Trial of BI 6727 (Volasertib) Monotherapy and BI 6727 in Combination With Pemetrexed Compared to Pemetrexed Monotherapy in Advanced NSCLC

• ClinicalTrials.gov Identifier: NCT00824408
• Recruitment Status: Completed
• First Posted: January 16, 2009
• Results First Posted: September 20, 2016
• Last Update Posted: September 20, 2016
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

Brief Summary:

The trial objective will be to evaluate whether BI 6727 monotherapy or in combination with pemetrexed may be effective in the treatment of advanced or metastatic NSCLC in patients who relapsed after or failed first-line platinum based therapy.

The secondary objectives are to identify the acceptable dose of BI 6727 in combination with pemetrexed and to characterize the pharmacokinetic profiles of BI 6727 alone. Arm A, BI6727 monotherapy arm is closed to further recruitment.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: pemetrexed; Drug: BI 6727	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 143 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomised Open-label Phase II Trial of BI 6727 Monotherapy and BI 6727 in Combination With Standard Dose Pemetrexed Compared to Pemetrexed Monotherapy in Second Line Non-small Cell Lung Cancer
• Study Start Date: March 2009
• Actual Primary Completion Date: September 2012
• Actual Study Completion Date: August 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: BI 6727 +pemetrexed; BI 6727 plus 500 mg/^m2 pemetrexed i.v. on day 1 of 21 day cycle	Drug: pemetrexed; 500 mg/m^2 i.v. on day 1 of 21 day cycle; Drug: BI 6727; BI 6727 i.v. on day 1 of a 21 day cycle
Active Comparator: pemetrexed; 500 mg/m^2 i.v. on day 1 of a 21 day cycle	Drug: pemetrexed; 500 mg/m^2 i.v. on day 1 of 21 day cycle

Outcome Measures

Primary Outcome Measures :

1. Progression Free Survival (PFS) Time From the Date of Randomization to Date of Disease Progression or Death, Whichever Occurred First. [ Time Frame: From randomization until disease progression or death ]

   Disease progression was defined according to the Response Evaluation Criteria in Solid Tumours (RECIST)) criteria. Progression-free survival time was calculated as the duration from the date of randomization to the date of disease progression or death, whichever occured first. For patients with known date of progression (or death): PFS [days] = min (date of progression, date of death) - date of randomization + 1 day. For patients without progression or death, PFS was censored at the last imaging date that showed no disease progression: PFS [days, censored] = date of last imaging showing no progression - date randomization + 1 day.

   The number of participants analysed displays the number of patients with an event (progression).

Secondary Outcome Measures :

1. Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria. [ Time Frame: From first drug infusion until 21 days after last drug infusion, up to 1100 days ]
   Objective tumor response, defined as complete response (CR), and partial response (PR), evaluated according to RECIST criteria. Evaluation of target lesions: Complete Response (CR): disappearance of all target lesions. Partial Response (PR): ≥30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Evaluation of nontarget lesions: Complete Response (CR): disappearance of all nontarget lesions.
2. Overall Survival (OS) [ Time Frame: From randomization until time of death ]
   Overall survival (OS) was defined as the duration of time from randomization to time of death.
3. Duration of Overall Response [ Time Frame: From the time measurement criteria were met for CR or PR (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented ]
   The duration of overall response was measured from the time measurement criteria were met for CR or PR (whichever was first recorded) until the first date that recurrent or progressive disease (PD) was objectively documented (taking as reference for PD the smallest measurements recorded since treatment began). The duration of overall CR was measured from the time measurement criteria were first met for CR until the first date that recurrent disease was objectively documented. Duration of disease control is presented here.
4. Occurrence and Intensity of AEs Graded According to CTCAE. [ Time Frame: From first drug infusion until 21 days after last drug infusion, up to 1100 days ]
   All patients were carefully monitored during and after each treatment cycle. Adverse events (AEs) were recorded and were graded according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE).
5. Occurence of DLT [ Time Frame: Patients were treated for repeated 21-day treatment cycles until disease progression or intolerability of the trial drug, whichever occurred first. ]

   Occurence of Dose-limiting toxicity (DLT). A DLT was defined as one or more of the following:

   • treatment-related CTCAE Grade 3 or 4 nonhematological toxicity (except emesis or diarrhea responding to supportive treatment).
   • treatment-related CTCAE Grade 4 neutropenia for ≥7 days and/or complicated by infection.
   • CTCAE Grade 4 thrombocytopenia.
6. Frequency of Patients With Possible Clinically Significant Abnormalities [ Time Frame: From first drug infusion until 21 days after last drug infusion, up to 1100 days ]
   Frequency of patients with possible clinically significant abnormalities
7. Cmax of Volasertib [ Time Frame: 5 minutes (min) before the start of Volasertib infusion and 1 hour (h), 2h, 4h, 24h, 168h and 336h after the start of Volasertib infusion ]
   Cmax - maximum measured concentration of volasertib in plasma.
8. Total Clearance (CL) of Volasertib [ Time Frame: 5 minutes (min) before the start of Volasertib infusion and 1 hour (h), 2h, 4h, 24h, 168h and 336h after the start of Volasertib infusion ]
   CL - total clearance of volasertib in plasma after IV administration
9. Vss of Volasertib [ Time Frame: 5 minutes (min) before the start of Volasertib infusion and 1 hour (h), 2h, 4h, 24h, 168h and 336h after the start of Volasertib infusion ]
   Vss - apparent volume of distribution at steady state following IV administration of volasertib
10. Cmax of Pemetrexed [ Time Frame: 5 minutes before pemetrexed infusion, at the end of the infusion and 1.5 hours (h), 2.5h, 4.5h and 25.5h after the end of pemetrexed infusion ]
    Cmax - maximum measured concentration of pemetrexed in plasma
11. CL of Pemetrexed [ Time Frame: 5 minutes before pemetrexed infusion, at the end of the infusion and 1.5 hours (h), 2.5h, 4.5h and 25.5h after the end of pemetrexed infusion ]
    CL - total clearance of pemetrexed in plasma after IV administration
12. Vss of Pemetrexed [ Time Frame: 5 minutes before pemetrexed infusion, at the end of the infusion and 1.5 hours (h), 2.5h, 4.5h and 25.5h after the end of pemetrexed infusion ]
    Vss - apparent volume of distribution at steady state following IV administration of pemetrexed

