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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Ovarian Neoplasms, Peritoneal Neoplasms

Intervention / Treatment
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* Drug: BIBF 1120 + PLD 30 mg/m2 + CBDCA AUC5 mg/mL*min
* Drug: BIBF 1120+ PLD 30 mg/m2 + CBDCA AUC5 mg/mL*min
* Drug: BIBF 1120 + PLD 30 mg/m2 + CBDCA AUC5 mg/mL*min


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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 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) Platinum based chemo in immediately preceding line Eligibility for treatment with i.v. chemotherapy regimen of carboplatin AUC 5 and PLD 30 mg/m2 every 4 weeks Life expectancy of at least 3 months Written informed consent that is consistent with International Conference of Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines Eastern Cooperative Oncology Group (ECOG) performance score 0 or1 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: Prior chemotherapy with doxorubicin (any formulation, liposomal or non-liposomal doxorubicin). Any contraindications for therapy with PLD or carboplatin, e.g. a history of hypersensitivity reactions to platinum-containing compounds and their excipients. Hypersensitivity to active substance or to any of the excipients of BIBF 1120. 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). Laboratory values indicating an increased risk for adverse events. Major surgery within 4 weeks prior to start of study treatment. Patients for whom surgery is planned, e.g. interval debulking surgery. Clinically relevant non-healing wound, ulcer (intestinal tract, skin) or bone fracture. Clinical symptoms or signs of gastrointestinal obstruction that require parenteral nutrition or hydration. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug. History of clinical symptoms of brain metastases. Prior thrombosis or thromboembolic event in the presence of an inherited coagulopathy. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 6 months. Known inherited or acquired bleeding disorder. Significant cardiovascular diseases. Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy. Other malignancy diagnosed within the past 5 years. Known serious illness or concomitant non-oncological disease. Patients unable to comply with the protocol. Patients with preserved reproductive capacity who are sexually active and unwilling to use a medically acceptable method of contraception. Pregnancy or breast feeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBF 1120 L+ Carboplatin + PLD<br>BIBF 1120 (100 mg twice daily (BID)) + Carboplatin (Area Under the Curve (AUC) 5 mg/mL*min) + PLD (30 mg/m2) | Drug: BIBF 1120 + PLD 30 mg/m2 + CBDCA AUC5 mg/mL*min<br>* BIBF1120 twice daily along with standard therapy of PLD + carboplatin<br>|
| Experimental: BIBF 1120 M + Carboplatin + PLD<br>BIBF 1120 (150 mg twice daily (BID)) + Carboplatin (Area Under the Curve (AUC) 5 mg/mL*min) + PLD (30 mg/m2) | Drug: BIBF 1120 + PLD 30 mg/m2 + CBDCA AUC5 mg/mL*min<br>* BIBF1120 twice daily along with standard therapy of PLD + carboplatin<br>|
| Experimental: BIBF 1120 H + Carboplatin + PLD<br>BIBF 1120 (200 mg twice daily (BID)) + Carboplatin (Area Under the Curve (AUC) 5 mg/mL*min) + PLD (30 mg/m2) | Drug: BIBF 1120+ PLD 30 mg/m2 + CBDCA AUC5 mg/mL*min<br>* BIBF1120 twice daily along with standard therapy of PLD + carboplatin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | First 28-day treatment cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 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 | 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. | 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. | 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). | 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). | 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). | 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). | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | From the first drug administration until 28 days after the last drug administration, up to 31 months |