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

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ClinicalTrials.gov Identifier: NCT02004184
Recruitment Status : Terminated (Poor enrollment due to the introduction of immunotherapy)
First Posted : December 9, 2013
Last Update Posted : June 23, 2020
Sponsor:
Collaborator:
St. Olavs Hospital
Information provided by (Responsible Party):
Norwegian University of Science and Technology

Tracking Information
First Submitted Date  ICMJE November 19, 2013
First Posted Date  ICMJE December 9, 2013
Last Update Posted Date June 23, 2020
Actual Study Start Date  ICMJE December 2013
Actual Primary Completion Date March 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 2, 2013)
overall survival [ Time Frame: 2 years ]
All patients will be followed until death of any reason - assessed up to 24 months after inclusion in the study.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 2, 2013)
  • progression free survival [ Time Frame: 2 years ]
    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.
  • Toxicity [ Time Frame: 2 years ]
    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).
  • Health related quality of life [ Time Frame: 2 years ]
    All patients will be followed until discontinuation of study therapy - up to 24 months after inclusion in the study.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: December 2, 2013)
  • Overall survival in elderly and PS 2 patients [ Time Frame: 2 years ]
    All patients will be followed until death of any reason - assessed up to 24 months after inclusion in the study.
  • Associations between clinical characteristics and blood biomarkers - and outcomes of therapy [ Time Frame: 2 years ]
    All patients will be followed until death of any reason - assessed up to 24 months after inclusion in the study.
  • Toxicity in elderly and PS 2 patients [ Time Frame: 2 years ]
    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).
  • Health related quality of life in elderly and PS 2 patients [ Time Frame: 2 years ]
    All patients will be followed until discontinuation of study therapy - up to 24 months after inclusion in the study.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Pemetrexed in Advanced Non-Small-Cell Lung Cancer: at Progression vs Maintenance Therapy After Induction Chemotherapy
Official Title  ICMJE Maintenance Pemetrexed Therapy After Induction Chemotherapy Versus Pemetrexed at Progression in Advanced Non-Small-Cell Lung Cancer: A Randomized Phase III Study
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Carcinoma, Non-small-cell Lung
Intervention  ICMJE
  • Drug: maintenance pemetrexed
    500 mg/m2 Body Surface Area is administered intravenously every 3 weeks
    Other Name: Alimta
  • Drug: pemetrexed at progression
    500 mg/m2 Body Surface Area is administered intravenously every 3 weeks
    Other Name: Alimta
Study Arms  ICMJE
  • Experimental: maintenance pemetrexed
    maintenance pemetrexed immediately after induction chemotherapy
    Intervention: Drug: maintenance pemetrexed
  • Active Comparator: pemetrexed at progression
    observation and pemetrexed therapy at disease progression
    Intervention: Drug: pemetrexed at progression
Publications * Halvorsen TO, Stokke K, Killingberg KT, Raj SX, Sørhaug S, Brustugun OT, Fløtten Ø, Helbekkmo N, Hornslien K, Madebo T, Fluge S, Grønberg 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 2, 2018)
230
Original Estimated Enrollment  ICMJE
 (submitted: December 2, 2013)
765
Actual Study Completion Date  ICMJE March 2018
Actual Primary Completion Date March 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Norway
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02004184
Other Study ID Numbers  ICMJE 2013/645
2013-001237-41 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Norwegian University of Science and Technology
Study Sponsor  ICMJE Norwegian University of Science and Technology
Collaborators  ICMJE St. Olavs Hospital
Investigators  ICMJE
Principal Investigator: Bjørn H Grønberg, MD PhD Norwegian University of Science and Technology
PRS Account Norwegian University of Science and Technology
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP