To Assess the Effect of Rifampicin on the Pharmacokinetics of Eribulin Mesylate in Participants With Advanced Solid Tumors

Tumor Clinical Trial

Official title:

An Open-Label Phase I Study to Assess the Effect of Rifampicin on the Pharmacokinetics of Eribulin Mesylate (E7389) in Subjects With Advanced Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03002493
• Other study ID #: E7389-E044-111
• Status: Completed
• Phase: Phase 1
• First received: December 21, 2016
• Last updated: March 13, 2017
• Start date: December 2009
• Est. completion date: June 2011

Study information

• Verified date: February 2016
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study was to assess the effect of cytochrome P450 3A4 enzyme (CYP3A4) induction by rifampicin on the pharmacokinetics (PK) of eribulin mesylate following intravenous (IV) administration in participants with advanced solid tumors. The secondary objectives of this study were to assess the safety of eribulin mesylate when co-administered with rifampicin and assess the safety and activity of eribulin mesylate as a single agent.

Description:

The study consisted of 3 phases: Pre-Treatment, Treatment, and Extension. Pre-Treatment Phase had 2 periods: Screening and Baseline. Treatment Phase consisted of intensive PK assessment with eribulin mesylate given IV alone on Day 1 followed by eribulin mesylate given IV on Day 15 with rifampicin given orally from Days 9 to 20. Extension Phase allowed eribulin mesylate treatment to continue for participants without progressive disease or unacceptable toxicity.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: June 2011
• Est. primary completion date: February 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Histologically or cytologically confirmed advanced solid tumors that have progressed following standard therapy or for which no standard therapy exists (including surgery or radiation therapy)

2. Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy and alopecia Grade 2

3. Age greater than or equal to 18 years

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

5. Life expectancy of greater than or equal to 3 months

6. Adequate renal function as evidenced by serum creatinine less than or equal to 2.0 mg/dL (less than or equal to 176 umol/L) or calculated creatinine clearance greater than or equal to 40 mL/minute per the Cockcroft and Gault formula

7. Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the upper limit of normal (ULN) and alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times the ULN (in the case of liver metastasis less than or equal to 5 times ULN). In the case ALP greater than 3 times the ULN (in the absence of liver metastasis) or greater than 5 times the ULN (in the presence of liver metastasis), and the participant was also known to have bone metastasis, the liver specific ALP were separated from the total and used to assess the liver function instead of the total ALP

8. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L, hemoglobin greater than or equal to 10.0 g/dL or greater than or equal to 6.2 mmol/L (hemoglobin less than 10.0 g/dL or less than 6.2 mmol/L were acceptable if it were corrected by growth factor or transfusion), and platelets greater than or equal to 100 x 109/L

9. Participants were willing and able to comply with the study protocol for the duration of the study

10. Written informed consent were obtained prior to any study-specific screening procedures with the understanding that the participant may withdraw consent at any time without prejudice

11. Females of childbearing potential with a negative serum beta-Human chorionic gonadotropin or a negative urine pregnancy test at Visit 1 (Screening) and prior to starting study drug(s) (Visit 3). Female participants of childbearing potential who agreed to be abstinent or to use a highly effective method of contraception (eg, condom + spermicide, condom + diaphragm with spermicide, intrauterine device [IUD], or have a vasectomised partner) starting prior to starting study drug, throughout the entire study period and for 30 days after the last dose of study drug. Those women using hormonal contraceptives must also have used an additional approved method of contraception (as described previously). Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential

12. Male participants who were not abstinent or have not undergone a successful vasectomy, who were partners of women of childbearing potential must have used, or their partners must have used a highly effective method of contraception (eg, condom + spermicide, condom + diaphragm with spermicide, IUD) starting prior to starting study drug(s) and throughout the entire study period and for 30 days after the last dose of study drug. Those with partners using hormonal contraceptives must also have used an additional approved method of contraception (as described previously)

Exclusion Criteria:

1. Hypersensitivity to halichondrin B and/or halichondrin B chemical derivatives or a hypersensitivity to rifampicin

2. Prior participation in an eribulin clinical study, even if not previously assigned to eribulin treatment

3. Preexisting neuropathy greater than Grade 2

4. Any of the following treatments within the specified period before eribulin treatment starts:

1. chemotherapy, radiation or biological therapy within 2 weeks,

2. hormonal therapy within 1 week with the exception of prostate cancer patients who are on medical castration with a gonadotropin-releasing hormone analog,

3. any investigational drug within 4 weeks

5. Any medication, dietary supplements or other compounds or substances known to induce or inhibit cytochrome P450 3A4 (CYP3A4) activity at the time the study starts

6. Presence of impaired intestinal absorption

7. Significant cardiovascular impairment such as history of congestive heart failure greater than Grade II (New York Heart Association [NYHA]), unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia

8. Clinically significant electrocardiograms (ECGs) abnormality, including a marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval greater than 500 msec)

9. Known positive human immunodeficiency virus (HIV) status

10. Brain or subdural metastases, unless they had completed local therapy and had discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment with eribulin

11. Presence of meningeal carcinomatosis

12. Any history of or concomitant medical condition that, in the opinion of the Investigator, that would have compromise the participant's ability to safely complete the study

Related Conditions & MeSH terms

• Tumor

Intervention

Drug:
• Eribulin mesylate
Treatment phase: During Cycle 1, eribulin mesylate was administered as a 2 to 5 minute (min) intravenous (IV) infusion at 1.4 mg/m2 on Day 1 and Day 15 of 21-day cycle. During subsequent cycles, eribulin mesylate administration as a 2 to 5 min IV infusion at 1.4 mg/m2 on Day 1 and Day 8 of a 21-day cycle. Extension phase: Eribulin mesylate was administered continuously as a 2 to 5 min IV infusion at 1.4 mg/m2 on Day 1 and Day 8 of 21-day cycles, as long as the Investigator considered eribulin mesylate therapy to be clinically appropriate.
• Eribulin mesylate

• Rifampicin
Treatment phase: Rifampicin 600 mg was administered orally once a day, from Day 9 to Day 20 of 28-day cycle of Cycle 1.

Locations

Country	Name	City	State
Netherlands	Netherlands Cancer Institute	Amsterdam
Netherlands	University Medical Center Utrecht	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Limited

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Best overall tumor response		From signing of Informed consent until disease progression, undue toxicity, withdrawal by participant, at the discretion of the investigator or up to approximately 8 Months
Primary	Area under the concentration-time curve from zero (pre-dose) extrapolated to infinite time (AUC 0-infinity) for eribulin mesylate +/- rifampicin		Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 minute (min), and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
Primary	Maximum observed plasma concentration (Cmax) for eribulin mesylate +/- rifampicin		Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
Primary	Area under the concentration-time curve from zero (pre-dose) to time of last quantifiable concentration (AUC 0-t) for eribulin mesylate		Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
Primary	Time of maximum observed plasma concentration (Tmax) for eribulin mesylate		Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
Primary	Half-life (t1/2) for eribulin mesylate		Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
Primary	Clearance (CL) for eribulin mesylate		Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
Primary	Volume of distribution at steady state (Vss) for eribulin mesylate		Day 1 and Day 15 of Cycle 1 (pre-dose, end of infusion, 15 min and 30 min, 1, 2, 4, 6, 10, 24, 48, 72, 96, 120 and 144 hours after each eribulin administration)
Secondary	Number of participants with adverse events (AEs) and serious adverse events (SAEs) as a measure of safety		From date of administration of first dose up to 30 days after the last dose of study treatment, up to approximately 8 months.