Description:
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.
Title
- Brief Title: Pemetrexed in Advanced Non-Small-Cell Lung Cancer: at Progression vs Maintenance Therapy After Induction Chemotherapy
- Official Title: Maintenance Pemetrexed Therapy After Induction Chemotherapy Versus Pemetrexed at Progression in Advanced Non-Small-Cell Lung Cancer: A Randomized Phase III Study
Clinical Trial IDs
- ORG STUDY ID:
2013/645
- SECONDARY ID:
2013-001237-41
- NCT ID:
NCT02004184
Conditions
- Carcinoma, Non-small-cell Lung
Interventions
Drug | Synonyms | Arms |
---|
maintenance pemetrexed | Alimta | maintenance pemetrexed |
pemetrexed at progression | Alimta | pemetrexed at progression |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
maintenance pemetrexed | Experimental | maintenance pemetrexed immediately after induction chemotherapy | |
pemetrexed at progression | Active Comparator | observation and pemetrexed therapy at disease progression | - pemetrexed at progression
|
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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | overall survival |
Time Frame: | 2 years |
Safety Issue: | |
Description: | All patients will be followed until death of any reason - assessed up to 24 months after inclusion in the study. |
Secondary Outcome Measures
Measure: | progression free survival |
Time Frame: | 2 years |
Safety Issue: | |
Description: | From date of inclusion until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. |
Measure: | Toxicity |
Time Frame: | 2 years |
Safety Issue: | |
Description: | All patients will be followed for 2 years (or until 1 month after the end of study therapy if study therapy is discontinued before 2 years after study inclusion). |
Measure: | Health related quality of life |
Time Frame: | 2 years |
Safety Issue: | |
Description: | All patients will be followed until discontinuation of study therapy - up to 24 months after inclusion in the study. |
Details
Phase: | Phase 3 |
Primary Purpose: | Interventional |
Overall Status: | Terminated |
Lead Sponsor: | Norwegian University of Science and Technology |
Trial Keywords
Last Updated
June 23, 2020