A Study of Bevacizumab in Combination With Standard of Care Treatment in Participants With Advanced Non-squamous Non-small Cell Lung Cancer (NSCLC)

• ClinicalTrials.gov Identifier: NCT01351415
• Recruitment Status: Completed
• First Posted: May 10, 2011
• Results First Posted: September 18, 2017
• Last Update Posted: September 18, 2017
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: May 9, 2011
• First Posted Date: May 10, 2011
• Results First Submitted Date: June 20, 2017
• Results First Posted Date: September 18, 2017
• Last Update Posted Date: September 18, 2017
• Actual Study Start Date: June 25, 2011
• Actual Primary Completion Date: June 25, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 17, 2017)

Overall Survival (OS) [ Time Frame: Up to data cut-off date 24 June 2016 (approximately 5 years) ]

Overall survival (OS) was defined as the time from the date of randomization at first progression of disease to the date of death, regardless of the cause of death.

• Original Primary Outcome Measures (submitted: May 9, 2011): Overall survival [ Time Frame: Approximately 3 years ]

Current Secondary Outcome Measures (submitted: August 17, 2017)

• Progression-free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [ Time Frame: Up to data cut-off date 24 June 2016 (approximately 5 years) ]
  PFS was defined as the time from start of treatment to the first event of death or PD. Tumor response was assessed by the IRF according to RECIST v1.1. Disease progression or PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS2 is defined as the time between randomization at PD1 and the date of PD2 or death, whichever occurs first. PFS3 is defined as the time between PD2 and the date of PD3 or death, whichever occurs first.
• Percentage of Participants With Objective Response According to RECIST v1.1 [ Time Frame: Up to data cut-off date 24 June 2016 (approximately 5 years) ]
  The objective response is defined as complete response (CR) or partial response (PR) assessed according to the RECIST v.1.1 criteria with baseline tumour assessment as the reference. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as greater than or equal to (≥) 30 percent (%) decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. Response was to be confirmed ≥4 weeks after the initial assessment of CR or PR.
• Percentage of Participants With Disease Control According to RECIST v1.1 [ Time Frame: Up to data cut-off date 24 June 2016 (approximately 5 years) ]
  The disease control rate is defined as CR or PR or stable disease (SD) assessed according to the RECIST v.1.1 criteria with baseline tumour assessment as the reference. SD was defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started for target lesions and the persistence of 1 or more non-target lesions.
• Duration of Response (DoR) According to RECIST v1.1 [ Time Frame: Up to data cut-off date 24 June 2016 (approximately 5 years) ]
  Duration of response is defined as the time that measurement criteria are met for objective response (CR/PR) (whichever status is recorded first) until the first date of progression or death is documented. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than < 10 mm. PR was defined as greater than or equal to ≥30 % decrease in sum of longest diameter of target lesions in reference to baseline sum longest diameter.
• Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to data cut-off date 24 June 2016 (approximately 5 years) ]
  An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. A SAE was any experience that: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically significant.
• Time to Progression (TTP) According to RECIST v1.1 [ Time Frame: Up to data cut-off date 24 June 2016 (approximately 5 years) ]
  The time to progression was defined as the time from baseline until disease progression as determined by the RECIST v1.1. TTP2 is defined as the interval between the day of randomization at PD1 and PD2. TTP3 is defined as the interval between the day of PD2 and PD3. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
• Percentage of Participants Who Are Alive at Month 6, 12, and 18 [ Time Frame: Month 6, 12, 18 ]
  Percentage of participants who were alive at Month 6, 12 and 18 were reported.

Original Secondary Outcome Measures (submitted: May 9, 2011)

• Progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Approximately 3 years ]
• Response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Approximately 3 years ]
• Disease control rate according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Approximately 3 years ]
• Duration of response according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Approximately 3 years ]
• Safety (incidence of adverse events) [ Time Frame: Approximately 3 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Bevacizumab in Combination With Standard of Care Treatment in Participants With Advanced Non-squamous Non-small Cell Lung Cancer (NSCLC)
• Official Title: An Open-label, Randomized, Phase IIIb Trial Evaluating the Efficacy and Safety of Standard of Care +/- Continuous Bevacizumab Treatment Beyond Progression of Disease (PD) in Patients With Advanced Non-squamous Non-small Cell Lung Cancer (NSCLC) After First Line Treatment With Bevacizumab Plus a Platinum Doublet-containing Chemotherapy
• Brief Summary: This open-label, randomized, multicenter study will evaluate the efficacy and safety of bevacizumab (Avastin) in combination with standard of care (SOC) treatment in participants with advanced non-squamous NSCLC. Participants will be enrolled at documentation of progression of disease (PD) after 4-6 cycles of first-line treatment with bevacizumab plus a platinum doublet-containing therapy and a minimum of two cycles of bevacizumab maintenance treatment prior to PD. Participants will be randomly assigned to one of two treatment arms to receive either bevacizumab plus SOC treatment or SOC treatment alone.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-Squamous Non-Small Cell Lung Cancer

Intervention

• Drug: Bevacizumab
  Participants will receive bevacizumab 7.5 or 15 milligrams per kilogram (mg/kg) intravenously.
  Other Name: Avastin
• Drug: Docetaxel
  Docetaxel 60 or 75 milligram per meter square (mg/m^2) on Day 1 every 21 days.
• Drug: Erlotinib
  Erlotinib 150 mg daily taken on an empty stomach at least one hour before or two hours after the ingestion of food.
• Drug: Pemetrexed
  Pemetrexed 500 mg/m^2 IV over 10 minutes on Day 1 every 21 days.

