BIBF 1120 + Carboplatin/Pegylated Liposomal Doxorubicin (PLD) in Patients With Advanced Ovarian Cancer, Fallopian Tube Carcinoma or Primary Peritoneal Cancer

NCT01314105CompletedPHASE1INTERVENTIONAL

Summary

This phase I, open label dose escalation study will investigate the addition of BIBF 1120 to treatment with the combination of carboplatin and Pegylated Liposomal Doxorubicin (PLD) in patients with advanced, platinum sensitive relapsed ovarian cancer, fallopian tube carcinoma or primary peritoneal cancer.

Key Facts

Lead Sponsor

Boehringer Ingelheim

Enrollment

19

Start Date

2011-03-15

Completion Date

2013-07-29

Study Type

INTERVENTIONAL

Official Title

Phase I Dose Escalation Trial to Determine the Maximum Tolerated Dose of BIBF 1120 in Combination With Carboplatin and Pegylated Liposomal Doxorubicin (PLD) in Patients With a First, Second or Third Platinum Sensitive Relapse of Advanced Epithelial Ovarian Cancer, Fallopian Tube or Primary Peritoneal Cancer

Interventions

BIBF 1120 + PLD 30 mg/m2 + CBDCA AUC5 mg/mL*minBIBF 1120+ PLD 30 mg/m2 + CBDCA AUC5 mg/mL*minBIBF 1120 + PLD 30 mg/m2 + CBDCA AUC5 mg/mL*min

Conditions

Ovarian NeoplasmsPeritoneal Neoplasms

Eligibility

Age Range

18 Years+

Sex

FEMALE

Inclusion criteria:

1. Female patients, age 18 years or older, with a first, second or third relapse of histologically (on initial diagnosis) confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal cancer
2. Up to three lines of prior chemo (chemotherapy before and after interval surgery to be counted as one line therapy), with treatment free interval of \> 6 months (= time between last administration of prior anti-cancer treatment, including chemotherapy, hormonal therapy, or radiation therapy, and diagnosis of progressive disease)
3. Platinum based chemo in immediately preceding line
4. Eligibility for treatment with i.v. chemotherapy regimen of carboplatin AUC 5 and PLD 30 mg/m2 every 4 weeks
5. Life expectancy of at least 3 months
6. Written informed consent that is consistent with International Conference of Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines
7. Eastern Cooperative Oncology Group (ECOG) performance score 0 or1
8. Prior treatment with angiogenesis inhibitor (bevacizumab, TKI inhibiting VEGFR-2) is allowed provided treatment with bevacizumab has been discontinued = 28 days prior to start of therapy and treatment with the TKI has been discontinued = 3 months prior to start of therapy, provided anti-angiogenic therapy was added to only one of the preceding lines of therapy

Exclusion criteria:

1. Prior chemotherapy with doxorubicin (any formulation, liposomal or non-liposomal doxorubicin).
2. Any contraindications for therapy with PLD or carboplatin, e.g. a history of hypersensitivity reactions to platinum-containing compounds and their excipients.
3. Hypersensitivity to active substance or to any of the excipients of BIBF 1120.
4. Treatment with other investigational drugs or participation in another clinical trial testing a drug within the past four weeks before start of therapy or concomitantly with this trial (exception: for previous treatment with angiogenesis inhibitors, cf. inclusion criterion #8).
5. Laboratory values indicating an increased risk for adverse events.
6. Major surgery within 4 weeks prior to start of study treatment.
7. Patients for whom surgery is planned, e.g. interval debulking surgery.
8. Clinically relevant non-healing wound, ulcer (intestinal tract, skin) or bone fracture.
9. Clinical symptoms or signs of gastrointestinal obstruction that require parenteral nutrition or hydration.
10. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug.
11. History of clinical symptoms of brain metastases.
12. Prior thrombosis or thromboembolic event in the presence of an inherited coagulopathy.
13. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 6 months.
14. Known inherited or acquired bleeding disorder.
15. Significant cardiovascular diseases.
16. Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy.
17. Other malignancy diagnosed within the past 5 years.
18. Known serious illness or concomitant non-oncological disease.
19. Patients unable to comply with the protocol.
20. Patients with preserved reproductive capacity who are sexually active and unwilling to use a medically acceptable method of contraception.
21. Pregnancy or breast feeding.