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

1. Pathologic or cytologic confirmed diagnosis of NSCLC
2. Recurrent, advanced or metastatic NSCLC that has progressed following one prior platinum based chemotherapy regimen (not counting adjuvant or neoadjuvant chemotherapy if completed more than 12 months prior to platinum based therapy)
3. Patients who are eligible for pemetrexed as second line chemotherapy
4. Measurable disease by one or more techniques (CT, MRI) according to RECIST
5. Patients aged 18 years or older
6. Life expectancy of at least three (3) months
7. Eastern Cooperative Oncology Group (ECOG) performance Score 0-2
8. Written informed consent that is consistent with ICH-GCP guidelines and local legislation

Exclusion criteria:

1. Treatment with an investigational drug in another clinical study within the past 28 days prior to the start of therapy or concomitantly with this study
2. Anti-cancer therapy for NSCLC (except radiotherapy for palliative reasons) within the past 28 days prior to Treatment Day 1 of Cycle 1 of this trial
3. Any persisting toxicities which are deemed to be clinically significant from the previous therapy
4. Patients who have received more than one prior chemotherapy regimen for advanced disease (not including prior adjuvant therapy). Patients may have received prior epidermal growth factor receptor tyrosine kinase inhibitors.
5. Patients who are unwilling or unable to take folic acid and vitamin B12 supplementation
6. Active brain metastases (stable for <28 days, symptomatic, or requiring concurrent steroids). Patients who have received prior whole brain irradiation and whose brain metastases are stable according to the criteria above will not be excluded.
7. Other active malignancy diagnosed within the past 3 years (other than non melanomatous skin cancer and cervical intraepithelial neoplasia)
8. Concomitant intercurrent illnesses including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness or social situation that would limit compliance with trial requirement or which are considered relevant for the evaluation of the efficacy or safety of the trial drug
9. Patients unable or unwilling to interrupt concomitant administration of NSAIDS 5 days prior to, the day of and 2 days after the administration of pemetrexed, with the exception of lose dose aspirin 81mg daily
10. Patients who have received prior therapy with pemetrexed
11. Absolute neutrophil count (ANC) less than 1,500/mm3
12. Platelet count less than 100,000/mm3
13. Hemoglobin <90g/L
14. Total bilirubin >26µmol/L
15. Alanine amino transferase (ALT) and/or aspartate amino transferase (AST) less than 2.5 X ULN, except in case of known liver metastasis where maximum 5 X ULN is acceptable
16. Serum creatinine level >133µmol/L and/or creatinine clearance (measured or calculated) <45 ml/min
17. Clinically relevant QTc prolongation
18. Women and men who are sexually active and unwilling to use a medically acceptable method of contraception
19. Pregnancy or breast feeding
20. Known or suspected active alcohol or drug abuse
21. Patients unable to comply with the protocol
22. Any known hypersensitivity to the trial drugs or their excipients
23. Patients with NSCLC of confirmed Squamous histology

Contacts and Locations

Locations

Bahamas

1230.5.00118 Boehringer Ingelheim Investigational Site

Nassau, Bahamas

Canada, Alberta

1230.5.00104 Boehringer Ingelheim Investigational Site

Edmonton, Alberta, Canada

Canada, British Columbia

1230.5.00114 Boehringer Ingelheim Investigational Site

Kelowna, British Columbia, Canada

1230.5.00109 Boehringer Ingelheim Investigational Site

Surrey, British Columbia, Canada

1230.5.00107 Boehringer Ingelheim Investigational Site

Vancouver, British Columbia, Canada

Canada, Ontario

1230.5.00105 Boehringer Ingelheim Investigational Site

Hamilton, Ontario, Canada

1230.5.00119 Boehringer Ingelheim Investigational Site

Kitchener, Ontario, Canada

1230.5.00116 Boehringer Ingelheim Investigational Site

Oshawa, Ontario, Canada

1230.5.00108 Boehringer Ingelheim Investigational Site

Ottawa, Ontario, Canada

1230.5.00110 Boehringer Ingelheim Investigational Site

Toronto, Ontario, Canada

Canada, Quebec

1230.5.00102 Boehringer Ingelheim Investigational Site

Montreal, Quebec, Canada

1230.5.00106 Boehringer Ingelheim Investigational Site

Montreal, Quebec, Canada

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ellis PM, Leighl NB, Hirsh V, Reaume MN, Blais N, Wierzbicki R, Sadrolhefazi B, Gu Y, Liu D, Pilz K, Chu Q. A Randomized, Open-Label Phase II Trial of Volasertib as Monotherapy and in Combination With Standard-Dose Pemetrexed Compared With Pemetrexed Monotherapy in Second-Line Treatment for Non-Small-Cell Lung Cancer. Clin Lung Cancer. 2015 Nov;16(6):457-65. doi: 10.1016/j.cllc.2015.05.010. Epub 2015 Jun 2.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00824408
• Other Study ID Numbers: 1230.5
• First Posted: January 16, 2009
• Results First Posted: September 20, 2016
• Last Update Posted: September 20, 2016
• Last Verified: July 2016

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Pemetrexed; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors