| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Stage IV unresectable, recurrent or metastatic
non-squamous non-small cell lung cancer (nsNSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| A certain common kind of inoperable, recurrent or metastatic Lung cancer. |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025055 |
| E.1.2 | Term | Lung cancer non-small cell stage IV |
| 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 |
| Compare the overall response rate (ORR) of MYL-1402O with that of Avastin, in combination with CP chemotherapy during the first 18 weeks of first-line treatment in patients with Stage IV nsNSCLC |
|
| E.2.2 | Secondary objectives of the trial |
1. Assess the safety profile of MYL-1402O as compared with that of Avastin when administered in combination with CP as
first-line treatment for Stage IV nsNSCLC and when administered alone in the maintenance setting
2. Assess other efficacy parameters: Disease Control Rate (DCR), Duration of Response (DR), Time To Progression (TP), Progression-Free survival (PFS), and Overall Survival (OS) of
MYL-1402O as compared to Avastin when administered in
combination with CP as first-line treatment for Stage IV
nsNSCLC
3. Assess the potential immunogenicity at Week 18 and 42 of
treatment of MYL-1402O as compared with that of Avastin
4. Compare the pharmacokinetic (PK) profile of MYL-1402O and Avastin using a population PK (PopPK) approach |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has demonstrated the ability to understand verbal and/or written instructions, to provide written informed consent, and is capable and agreeable to comply with protocol requirements.
2. Male or female at least 18 years of age at the time of signing an informed consent form.
3. Has a documented imaging diagnosis of Stage IV unresectable, recurrent or metastatic nsNSCLC.
4. Has documented histologic or cytologic diagnosis of advanced nsNSCLC with negative or unknown sensitizing epidermal growth factor receptor (EGFR) mutation, and negative or unknown echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement.
5. Has measurable disease with at least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors
(RECIST 1.1; Section 12.1 [Appendix A]). All target (up to
5 lesions) and nontarget lesions (other measurable not included in target, nonmeasurable, nonevaluable, or evaluable lesions) should be included in the assessment or evaluation of disease response as defined by RECIST 1.1 (Eisenhauer et al 2009).
6. Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group scale.
7. Has at least 6 months of expected survival.
8. Has not received any prior systemic therapy for first-line treatment of advanced lung cancer, except adjuvant chemotherapy, and remained disease-free for at least 12 months from time
9. May have had prior radiation therapy provided <25% of bone marrow is involved (Section 12.3 [Appendix C]), except for previous mediastinal irradiation that is not allowed.
a. Prior radiation therapy must have been completed at least
2 weeks prior to Day 0 of Cycle 1
b. Patient must have recovered from acute toxicities associated with radiation therapy. Radiation-related toxicities must have resolved to Grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; version 4.03) grade prior to Day 0 of Cycle 1.
10. May have brain metastasis provided the metastasis has been treated and is considered stable at the time of signing the informed consent form. Treated, stable brain metastasis is defined as:
a. Metastasis having no evidence of progressive disease (PD) or hemorrhage after treatment.
b. No ongoing requirement for dexamethasone, as ascertained by clinical examination and post-treatment brain imaging (computed tomography [CT] scan or magnetic resonance imaging [MRI]) at baseline.
c. Anticonvulsants are allowed, provided the dose regimen has been unchanged (stable) for at least 2 weeks prior to patient signing informed consent.
d. Treatment for brain metastasis may include whole brain
radiotherapy, radiosurgery (Gamma Knife®, linear particle
accelerator, or equivalent), or a combination thereof, as
deemed appropriate by the treating physician. All brain
metastasis treatments must be completed at least 14 days prior to Day 0 of Cycle 1.
11. Has adequate organ functions based on the following:
a. Bone marrow reserve:
i. White blood cell count ≥3 × 103/μL;
ii. Absolute neutrophil count (segmented and bands)
≥1.5 × 103/μL;
iii. Platelet count ≥100 × 103/μL;
iv. Hemoglobin ≥9.0 g/dL with at least 2 weeks without
transfusions before Day 0 of Cycle 1.
b. Hepatic:
i. Total bilirubin ≤1.5 × upper limit of normal (ULN); except
if elevation is due to Gilbert’s Syndrome with transitory
elevations of indirect bilirubin.
ii. Alkaline phosphatase, alanine transaminase, and/or
aspartate transaminase ≤3 × ULN. Significant levels of
alanine transaminase or aspartate transaminase should be
further assessed for viral hepatitis. (Note: Isolated alkaline
phosphatase elevation beyond 3 × ULN due to bone
metastasis is allowed).
c. Renal:
i. Calculated creatinine clearance ≥45 mL/min based on the
original, weight-based Cockcroft and Gault formula
(Cockcroft and Gault 1976; Section 12.4 [Appendix D])
ii. Urine protein to creatinine ratio ≤1. A patient with urine
protein to creatinine ratio > 1 may be enrolled if ≤2g of
protein in 24-hour urine collection.
12. If capable of reproduction, patients and their partners must use contraceptive methods during the full duration of the study and for 6 months after discontinuation of study.
A patient who is capable of reproduction must be willing to
practice birth control by using 2 different highly effective double barrier methods of contraception, or abstinence from sexual intercourse for the duration of the study.
In particular a female patient of childbearing potential must use a method that results in less than 1% failure rate per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or vasectomized partner.