Outcome Measures

Primary Outcomes

Maximum Tolerated Dose of Nintedanib Based on the Occurrence of DLTs During Treatment Course 1

Maximum Tolerated Dose (MTD) of nintedanib in combination with carboplatin and pegylated liposomal doxorubicin based on the occurrence of dose limiting toxicities (DLTs) during treatment course 1. MTD will be determined among the first 6 evaluable patients in each dose level. MTD is the highest dose at which the incidence of DLT is less than 2/6.

Time frame: First 28-day treatment cycle

Dose Limiting Toxicities During Treatment Course 1

Number of patients with dose limiting toxicity (DLT) occurring during treatment course 1 The following AEs were to be reported as DLT events if their occurrence was considered to be drug-related: Haematological toxicity: * Any CTCAE grade 4 haematological toxicity * CTCAE grade 4 neutropenia that was not associated with fever ≥38.5°C, if persisting for \>7 days despite adequate supportive treatment * CTCAE grade ≥3 neutropenia of any duration if associated with fever ≥38.5°C * Any CTCAE grade 4 thrombocytopenia * CTCAE grade ≥3 thrombocytopenia if associated with bleeding of CTCAE grade ≥2 Non-haematological toxicity: * CTCAE grade ≥3 diarrhoea despite optimal medical management * CTCAE grade 2 diarrhoea persisting for more than 7 days despite optimal medical management * CTCAE grade ≥2 vomiting despite optimal medical management * ALT and/or AST elevation of CTCAE grade ≥3 * ALT and/or AST elevation of \>3x ULN in conjunction with bilirubin increase \>2x ULN

Time frame: First 28-day treatment cycle

Secondary Outcomes

Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Nintedanib

Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) of nintedanib during course 1 and course 2

Time frame: 5 minutes (min) before drug administration and 1 hour (h) 2h, 3h, 4h, 6h, 8h, 10h, 24h, 144h, 312h and 456h after drug administration

Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Nintedanib

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable drug concentration (AUC0-tz) of nintedanib during course 1 and course 2.

Time frame: 5 minutes (min) before drug administration and 1 hour (h) 2h, 3h, 4h, 6h, 8h, 10h, 24h, 144h, 312h and 456h after drug administration

Maximum Measured Plasma Concentration (Cmax) of Nintedanib

Maximum measured plasma concentration (Cmax) of nintedanib during course 1 and course 2

Time frame: 5 minutes (min) before drug administration and 1 hour (h) 2h, 3h, 4h, 6h, 8h, 10h, 24h, 144h, 312h and 456h after drug administration

Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carboplatin (Determined as Total Platinum)

Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) of carboplatin (determined as total platinum) during treatment course 1 and course 2.

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 23h 55min, 26h, 28h, 32h, 48h, 168h, 336h and 480h after drug administration

Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity (AUC 0-inf) of Carboplatin During Treatment Course 1 and Course 2 (Determined as Ultrafilterable Platinum)

Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity (AUC 0-inf) of carboplatin during treatment course 1 and course 2 (determined as ultrafilterable platinum). Geometric mean (gMean) and Geometric coefficient of Variation (gCV) were not calculable for treatment course 2 as 2/3 of patients had quantifiable values.

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 23h 55min, 25h, 26h, 27h, 28h, 30h, 32h, and 34h after drug administration

Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Carboplatin (Determined as Total Platinum)

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable drug concentration (AUC0-tz) of carboplatin during course 1 and course 2 (determined as total platinum).

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 23h 55min, 26h, 28h, 32h, 48h, 168h, 336h and 480h after drug administration

Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Carboplatin (Determined as Ultrafilterable Platinum)

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable drug concentration (AUC0-tz) of carboplatin during course 1 and course 2 (determined as ultrafilterable platinum).

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 23h 55min, 25h, 26h, 27h, 28h, 30h, 32h, and 34h after drug administration

Maximum Measured Plasma Concentration (Cmax) of Carboplatin (Total Platinum)

Maximum measured plasma concentration (Cmax) of carboplatin during course 1 and course 2 (determined as total platinum).

