BI 6727 (Volasertib) Monotherapy Phase I Trial in Japanese Patients With Advanced Solid Tumours

An Open-label Phase I Study of Once Every Three Weeks Intravenous Treatment With BI 6727 in Japanese Patients With Advanced Solid Tumours

This open-label phase I dose escalation trial, 1230.15, is the first trial with Volasertib in Japanese advanced cancer patients. The trial will investigate the maximum tolerated dose (MTD), safety, tolerability, and preliminary efficacy of this specific polo-like kinase 1 (Plk1) inhibitor in advanced cancer patients.

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Volasertib, low dose, d1q3w; Drug: Volasertib, middle dose, d1q3w; Drug: Volasertib, high dose, d1q3w

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chuo-ku, Tokyo, Japan
    • 1230.15.001 National Cancer Center Hospital,

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. Patients with histologically or cytologically confirmed according to the discretion of the investigator
2. Patients who have advanced, non-resectable and/or metastatic solid tumours according to the discretion of the investigator
3. Patients who have failed conventional treatment, or for whom no therapy of proved efficacy exists, or who are not amenable to established forms of treatment according to the discretion of the investigator
4. Age >=20 years old at the time of informed consent
5. Written informed consent
6. Life expectancy of at least 12 weeks according to the discretion of the investigator
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
8. Recovery to Common Terminology Criteria for Adverse Events (CTCAE) grade =1 of therapy-related toxicities from previous chemo-, hormonal-, immuno-, or radiotherapy (except alopecia and hyperpigmentation)

9. Adequate bone marrow, renal and hepatic function;

   • Neutrophil count: more than 1500/mm3
   • Platelet count: more than 100 000/mm3
   • Haemoglobin: more than 9.0 g/dL
   • Total bilirubin: less than 1.5 times the upper limit of normal (ULN)
   • Aspartate amino transferase (AST): less than 2.5 × ULN
   • Alanine amino transferase (ALT): less than 2.5 × ULN
   • Serum creatinine: less than 1.5 × ULN
10. Patients who can be hospitalised during the first course

Exclusion criteria:

1. Major surgery within 4 weeks prior to registration or the side effects/toxicities of such surgery that have not recovered to CTCAE grade =1
2. Known seropositivity to human immunodeficiency virus (HIV) antibody, hepatitis B antigen or hepatitis C antibody
3. Accumulation of coelomic fluid (e.g. pleural effusion, ascites fluid) requiring treatment during the trial (Patients are eligible if treated curatively and with no evidence of recurrence.)
4. Current symptomatic brain metastases or patients who require treatment of the brain metastases
5. Previous double cancers. Other tumours (except for non-invasive and/or non-melanomatous skin cancer, completely removed in situ carcinoma of the epithelium or mucosa) treated curatively and with no evidence of recurrence for at least 5 years prior to the initial study treatment will be eligible.