A male patient of reproductive potential (defined as a male that has not had a vasectomy) must use a condom with spermicide and their female partner to use another highly effective form of contraception. |
|
| E.4 | Principal exclusion criteria |
1. Is pregnant or breast-feeding.
2. Has documented histology/cytology confirming any of the
following:
a. Squamous non-small cell lung cancer. (Note: In the event of mixed tumor histology/cytology or predominant cell type other than non-squamous, eligibility will be determined based on the predominant cell type, which must be non-squamous.)
b. A patient with any small cell type or large cell neuroendocrine histology.
3. Has a recent (within 6 months prior to Day 0 of Cycle 1) cardiac condition as defined by the New York Heart Association Class II, III, or IV (AHA 1994).
4. Has a recent (within 6 months prior to Day 0 of Cycle 1) history of a significant vascular event (such as aortic aneurysm requiring surgical repair or a recent peripheral arterial thrombosis) and/or history of significant and unstable vascular disease.
5. Has a history of stroke or transient ischemic attack within
6 months prior to Day 0 of Cycle 1, or has a long-term history of more than one of the following vascular thromboembolic events:
a. Cerebrovascular accidents
b. Transient ischemic attacks
c. Myocardial infarctions
d. Venous thromboembolic reactions, including pulmonary
embolism
6. Is receiving anticoagulant therapy that:
a. Is not considered ‘stable’, defined as dosage not maintained
for at least 3 months prior to Day 0 of Cycle 1.
b. Is not within the targeted international normalized ratio at the time of consent signing.
7. Has a current diagnosis, history, or risk of hemorrhage in the central nervous system (CNS), including the following:
a. Patient with CNS metastasis treated by neurosurgical resection or brain biopsy performed within 8 weeks prior to Day 0 of Cycle 1.
b. Patient should be off corticosteroids for at least 1 week
(7 days) at the time of the post-treatment (for CNS metastasis) brain CT/MRI.
8. Has any prior history of hypertensive crisis and/or
hypertensive encephalopathy, or has a current diagnosis or
recent history of inadequately controlled hypertension (defined as systolic blood pressure >150 mm Hg and/or diastolic >100 mm Hg, while on antihypertensive medications).
9. Has a recent history of any of the following:
a. A major surgical procedure, open biopsy, open pleurodesis, or significant traumatic injury within 28 days prior to Day 0 of Cycle 1.
b. Documented history of conditions that may need surgery
during the study or within 6 months of signing informed
consent.
c. Has had either a core biopsy or other minor surgical procedure within 7 days prior to Day 0 of Cycle 1. (Note: Placement of a vascular access device, or a closed pleurodesis, thoracentesis, or mediastinoscopy are allowed).
10. Has a history of any of the following:
a. Hemoptysis (approximately >2.5 mL or a half teaspoon)
within 3 months prior to Day 0 of Cycle 1.
b. A thoracic, central, mediastinal tumor location in contact with major vessels
c. A cavitated lung tumor.
11. Has a history of gastrointestinal fistula, perforation, or abscess.
12. Has a current diagnosis or history of a nonhealing wound, active ulcer, or untreated bone fracture.
13. Has prior history of another active malignancy within the last 5 years, other than adequately treated superficial basal cell, superficial/skin squamous cell carcinoma, or carcinomas in situ.
14. Has a known hypersensitivity to any component of carboplatin, paclitaxel, bevacizumab, Chinese hamster ovary cell products, or other recombinant human or humanized antibodies.
15. Has received treatment with any other investigational drug, within the last 30 days or at least 5 half-lives (if available), whichever is longer, should have elapsed prior to Day 0 of Cycle 1.
16. Has previously received treatment with the following:
a. Paclitaxel.
b. Bevacizumab (Note: Prior intravitreal administration of
bevacizumab does not preclude study participation).
c. Anthracycline. (Note: May be allowed on a case by case basis after consulting with the medical monitor to rule out an
increased risk of cardiac failure).
17. Has documented or known current alcohol/drug abuse that precludes his/her ability to adhere to the protocol.
18. Has any of the following concomitant treatments or conditions:
a. Concomitant vaccination that contains an attenuated virus, for instance Yellow Fever vaccine.
b. Has a known history of active or latent tuberculosis.
c. Has a concomitant systemic disorder (e.g., active infection
including known human immunodeficiency virus, viral
hepatitis B or C) that, in the opinion of the principal
investigator (PI; or designee), would compromise the patient's safety (for instance potential drug interactions, or ability to adhere to the protocol).
d. Has any other concomitant condition that precludes the
participation in the study through increased risk to the patient and/or potential to impact the PI’s (or designee’s) ability to administer this protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the ORR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy Endpoints:
· DCR (CR, PR, or stable disease)
· PFS
· OS
· DR
· TP
PK Endpoints:
PopPK measures of exposure of MYL-1402O and the reference product Avastin (e.g., AUC, Cmax, Cmin, CL, Vc, and the terminal elimination half-life).
Safety Endpoints:
· Incidence, nature, and severity of AEs including adverse drug reactions graded according to CTCAE.
· Detection of antibodies to bevacizumab. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoints will be assessed during the entire duration of the study in line with the protocol schedule of events.
|
|
| 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 | 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 | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Argentina |
| Belarus |
| Bosnia and Herzegovina |
| Brazil |
| Bulgaria |
| Croatia |
| Georgia |
| Hungary |
| India |
| Indonesia |
| Italy |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| 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
|
| The end of study will occur when any of the following conditions are first met: 15 months after randomization of the last patient, 250 death events recorded, all patients have discontinued the study, or administrative closing of study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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