Study Arms

• Experimental: Bevacizumab + Standard of Care
  Participants will receive bevacizumab on Day 1 of every 21-days cycle along with standard of care (Erlotinib or Docetaxel or Pemetrexed) as second line treatment, until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
  Interventions:

  • Drug: Bevacizumab
  • Drug: Docetaxel
  • Drug: Erlotinib
  • Drug: Pemetrexed
• Active Comparator: Standard of Care
  Participants will receive investigator's choice of standard of care (Erlotinib or Docetaxel or Pemetrexed) according to local practice until the occurrence of an unacceptable toxicity or withdrawal of consent (whichever occurs first).
  Interventions:

  • Drug: Docetaxel
  • Drug: Erlotinib
  • Drug: Pemetrexed

Publications *

• Gridelli C, de Castro Carpeno J, Dingemans AC, Griesinger F, Grossi F, Langer C, Ohe Y, Syrigos K, Thatcher N, Das-Gupta A, Truman M, Donica M, Smoljanovic V, Bennouna J. Safety and Efficacy of Bevacizumab Plus Standard-of-Care Treatment Beyond Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer: The AvaALL Randomized Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):e183486. doi: 10.1001/jamaoncol.2018.3486. Epub 2018 Dec 13. Erratum In: JAMA Oncol. 2018 Dec 1;4(12):1792.
• Takeda M, Yamanaka T, Seto T, Hayashi H, Azuma K, Okada M, Sugawara S, Daga H, Hirashima T, Yonesaka K, Urata Y, Murakami H, Saito H, Kubo A, Sawa T, Miyahara E, Nogami N, Nakagawa K, Nakanishi Y, Okamoto I. Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy in advanced nonsquamous non-small cell lung cancer (West Japan Oncology Group 5910L): An open-label, randomized, phase 2 trial. Cancer. 2016 Apr 1;122(7):1050-9. doi: 10.1002/cncr.29893. Epub 2016 Feb 1.
• Gridelli C, Bennouna J, de Castro J, Dingemans AM, Griesinger F, Grossi F, Rossi A, Thatcher N, Wong EK, Langer C. Randomized phase IIIb trial evaluating the continuation of bevacizumab beyond disease progression in patients with advanced non-squamous non-small-cell lung cancer after first-line treatment with bevacizumab plus platinum-based chemotherapy: treatment rationale and protocol dynamics of the AvaALL (MO22097) trial. Clin Lung Cancer. 2011 Nov;12(6):407-11. doi: 10.1016/j.cllc.2011.05.002. Epub 2011 Jun 25.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 17, 2017): 485
• Original Estimated Enrollment (submitted: May 9, 2011): 600
• Actual Study Completion Date: June 25, 2016
• Actual Primary Completion Date: June 25, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed non-squamous NSCLC
• Documented progression of disease (locally recurrent or metastatic) per investigator assessment following first-line treatment with 4-6 cycles of Bevacizumab plus a platinum doublet-containing chemotherapy regimen and a minimum of 2 cycles of Bevacizumab (monotherapy) maintenance treatment prior to first progression of disease
• No treatment interruption of Bevacizumab treatment greater than 2 consecutive cycles (42 days) between the start of first-line treatment to start of Cycle 1 of second line treatment
• Randomization within 4 weeks of progression of disease
• At least one unidimensionally measurable lesion meeting RECIST v1.1 criteria
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Participants with adequate hematological, liver, and renal function
• Female participants must not be pregnant or breast-feeding. Female participants of childbearing potential and fertile male participants must agree to use a highly effective contraceptive during the trial and for a period of at least 6 months following the last administration of trial drug(s)

Exclusion Criteria:

• Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component
• Epidermal growth factor receptor (EGFR)-mutation-positive disease according to local laboratory testing
• History of hemoptysis greater than or equal to (>/=) grade 2 within 3 months of randomization
• History or evidence of inherited bleeding diathesis or coagulopathy with a risk of bleeding and active gastrointestinal bleeding
• Major cardiac disease
• Treatment with any other investigational agent within 28 days prior to randomization
• Known hypersensitivity to bevacizumab or any of its excipients, or any SOC drugs foreseen
• Malignancy other than NSCLC within 5 years prior to randomization and evidence of any other disease that contraindicates the use of an investigational or SOC drug

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Austria, Belgium, Brazil, Denmark, France, Germany, Greece, Italy, Japan, Lebanon, Mexico, Netherlands, Oman, Slovakia, Spain, United Arab Emirates, United States
• Removed Location Countries: Jordan, Qatar

Administrative Information

• NCT Number: NCT01351415
• Other Study ID Numbers: MO22097; 2010-022645-14 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Disclosures Group, Hoffmann-La Roche
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: August 2017