| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced 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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 evaluate the efficacy of pemetrexed in combination with TH-302 as determined by overall survival (OS) in patients with advanced non-squamous NSCLC in the second-line chemotherapy setting compared with pemetrexed in combination with placebo |
|
| E.2.2 | Secondary objectives of the trial |
1. To assess the safety of pemetrexed in combination with TH-302 compared with pemetrexed in combination with placebo in this setting
2. To evaluate the anti-tumor activity of pemetrexed in combination with TH-302 as determined by progression-free survival (PFS) and response rate (RR) compared with pemetrexed in combination with placebo
3. To investigate the pharmacokinetics of TH-302 and Br-IPM in this patient population
4. To explore and compare quality of life and derive health state utilities as measured by the EQ-5D-5L and to compare time to symptomatic progression as measured by the Lung Cancer Symptom Scale (LCSS) in patients treated with pemetrexed in combination with TH-302 and pemetrexed in combination with placebo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men and women ≥ 18 years of age.
2. Ability to understand the purposes and risks of the trial and has signed a written informed consent form approved by the investigator’s IRB/EC
3. Histologically or cytologically confirmed stage IIIB or IV (AJCC/UICC 7th edition) NSCLC with non-squamous histology (mixed histology allowed if all components are consistent with NSCLC)
4. Recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance
a. Neoadjuvant/adjuvant cytotoxic chemotherapy initiated < 12 months prior to study randomization will be counted as one prior treatment
b. Neoadjuvant/adjuvant cytotoxic chemotherapy initiated ≥ 12 months prior to study randomization will not be counted as one prior chemotherapy treatment
c. Use of targeted agents (e.g., monoclonal antibodies or kinase inhibitors) will not be counted as a prior chemotherapy treatment
5. Patients with known EGFR-activating mutations or ALK rearrangements should have received treatment with a targeted kinase inhibitor (e.g., erlotinib, crizotinib) and no longer be considered as a candidate for such treatment
6. Measurable disease according to RECIST 1.1
7. ECOG performance status 0-1
8. Life expectancy of ≥ 3 months
9. Resolution to Grade ≤ 1 Adverse Events, of all clinically significant toxic effects of prior therapy (e.g. radiation therapy, maintenance therapy, biopsy procedure; surgery)
10. Adequate hematologic, hepatic, and renal function
a. Hemoglobin ≥10 g/dl
b. Neutrophils ≥1,500/mm3 (not requiring G-CSF support)
c. Platelets ≥ 100,000/mm3
d. Bilirubin <1.5 x ULN (except for patients with Gilbert syndrome)
e. AST and/or /ALT ≤ 5 ULN
f. Creatinine clearance ≥ 45mL/min (Cockcroft-Gault)
11. QTc interval of ≤ 450 msec (males) or 470 msec (females) calculated according to Fridericia’s formula (QTc = QT/RR0.33; RR=RR interval)
12. If the patient has reproductive potential, must either be postmenopausal for more than 1 year, surgically sterile, or using effective contraception and agrees to use double barrier or hormonal contraception during the study period and for up to 6 months after the last dose of study medication
13. Female patients of childbearing potential must have a negative serum or urine pregnancy test, whichever is considered standard by the institution. |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of small cell carcinoma of the lung, squamous cell carcinoma of the lung or NSCLC NOS (not otherwise specified)
2. Prior therapy with pemetrexed
3. Inability or unwillingness to take folic acid, vitamin B12 supplementation or corticosteroids
4. Inability to discontinue non-steroidal anti-inflammatory drugs for 5 days (long half-life) or for 2 days (short half-life, if CrCL <80 mL/min) before pemetrexed dosing and until 2 days after pemetrexed dosing
5. Leptomeningial disease or any untreated or symptomatic brain metastases, unless the following criteria are met:
a. Brain metastases are stable and have been previously treated with either whole-brain radiotherapy or gamma-knife surgery
b. Steroids are currently not required and more than 14 days since last steroid treatment
6. Symptomatic pleural effusion (> CTCAE Grade 1 dyspnea) that is not amenable to drainage
7. Treatment with other systemic anticancer therapy within 4 weeks prior to the first dose of study medication
8. Treatment with full field radiation therapy within 4 weeks or limited field radiation therapy within 2 weeks prior to the first dose of study medication
9. Major surgery within 4 weeks or minor surgery within 2 weeks prior the first dose of study medication
10. Elective or a planned major surgery while on study treatment
11. Radiation therapy to greater than 25% of the bone marrow
12. Clinically significant active infection (e.g. tuberculosis, viral hepatitis, HIV)
13. Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, HIV), recent (within 6 months) myocardial infarction or unstable angina, unstable arrhythmia, poorly-controlled hypertension or diabetes, or psychiatric condition or history of drug abuse that may interfere with the patient’s ability to follow study procedures
14. Concurrent active malignancy other than adequately treated basal cell or squamous cell carcinoma of the skin or pre-invasive carcinoma of the cervix. A patient with previous history of malignancy other than NSCLC is eligible, provided that he/she has been free of disease for ≥ 3 years
15. Pregnant or breast feeding
16. Patients who are taking medications that prolong QT interval and have a risk of Torsades de Pointes (Appendix F) or who have a history of long QT syndrome
17. Patients who are taking medications that are strong inducers or inhibitors of CYP3A4 (Appendix E)
18. History of hypersensitivity reaction to any of the study treatment components, including polysorbate 80 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is overall survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary endpoint, overall survival (OS), is event based and will occur after 321 deaths. This is projected to occur approximately 15 months after the last patient is enrolled. |
|
| E.5.2 | Secondary end point(s) |
| RECIST 1.1 will be used to determine progression-free survival, objective tumor response, stable disease or better rate and duration of response. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Progression-free survival and overall response (secondary endpoints) data may mature sooner than OS data, however, both analyses will be performed with the same cut-off point as the OS data. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Pemetrexed+TH-302 vs Pemetrexed +Placebo |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
| Canada |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| United States |
|
| 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
|
| Last subject last visit including survival follow-up assessments. |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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