| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Second line FR(++) non-small cell lung cancer (adenocarcinoma, squamous, adenosquamous, or adenocarcinoma with other NSCLC variants of the lung) (Stage IIIB or IV). |
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| E.1.1.1 | Medical condition in easily understood language |
| Non-small cell lung cancer |
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| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025054 |
| E.1.2 | Term | Lung cancer non-small cell stage IIIB |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 |
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| 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 |
This study tests the activity of single-agent EC145 and the combination of EC145 plus docetaxel against the current standard docetaxel in second line NSCLC in participants with all target lesions expressing the folate receptor [FR(++)].
Primary objective: progression free survival (PFS) |
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| E.2.2 | Secondary objectives of the trial |
| Overall response rate (ORR=CR+PR), Duration of response (DOR), disease control rate (DCR=CR+PR+SD), duration of DCR, and overall survival (OS) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participants must have the ability to sign an approved informed consent form (ICF).
2. Participants must be ≥ 18 years of age.
3. Participants must have histology confirmed diagnosis of NSCLC (adenocarcinoma, squamous, adenosquamous carcinoma, or adenocarcinoma with other NSCLC variants of the lung) (Stage IIIB or IV).
4. Participants must have all (RECIST v1.1-defined) target lesions positive for the folate receptor [FR(++)] by SPECT scan.
5. Only one prior systemic therapy for advanced disease (e.g., a platinum doublet or a maintenance regimen that includes a platinum doublet; in addition, the participant may have received an epidermal growth factor receptor [EGFR] inhibitor).
6. For the purpose of obtaining a RECIST v1.1 baseline scan, participants must have a radiological evaluation conducted no more than 28 days prior to beginning study therapy. Note: For participants with a history of CNS metastasis, or with current signs/symptoms of neurological compromise, baseline radiological imaging must include evaluation of the brain (MRI preferred or CT with contrast).
7. Participants must have radiologic evidence of disease progression following the most recent prior treatment.
8. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1.
9. Participants must have recovered (to baseline/stabilization) from prior cytotoxic therapy-associated acute toxicities.
10. Participants with prior radiation therapy are eligible if they meet the following criteria:
a. Previous radiation therapy is allowed to <25% of the bone marrow, but whole pelvis radiation is excluded.
b. Prior radiotherapy must be completed at least 2 weeks before patient is randomized.
c. Participants must have recovered from the acute toxic effects of the treatment before randomized.
d. Prior thoracic radiation must be completed 30 days before study enrollment.
e. Irradiated pulmonary lesions cannot be used as target or non-target lesions (and must be excluded) unless there is previous documented progression of these lesions.
f. Palliative extrathoracic radiotherapy can continue, but these lesions must be excluded as target and non-target lesions.
11. Participants must have adequate organ function:
a. Bone marrow reserve:i. Absolute neutrophil count (ANC) ≥ 1.5 x 10(9)/L. Platelets ≥ 100 x 10(9)/L. Hemoglobin ≥ 9 g/dL.
ii. Use of supportive care measures (eg, use of white blood cell [WBC] growth factors, antiemetics, or epoetin) should follow ASCO guidelines. Participants should receive full supportive care, including transfusion of blood as mandated by clinical need; however, transfusions administered for the sole purpose of meeting the study inclusion criteria between the time informed consent is signed and first dose of EC145 and or docetaxel is administered are not allowed.
b. Hepatic: Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and lactate dehydrogenase (LDH) and alkaline phosphatase ≤ 2.5 x ULN.
c. Renal: Serum creatinine ≤ 1.5 x ULN, or for participants with serum creatinine > 1.5 ULN, creatinine clearance ≥ 50 mL/min/1.73 m2 (50 mL/min/1.73m2 is equivalent to 0.83 mL/s/m2).
12. Participants of childbearing potential:
a. Women who are capable of becoming pregnant must have a negative serum pregnancy test within 1 week prior to exposure to EC20 and within 1 week prior to treatment with EC145 and/or docetaxel. If the pre-EC20 pregnancy test falls within 1 week prior to Cycle 1 Day 1, a repeat pregnancy test is not required.
b. Women who are capable of becoming pregnant must practice an effective method of birth control (eg, oral, transdermal or injectable contraceptives, intrauterine device [IUD], double-barrier contraception, such as diaphragm and spermicidal jelly) or abstinence for the duration of their participation in the trial through 3 months following the last dose of EC145 and through 6 months following the last dose of docetaxel.
c. Male participants who are sexually active must practice an effective method of birth control (eg, condom and spermicidal jelly or abstinence).Effective birth control methods must be used throughout study participation and for at least 3 months following the last dose of EC145 and at least 6 months following the last dose of docetaxel. |
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| E.4 | Principal exclusion criteria |
1. Prior therapy with docetaxel, vinorelbine, or vinca-containing compounds.
2. Known hypersensitivity to docetaxel or polysorbate 80.
3. Symptomatic central nervous system (CNS) metastases or metastases that result in midline shift, significant edema. Patients who received treatment for CNS metastases with steroids or anti-seizure medications should be off all medications for at least 7 days prior to randomization. At least 2 weeks should have elapsed from CNS radiotherapy (including WBRT, stereotactic radiotherapy, etc)
4. Malignancies other than NSCLC that are expected to alter life expectancy or may interfere with disease assessment. For instance, patients with adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, or low-grade (Gleason score ≤ 6) localized prostate cancer and patients with prior history of malignancy who have been disease-free for more than 3 years are eligible.
5. Serious cardiac illness or medical conditions such as unstable angina, pulmonary embolism, or uncontrolled hypertension.
6. Antifolate therapy such as methotrexate for rheumatoid arthritis).
7. Baseline peripheral neuropathy CTCAE ≥ Grade 2.
8. Pregnant or lactating women.
9. Other concurrent chemotherapy, immunotherapy, radiotherapy, or investigational therapy.
10. Active infections (eg, hepatitis or HIV carriers) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Compare progression-free survival (PFS), based on investigator assessment using RECIST V1.1 in participants with 2nd line FR(++) NSCLC. Comparison of primary interest are: 1)EC145+docetaxel versus docetaxel and 2) EC145 single-agent versus docetaxel
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary efficacy endpoint for this study is PFS, defined as the duration from randomization to the first occurrence of either PD or death. A participant may be declared to have PD on the basis of RECIST v1.1-defined criteria. The date of disease progression is defined as the date of the radiologic assessment on which RECIST-defined progression is identified. |
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| E.5.2 | Secondary end point(s) |
| Overall response rate (ORR=CR+PR), Duration of response (DOR), disease control rate (DCR=CR+PR+SD), duration of DCR, and overall survival (OS) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR will be based on subjects achieving an OR. At each cycle of RECIST evaluation, actual measured tumor assessments will be used to determine whether subjects have an assessment of CR or PR, which will be considered as an OR. DCR will be based on participants achieving an overall best response of CR, PR, or stable disease.
OS is defined as the duration from the date of randomization to the date of death from any cause. Subjects who are alive or lost to F-up at the time of the analysis will be censored at the last known date they were alive. If a subject has not died then OS will be censored at last study visit/last contact date/last date the subject was alive, whichever is more temporally distal. |
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| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | 3 |
| 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 | 52 |
| 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 |
| Bulgaria |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
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| 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 last site will not be closed with their Ethics Committee until the last patient has completed Long Term Follow Up (LTFU) |
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| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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