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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01348347

Enrollment

Registered

2011-05-05

Start date

2011-04-25

Completion date

2014-05-15

Last updated

2018-08-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neoplasms

Brief summary

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.

Interventions

DRUGVolasertib, low dose, d1q3w

Patient to receive low dose of Volasertib IV

DRUGVolasertib, middle dose, d1q3w

Patient to receive middle dose of Volasertib IV

DRUGVolasertib, high dose, d1q3w

Patient to receive high dose of Volasertib IV

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

20 Years to No maximum

Healthy volunteers

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.)

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Dose Limiting Toxicities (DLTs) in Process for the Determination of the Maximum Tolerated Dose (MTD).	21 days	The following drug-related adverse events (AE) were defined as DLT; 1. 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. 2. 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.
Maximum Tolerated Dose (MTD) of Volasertib	21 days	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.

Secondary

Measure	Time frame	Description
Cmax of Volasertib (BI 6727)	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.	Maximum concentration of an analyte in plasma
Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1	6 months	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.
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.	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 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 extrapolated to infinity (AUC0-infinity) of Volasertib (BI 6727).
Disease Control Rate According to RECIST v1.1	6 months	Disease control rate according to RECIST v1.1 - Unconfirmed disease control. The patients with complete response (CR), partial response (PR) or stable disease (SD).

Countries

Japan

Participant flow

Recruitment details

15 patients were treated and analysed.

Pre-assignment details

This was an open-label, uncontrolled, dose escalation phase I study of once every three weeks intravenous treatment with BI 6727(volasertib) in Japanese patients with advanced solid tumours.

Participants by arm

Arm	Count
Volasertib 200 mg Cohort Volasertib 200 mg was infused intravenously (over 2 hours) on Day 1 in a 3-week treatment course.	3
Volasertib 300 mg Cohort Volasertib 300 mg was infused intravenously (over 2 hours) on Day 1 in a 3-week treatment course.	6
Volasertib 350 mg Cohort Volasertib 350 mg was infused intravenously (over 2 hours) on Day 1 in a 3-week treatment course.	6
Total	15

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Progressive disease	2	5	5
Overall Study	Withdrawal by Subject	1	1	1

Baseline characteristics

Characteristic	Volasertib 200 mg Cohort	Volasertib 300 mg Cohort	Volasertib 350 mg Cohort	Total
Age, Continuous	69.0 Years STANDARD_DEVIATION 7.9	58.8 Years STANDARD_DEVIATION 11.4	60.8 Years STANDARD_DEVIATION 8.6	61.7 Years STANDARD_DEVIATION 9.8
Sex: Female, Male Female	1 Participants	0 Participants	1 Participants	2 Participants
Sex: Female, Male Male	2 Participants	6 Participants	5 Participants	13 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	3 / 3	6 / 6	6 / 6
serious Total, serious adverse events	0 / 3	0 / 6	1 / 6

Outcome results

Primary

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.

Time frame: 21 days