Study of TH-302 or Placebo in Combination With Pemetrexed in Patients With Advanced Non-Small Cell Lung Cancer

• Register: EUCTR
• Last refreshed on: 24 October 2016
• Main ID: EUCTR2013-004698-29-DE
• Date of registration: 04/03/2014
• Prospective Registration: Yes
• Primary sponsor: Threshold Pharmaceuticals, Inc.
• Public title: Study of TH-302 or Placebo in Combination With Pemetrexed in Patients With Advanced Non-Small Cell Lung Cancer
• Scientific title: A Randomized Phase 2, Double-blind, Placebo-controlled, Multi-center Study Comparing Pemetrexed in Combination with TH-302 vs. Pemetrexed in Combination with Placebo as Second-line Chemotherapy for Advanced Non-Squamous, Non-Small Cell Lung Cancer - TH-CR-415
• Date of first enrolment: 28/05/2014
• Target sample size: 440
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-004698-29
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Pemetrexed+TH-302 vs Pemetrexed +Placebo Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Canada, Czech Republic, France, Germany, Greece, Hungary, Italy, Poland, Romania, Russian Federation, Spain, United States

Contacts

• Name: Leslie Brand
• Affiliation: Threshold Pharmaceuticals, Inc.

• Name: Leslie Brand
• Affiliation: Threshold Pharmaceuticals, Inc.

Key inclusion & exclusion criteria

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 must have been tested for EGFR-activating mutations, and if negative, ALK rearrangements, and if identified have received treatment with a targeted tyrosine kinase inhibitor (e.g., erlotinib, crizotinib).
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 =8 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 = 3 x ULN, except for known liver metastases
f. Creatinine clearance = 45 mL/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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 295
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 145

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 of patients with mild to moderate renal insufficiency (creatinine clearance 45 to 79 mL/min) to discontinue non-steroidal anti-inflammatory
drugs for 5 days (long half-life) or for 2 days 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. Patients with a previous malignancy within the past 3 years are excluded other than curatively treated basal cell or squamous cell carcinoma of the skin, early gastrointestinal or bladder cancer by endoscopic resection, in situ carcinoma of the Cervix or any cured cancer, that is considered to have no impact on PFS and OS for the current NSCLC diagnosis.
15. Pregnant or breast feeding
16. Patients who are taking medications that prolong QT interval and have a risk of Torsades de Pointes (Appendix E) or who have a history of long QT syndrome
17. Patients who are taking medications that are strong inducers or inhibitors of CYP3A4 (Appendix D)
18. History of hypersensitivity reaction to any of the study treatment components, including polysorbate 80
19. Concurrent participation in another clinical trial or study


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Advanced Non-Squamous, Non-Small Cell Lung Cancer
MedDRA version: 18.1 Level: PT Classification code 10029522 Term: Non-small cell lung cancer stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 18.1 Level: PT Classification code 10029521 Term: Non-small cell lung cancer stage IIIB System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Code: TH-302
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: NA
CAS Number: 918633-87-1
Current Sponsor code: TH-302
Other descriptive name: TH-302
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Trade Name: Alimta
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: PEMETREXED
CAS Number: 137281-23-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Alimta
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: PEMETREXED
CAS Number: 137281-23-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Primary Outcome(s)

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.

Primary end point(s): The primary efficacy endpoint is overall survival.

Main Objective: 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

Secondary Objective: 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

Secondary Outcome(s)

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.

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.

Secondary ID(s)

TH-CR-415

121080

2013-004698-29-HU

Source(s) of Monetary Support

Threshold Pharmaceuticals, Inc.