AVAPERL1 Study: A Study of Avastin (Bevacizumab) With or Without Pemetrexed as Maintenance Therapy After Avastin in First Line in Patients With Non-Squamous Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This open-label study will assess the efficacy and safety of Avastin with or without pemetrexed as maintenance therapy in patients with advanced, metastatic or recurrent non-small cell lung cancer. In Part 1, patients will receive 4 cycles of treatment with Avastin (7.5mg/kg iv) plus cisplatin (75mg/m2 iv) plus pemetrexed (500mg/m2 iv) on day 1 of each 3-week cycle. In Part 2, patients responding to treatment will be randomized to receive further treatment cycles of Avastin (7.5mg/kg iv every 3 weeks) with or without pemetrexed (500mg/m2 iv every 3 weeks). Anticipated time on study treatment is until disease progression. Target sample size is <500 individuals.

Official Title
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Open-label Study of Bevacizumab Maintenance Therapy (AVASTIN®) With or Without Pemetrexed After First-line Chemotherapy With Bevacizumab-cisplatin-pemetrexed in Patients With Advanced, Metastatic or Recurrent Non-squamous Non-small Cell Lung Cancer (NSCLC)

Conditions
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Non-Squamous Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: bevacizumab [Avastin]
* Drug: cisplatin
* Drug: pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adults >/=18 years of age inoperable, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) at least 1 measurable lesion meeting RECIST criteria ECOG performance status 0-2 adequate hematological, liver and renal function Exclusion Criteria: prior chemotherapy or treatment with another systemic anti-cancer agent malignancies other than NSCLC within 5 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer or DCIS evidence of tumor invading major blood vessels current or recent use of aspirin (>325mg/day) or full-dose anticoagulants or thrombolytic agents for therapeutic purposes history of haemoptysis >/=grade 2 clinically significant cardiovascular disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1<br> | Drug: bevacizumab [Avastin]<br>* 7.5mg/kg iv on day 1 of each 3-week cycle<br>Drug: cisplatin<br>* 75mg/m2 iv on day 1 of each 3-week cycle<br>Drug: pemetrexed<br>* 500mg/m2 iv on day 1 of each 3-week cycle<br>|
| Experimental: Part 2A<br> | Drug: bevacizumab [Avastin]<br>* 7.5mg/kg iv on day 1 of each 3-week cycle<br>|
| Active Comparator: Part 2B<br> | Drug: bevacizumab [Avastin]<br>* 7.5mg/kg iv on day 1 of each 3-week cycle<br>Drug: pemetrexed<br>* 500mg/m2 iv on day 1 of each 3-week cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival During Maintenance Treatment Phase | Progression free survival (PFS) is defined as the time from randomization to the date of documented disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) , or the date of occurrence of a second primary cancer, or date of death from any cause, whichever comes first. Progression is defined using (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, the appearance of new lesions and increase of at least 5 mm in the sum of diameters of target lesions.Tumor assessment was done before Cycle 3, at Cycle 2 of maintenance therapy and every nine weeks thereafter. | Up to 21 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival During Maintenance Treatment Phase | Overall survival (OS) is assessed from the date of first induction treatment until the date of death. Tumor assessment was done before Cycle 3, at Cycle 2 of maintenance therapy and every nine weeks thereafter. | Up to 21 months | 
| Best Overall Response Rate During Maintenance Treatment Phase | The best overall response rate (BORR) is defined as the percentage of participants having achieved confirmed Complete Response (CR) and Partial Response (PR) as the best overall response. CR was defined as complete disappearance of all target lesions and non-target disease. PR was defined as a greater than or equal to (≥) 30% decrease under baseline of the sum of diameters of all target lesions. Stable disease (SD) is defined as steady state of disease with neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).Tumor assessment was done before Cycle 3, at Cycle 2 of maintenance therapy and every nine weeks thereafter. | Up to 21 months | 
| Duration of Response During Maintenance Treatment Phase | Duration of response is defined as the time in months from the initial start of response PR or better to the earlier of documented PD or death due to any cause. Participants who had neither progressed nor died at the date of clinical cutoff, who withdrew from the study, were lost to follow-up, or were without documented disease progression were censored at the date of the last available tumor assessment. The analysis was based on all participants with measurable disease at baseline who achieved response.Tumor assessment was done before Cycle 3, at Cycle 2 of maintenance therapy and every nine weeks thereafter. | Up to 21 months | 
| Duration of Disease Control During Maintenance Treatment Phase | Duration of disease control is defined as the time in months from randomization to the earlier of documented PD or death due to any cause. Tumor assessment was done before Cycle 3, at Cycle 2 of maintenance therapy and every nine weeks thereafter. | Up to 21 months | 
| Incidence of Adverse Events and Serious Adverse Event | An adverse events (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. An serious adverse event (SAE) is any experience that suggests a significant hazard, contraindication, side effect, or precaution. | Up to 21 months | 
| Number of Participants With Marked Laboratory Abnormalities | Marked laboratory abnormalities were defined as those values that were outside the reference range and showed a clinically relevant change from Baseline. The reference range for Platelets was 100-550 (10^9/L), for White blood cells (WBC) was 3.0-18.0 (10^9/L), for Lymphocytes was 0.70-7.60 (10^9/L), and Neutrophil 1.50-9.25 (10^9/L ). | Up to 21 months | 
| Quality of Life | European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Cancer 30 (EORTC QLQ-C30): included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). The European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Lung Cancer 13 [EORTC QLQ-LC13]consisted of 1 multi-item scale and 9 single items that assessed the specific symptoms (dyspnea, cough, hemoptysis, and site specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use of lung cancer participants receiving chemotherapy. Scale score range: 0 to 100. Higher symptom score = greater degree of symptom severity. QOL was assessed using Pre-Induction Baseline (Pre-ind BL), Maintenance (MTC), End of study (EOS) cycles. | Up to 21 months |