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 23h 55min, 26h, 28h, 32h, 48h, 168h, 336h and 480h after drug administration

Maximum Measured Plasma Concentration (Cmax) of Carboplatin During Course 1 and Course 2 (Determined as Ultrafilterable Platinum)

Maximum measured plasma concentration (Cmax) of carboplatin during course 1 and course 2 (determined as ultrafilterable platinum).

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 23h 55min, 25h, 26h, 27h, 28h, 30h, 32h, and 34h after drug administration

Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity (AUC 0-inf) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2

Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity (AUC 0-inf) of pegylated liposomal doxorubicin (PLD) (determined as total plasma doxorubicin) during treatment course 1 and course 2. Geometric mean (gMean) and Geometric coefficient of Variation (gCV) were not calculable for treatment course 1 as for only 2 patients evaluable concentrations were available.

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 25h, 27h, 30h, 34h, 48h, 168h, 336h and 480h after drug administration

Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable drug concentration (AUC0-tz) of pegylated liposomal doxorubicin (PLD) (determined as total plasma doxorubicin) during treatment course 1 and course 2. Geometric mean (gMean) and Geometric coefficient of Variation (gCV) were not calculable for treatment course 1 as for only 2 patients evaluable concentrations were available.

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 25h, 27h, 30h, 34h, 48h, 168h, 336h and 480h after drug administration

Maximum Measured Plasma Concentration (Cmax) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2

The maximum measured plasma concentration (Cmax) of pegylated liposomal doxorubicin (PLD) (determined as total plasma doxorubicin) during treatment course 1 and course 2. Geometric mean (gMean) and Geometric coefficient of Variation (gCV) were not calculable for treatment course 1 as for only 2 patients evaluable concentrations were available.

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 25h, 27h, 30h, 34h, 48h, 168h, 336h and 480h after drug administration

Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity (AUC 0-inf) of PLD (Determined as Plasma Doxorubicinol)

Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity (AUC 0-inf) of pegylated liposomal doxorubicin (PLD) (determined as plasma doxorubicinol). Due to interference from doxorubicin, doxorubicinol concentrations could not be determined and doxorubicinol PK parameters could not be evaluated.

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 25h, 27h, 30h, 34h, 48h, 168h, 336h and 480h after drug administration

Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of PLD (Determined as Plasma Doxorubicinol)

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable drug concentration (AUC0-tz) of pegylated liposomal doxorubicin (PLD) (determined as plasma doxorubicinol). Due to interference from doxorubicin, doxorubicinol concentrations could not be determined and doxorubicinol PK parameters could not be evaluated.

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 25h, 27h, 30h, 34h, 48h, 168h, 336h and 480h after drug administration

Maximum Measured Plasma Concentration (Cmax) of PLD (Determined as Plasma Doxorubicinol)

The maximum measured plasma concentration (Cmax) of pegylated liposomal doxorubicin (PLD) (determined as plasma doxorubicinol). Due to interference from doxorubicin, doxorubicinol concentrations could not be determined and doxorubicinol PK parameters could not be evaluated.

Time frame: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 25h, 27h, 30h, 34h, 48h, 168h, 336h and 480h after drug administration

Incidence and Intensity of Adverse Events

Safety of nintedanib as indicated by intensity and incidence of adverse events, graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. The CTCAE grades are the worst grade per patient. The CTCAE grades are Grade 1 as mild AE, Grade 2 as moderate AE, Grade 3 as severe AE, Grade 4 as lifethreatening or disabling AE, and Grade 5 as death related to AE.

Time frame: From the first drug administration until 28 days after the last drug administration, up to 31 months

Change From Baseline in Safety Laboratory Parameters

Change from baseline in safety laboratory parameters.

Time frame: From the first drug administration until 28 days after the last drug administration, up to 31 months

Locations

Hospital Vall d'Hebron, Barcelona, Spain

Hospital Clínic de Barcelona, Barcelona, Spain

Hospital Duran i Reynals, L'Hospitalet de Llobregat, Spain

Linked Diseases

Ovarian Neoplasms

Ovarian Neoplasms — a type of gynecological cancer.

BIBF 1120 + Carboplatin/Pegylated Liposomal Doxorubicin (PLD) in Patients With Advanced Ovarian Cancer, Fallopian Tube Carcinoma or Primary Peritoneal Cancer