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

NCT ID: NCT02004184

Last Updated: 2020-06-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 230 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2018-03-31

Brief Summary

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.

Detailed 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.

Conditions

Carcinoma, Non-small-cell Lung

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

maintenance pemetrexed

maintenance pemetrexed immediately after induction chemotherapy

Group Type: EXPERIMENTAL

maintenance pemetrexed

Intervention Type: DRUG

500 mg/m2 Body Surface Area is administered intravenously every 3 weeks

pemetrexed at progression

observation and pemetrexed therapy at disease progression

Group Type: ACTIVE_COMPARATOR

pemetrexed at progression

Intervention Type: DRUG

500 mg/m2 Body Surface Area is administered intravenously every 3 weeks

Interventions

maintenance pemetrexed

500 mg/m2 Body Surface Area is administered intravenously every 3 weeks

Intervention Type: DRUG

pemetrexed at progression

500 mg/m2 Body Surface Area is administered intravenously every 3 weeks

Intervention Type: DRUG

Other Intervention Names

Alimta; Alimta

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

St. Olavs Hospital

OTHER

Sponsor Role: collaborator

Norwegian University of Science and Technology

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bjørn H Grønberg, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Norwegian University of Science and Technology

Locations

St Olavs Hospital

Trondheim, , Norway

Countries

Norway

References

Halvorsen TO, Stokke K, Killingberg KT, Raj SX, Sorhaug S, Brustugun OT, Flotten O, Helbekkmo N, Hornslien K, Madebo T, Fluge S, Gronberg BH. Randomized phase III trial comparing switch-maintenance pemetrexed with observation followed by pemetrexed at progression in advanced NSCLC. Acta Oncol. 2020 Sep;59(9):1051-1057. doi: 10.1080/0284186X.2020.1778179. Epub 2020 Jun 16.

Reference Type: RESULT

PMID: 32543258 (View on PubMed)

Stokke K, Sandvei MS, Gronberg BH, Slaaen M, Killingberg KT, Halvorsen TO. Prognostic Value of Post First-Line Chemotherapy Glasgow Prognostic Score in Advanced Non-Small Cell Lung Cancer. Clin Med Insights Oncol. 2022 Mar 22;16:11795549221086578. doi: 10.1177/11795549221086578. eCollection 2022.

Reference Type: DERIVED

PMID: 35342321 (View on PubMed)

Other Identifiers

2013-001237-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2013/645

Identifier Type: -

Identifier Source: org_study_id