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

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

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.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: pemetrexed; Drug: BI 6727

• Study Type: Interventional
• Enrollment (Actual): 143
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bahamas
  • Nassau, Bahamas
    • 1230.5.00118 Boehringer Ingelheim Investigational Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • 1230.5.00104 Boehringer Ingelheim Investigational Site
  • British Columbia
    • Kelowna, British Columbia, Canada
      • 1230.5.00114 Boehringer Ingelheim Investigational Site
    • Surrey, British Columbia, Canada
      • 1230.5.00109 Boehringer Ingelheim Investigational Site
    • Vancouver, British Columbia, Canada
      • 1230.5.00107 Boehringer Ingelheim Investigational Site
  • Ontario
    • Hamilton, Ontario, Canada
      • 1230.5.00105 Boehringer Ingelheim Investigational Site
    • Kitchener, Ontario, Canada
      • 1230.5.00119 Boehringer Ingelheim Investigational Site
    • Oshawa, Ontario, Canada
      • 1230.5.00116 Boehringer Ingelheim Investigational Site
    • Ottawa, Ontario, Canada
      • 1230.5.00108 Boehringer Ingelheim Investigational Site
    • Toronto, Ontario, Canada
      • 1230.5.00110 Boehringer Ingelheim Investigational Site
  • Quebec
    • Montreal, Quebec, Canada
      • 1230.5.00102 Boehringer Ingelheim Investigational Site
    • Montreal, Quebec, Canada
      • 1230.5.00106 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) Time From the Date of Randomization to Date of Disease Progression or Death, Whichever Occurred First.	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).	From randomization until disease progression or death

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Tumor Response, Defined as Complete Response (CR), and Partial Response (PR), Evaluated According to RECIST Criteria.	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.	From first drug infusion until 21 days after last drug infusion, up to 1100 days
Overall Survival (OS)	Overall survival (OS) was defined as the duration of time from randomization to time of death.	From randomization until time of death
Duration of Overall Response	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.	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
Occurrence and Intensity of AEs Graded According to CTCAE.	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).	From first drug infusion until 21 days after last drug infusion, up to 1100 days
Occurence of DLT	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.	Patients were treated for repeated 21-day treatment cycles until disease progression or intolerability of the trial drug, whichever occurred first.
Frequency of Patients With Possible Clinically Significant Abnormalities	Frequency of patients with possible clinically significant abnormalities	From first drug infusion until 21 days after last drug infusion, up to 1100 days
Cmax of Volasertib	Cmax - maximum measured concentration of volasertib in plasma.	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
Total Clearance (CL) of Volasertib	CL - total clearance of volasertib in plasma after IV administration	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 of Volasertib	Vss - apparent volume of distribution at steady state following IV administration of volasertib	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 of Pemetrexed	Cmax - maximum measured concentration of pemetrexed in plasma	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 of Pemetrexed	CL - total clearance of pemetrexed in plasma after IV administration	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 of Pemetrexed	Vss - apparent volume of distribution at steady state following IV administration of pemetrexed	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: January 15, 2009
• First Submitted That Met QC Criteria: January 15, 2009
• First Posted (Estimate): January 16, 2009

Study Record Updates

• Last Update Posted (Estimate): September 20, 2016
• Last Update Submitted That Met QC Criteria: July 28, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; Pemetrexed
• Other Study ID Numbers: 1230.5