6. Known history of cardiac dysfunction;

   • Correction of QT intervals according to Fridericias formula (QTc) over 470 ms
   • History of unstable angina pectoris within 6 months or current unstable angina pectoris
   • History of myocardial infarction within 6 months
   • Arrhythmia currently required active therapy
   • Previous and current cardiac failure
   • History of other clinically significant cardiac diseases according to the discretion of the investigator
7. Pregnant or breastfeeding women
8. Women and men who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices, vasectomised partner, or condoms) during the trial and for at least 6 months after the end of active therapy. Women who are sexually active are premenopausal female patients. Premenopausal female patient is defined as the patient who observed menses within 12 months except for an alternative medical cause. Women who underwent an operation for sterilisation is excluded for this criteria.
9. Treatment with other investigational drugs within the past 4 weeks before registration or concomitantly with this trial (except for present trial drug)
10. Chemo-, radio-, immuno-, or molecular-targeted therapy within the past 4 weeks before registration or concomitantly with this trial. This restriction does not apply to bisphosphonates.
11. Patients unable to comply with the protocol according to the discretion of the investigator or sub-investigators
12. Current alcohol abuse or drug abuse according to the discretion of the investigator
13. Patients who are inappropriate for this trial by the discretion of investigator or sub-investigators (e.g. uncontrolled diabetes mellitus, evidence of serious active infection, medically significant abnormal laboratory finding, etc.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Volasertib; Patient to receive low, middle and high doses of Volasertib IV	Drug: Volasertib, low dose, d1q3w; Patient to receive low dose of Volasertib IV; Drug: Volasertib, middle dose, d1q3w; Patient to receive middle dose of Volasertib IV; Drug: Volasertib, high dose, d1q3w; Patient to receive high dose of Volasertib IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities (DLTs) in Process for the Determination of the Maximum Tolerated Dose (MTD).	The following drug-related adverse events (AE) were defined as DLT; Haematological toxicities: CTCAE(Common Terminology Criteria for Adverse Events) grade 4 neutropenia persisted for 7 or more days, CTCAE grade 4 thrombocytopenia or CTCAE grade 3 thrombocytopenia requiring blood transfusion.; Non-haematological toxicities: CTCAE grade ≥3 non-haematological toxicities. The following toxicity with neutropenia was defined as DLT.- CTCAE grade 3 febrile neutropenia persisted for over 2 days, Clinically significant laboratory abnormalities of CTCAE grade ≥3 persisted for over 3 days. The following laboratory abnormalities should be defined as DLT. - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): >5.0 × ULN persisted for 7 days or longer - Creatinine: >3.0 × upper limit of normal(ULN) (if the creatinine abnormality was observed even once) - Persistent electrolyte abnormality assessed by the investigator.	21 days
Maximum Tolerated Dose (MTD) of Volasertib	Maximum tolerated dose (MTD) of volasertib was the highest dose tested at which DLT was developed in not more than 1 of 6 patients in the course 1.	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1	Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1: Unconfirmed objective response. The patients with complete response (CR) or partial response (PR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by magnetic resonance imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	6 months
Disease Control Rate According to RECIST v1.1	Disease control rate according to RECIST v1.1 - Unconfirmed disease control. The patients with complete response (CR), partial response (PR) or stable disease (SD).	6 months
Cmax of Volasertib (BI 6727)	Maximum concentration of an analyte in plasma	Pharmacokinetic (PK) plasma samples were taken at: 5 minutes predose, 1hour, 2hours (h), 3h, 4h, 8h, 24h, 48h, 72h, 96h, 168h and 336h of course1.
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity) of Volasertib (BI 6727)	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity) of Volasertib (BI 6727).	PK plasma samples were taken at: 5 minutes predose, 1hour, 2hours (h), 3h, 4h, 8h, 24h, 48h, 72h, 96h, 168h and 336h of course1.
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz) of Volasertib (BI 6727)	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 up to the last quantifiable data point (AUC0-tz) of Volasertib (BI 6727).	PK plasma samples were taken at: 5 minutes predose, 1hour, 2hours (h), 3h, 4h, 8h, 24h, 48h, 72h, 96h, 168h and 336h of course1.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Nokihara H, Yamada Y, Fujiwara Y, Yamamoto N, Wakui H, Nakamichi S, Kitazono S, Inoue K, Harada A, Taube T, Takeuchi Y, Tamura T. Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with advanced solid tumors. Invest New Drugs. 2016 Feb;34(1):66-74. doi: 10.1007/s10637-015-0300-0. Epub 2015 Dec 2.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2011
• Primary Completion (Actual): August 27, 2012
• Study Completion (Actual): May 15, 2014

Study Registration Dates

• First Submitted: April 29, 2011
• First Submitted That Met QC Criteria: May 4, 2011
• First Posted (Estimate): May 5, 2011

Study Record Updates

• Last Update Posted (Actual): August 6, 2018
• Last Update Submitted That Met QC Criteria: August 3, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Other Study ID Numbers: 1230.15