).
Immunogenicity:
ADA and NADA correlated with Bevacizumab. Sampling: Baseline, end of cycle 4, end of cycle 7 and at EoT
Pharmacokinetics:
Bevacizumab though following treatments of HD204 or EU-Avastin®.
Sampling:
-Baseline
-Cycle 2 (pre- and 1 hour post- infusion and 5-hour post-infusion);
-Cycle 4 (pre- and 1 hour post- infusion and 5-hour post-infusion);
-Cycle 6 (pre- and 1 hour post- infusion and 5-hour post-infusion);
-EoT |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: Week 6, 12 and 18. Month 12
Immunogenicity: Baseline, end of cycle 4, EoT
Pharmacokinetics: At the end of cycle 2, 4, 6 and EoT |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
| Bulgaria |
| Chile |
| Croatia |
| Georgia |
| Greece |
| Hungary |
| India |
| Latvia |
| Malaysia |
| Philippines |
| Poland |
| Russian Federation |
| Serbia |
| Slovakia |
| Thailand |
| Turkey |
| Ukraine |
|
| 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
|
The study will be closed when all randomised and treated patients have died, are lost to followup,
have withdrawn consent or for a maximum of 12 months has passed after the last patient
was randomised, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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