Pemetrexed in Advanced Non-Small-Cell Lung Cancer: at Progression vs Maintenance Therapy After Induction Chemotherapy (IDA)

Norwegian University of Science and Technology

Status and phase

Terminated

Phase 3

Conditions

Carcinoma, Non-small-cell Lung

Treatments

Drug: pemetrexed at progression

Drug: maintenance pemetrexed

Study type

Interventional

Funder types

Other

Identifiers

NCT02004184

2013-001237-41 (EudraCT Number)

2013/645

Details and patient eligibility

About

Non-small-cell lung cancer (NSCLC) accounts for a majority (approximately 85%) of lung cancer cases. Patients with localized disease can be cured through surgery, but only 20 % are operable.For the majority of patients with advanced disease, palliative cytotoxic chemotherapy remains the recommended therapy. Chemotherapy prolongs survival and improves quality of life.

The recommended first-line therapy is 4-6 courses of a platinum in combination with a third generation compound (e.g. gemcitabine, vinorelbine, docetaxel, pemetrexed, paclitaxel). After first-line therapy, it has been recommended to observe the patients and offer second-line chemotherapy at disease progression.

Regimens for second-line therapy include docetaxel or pemetrexed monotherapy. Pemetrexed is less toxic and superior to gemcitabine in non-squamous NSCLC, whereas docetaxel is the recommended second-line therapy in squamous cell carcinoma.

The results of the studies of maintenance pemetrexed therapy are encouraging; the observed survival benefit is clinically relevant and relatively large considering the poor survival in patients with advanced NSCLC. Furthermore, pemetrexed appears to be well tolerated. There are, however, several limitations to the studies that have been conducted: Relatively few elderly patients and no PS 2 patients were enrolled - and not all patients on the control-arms received pemetrexed at progression.

The overall aim of this study is to investigate whether immediate maintenance pemetrexed therapy prolongs survival compared to observation and pemetrexed therapy at progression in patients with advanced NSCLC. Furthermore, it will be explored whether patients with 'performance status' 2 and elderly ≥ 70 years tolerate and benefit from maintenance therapy; and what characteristics and blood biomarkers are associated with sensitivity and tolerability of such therapy.

Full description

In previous studies without maintenance therapy, median overall survival (OS) for performance status (PS) 0-1 patients has been approximately 9 months, corresponding to 6 months from randomization in this study. We consider an improvement in overall survival of two months to be the minimum difference that will lead to routine use of maintenance pemetrexed in Norway. To demonstrate an improvement in median overall survival from 6 to 8 months with an α =0.05 and β =0.20, 198 evaluable patients are required on each arm. We expect a drop-out rate of maximum 10 %, and therefore intend to randomize a total of 436 patients (PS 0-1) - of which we expect 150 to be 70 years or older.

Sample size is calculated on PS 0-1 patients only. In addition, PS 2 patients will be randomized until the required number of PS 0-1 patients have been accrued. We estimate that a total of 100 PS 2 patients will be enrolled - sufficient for hypothesis-generating analyses of the benefit of maintenance therapy in elderly and PS 2 patients.

Based on experience from our previous studies we estimate that approximately 30% of patients will not complete or progress during induction chemotherapy; or be ineligible due deterioration of PS. Consequently, we need to include approximately 765 patients.

Enrollment

230 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Measureable disease according to the RECIST 1.1
Previous radiotherapy is acceptable provided there are measurable, previously not irradiated lesions present
Histologically or cytologically confirmed non-squamous non-small cell lung cancer
Stage IIIB ineligible for curative therapy or stage IV disease
ECOG Performance 0-2
Adequate organ function defined as:
1. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 x upper limit of normal (ULN), or AST and ALT ≤ 5 x ULN if liver function abnormalities are due to underlying malignancy.
2. Total serum bilirubin ≤ 1.5 x ULN
3. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
4. Platelets ≥ 100 x 109/L
5. Creatinine clearance > 45 ml/min
Able to discontinue NSAIDs and ASA if reduced renal function
All fertile patients should use safe contraception
Written informed consent

Exclusion criteria

prior systemic therapy for advanced non-small-cell lung cancer (including EGFR-TKI). Previous chemotherapy (e.g. adjuvant after surgery or for other cancer) is allowed if ≥ 3 months since the last course was administered.
activating EGFR-mutation or ALK-translocation detected
serious concomitant systemic disorders (for example active infection, unstable cardiovascular disease) that in the opinion of the investigator would compromise the patient's ability to complete the study or interfere with the evaluation of the efficacy and safety of the study treatment
conditions - medical, social, psychological - which could prevent adequate information and follow-up
clinically active cancer other than NSCLC
known hypersensitivity or contraindications for the study drugs (vinorelbine, carboplatin, pemetrexed, B12, folate)
pregnant or lactating women