Ovarian Neoplasms
Conditions
Brief summary
The primary objective of this study is to estimate the Progression Free Survival Rates (PFS) of patients with relapsed ovarian cancer after 9 months of continuous treatment with either BIBF 1120 or matching placebo.
Interventions
DRUGBIBF1120
DRUGPlacebo
Sponsors
Boehringer Ingelheim
Study design
Intervention model
PARALLEL
Primary purpose
PREVENTION
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female patients with histologically confirmed advanced ovarian carcinoma, fallopian tube carcinoma or primary peritoneal cancer of serous type with recurrent disease and who responded to 2nd, 3rd or 4th line chemotherapy. Response is defined as either a confirmed decline in CA125 of at least 50% from the pre-treatment value or an Objective Response, i.e. a Partial Response (PR) or Complete Response (CR) according to the RECIST criteria in patients with measurable disease. * Treatment-free interval of \< 12 months since commencing prior treatment regimen for relapsed ovarian cancer. * Full recovery from all therapy related toxicities of previous chemotherapy and or radiotherapy or recovery in as much as no further improvement may be expected by the investigator. * Age \> 18 years. * Life expectancy of at least 3 months. * ECOG Performance Score \< 2. * Adequate hepatic function: total bilirubin 26µmol/L, ALT and/or AST 1.5x upper limit of normal (ULN). INR, Prothrombin time (PT) and partial thromboplastin time (PTT): maximum 50% deviation from normal limits. * Adequate renal function: serum creatinine 1.5 x ULN. * Absolute neutrophil count (ANC) \>1.5 x 109l, Platelets \> 100 x 109/l, Haemoglobin \> 9.0 g/dl. * Written informed consent consistent with ICH-GCP guidelines. * Minimum time elapsed since last chemotherapy (including hormonal treatment other than Hormone Replacement Therapy \[HRT\]) or immunotherapy and the first administration of BIBF 1120 must be more than 4 but less than 8 weeks.
Exclusion criteria
* Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study. * Major injuries and/or surgery within past 4 weeks with incomplete wound healing or bone fracture and planned surgical procedures during the study period. * Hypersensitivity to BIBF 1120 or the excipients of the study drug. * Significant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within past 9 months, congestive heart failure \> NYHA II). * History of haemorrhagic or thrombotic event in the past 12 months. Known inherited predisposition to bleeds or to thrombosis. * Patients who require full-dose anticoagulation. * Gastrointestinal disorders or abnormalities that would inhibit absorption of the study drug. * Brain metastases or leptomeningeal disease. * Treatment with other investigational drugs or participation in another clinical trial within the past four weeks before start of therapy or concomitantly with this trial. * Chemo-, radio-, or immunotherapy within the past four weeks prior to treatment with the trial drug. * Patients unable to comply with the protocol. * Active alcohol or drug abuse. * Other documented malignancy with the exception of non-melanomatous skin cancer within the past 5 years. * Patients who are not clinically sterile.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS Rate at 36 Weeks (After 9 Months) | 36 weeks (after 9 months) | The rate (probability) of being progression free at Week 36. Progression Free Survival (PFS) was defined according to RECIST version 1.0 from the time of first study drug administration to the first time of either objective tumour progression, the appearance of ≥1 new tumour lesion(s), occurrence or significant progression of malignant ascites, tumour related death, or the time when patients were censored at last known follow up. The rate is the Kaplan-Meier estimated percent probability. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS Rate at 12 Weeks (After 3 Months) and 24 Weeks ( After 6 Months) | 12 weeks (after 3 months) and 24 weeks ( after 6 months) | The rate (probability) of being progression free at Week 12 and Week 24. Progression Free Survival (PFS) was defined according to RECIST version 1.0 from the time of first study drug administration to the first time of either objective tumour progression, the appearance of ≥1 new tumour lesion(s), occurrence or significant progression of malignant ascites, tumour related death, or the time when patients were censored at last known follow up. The rate is the Kaplan-Meier estimated percent probability. |
| Time to Tumour Progression | 9 months | Time to Tumour Progression according to RECIST version 1.0 , CA-125 (ovarian tumour marker) levels and RECIST + CA-125 levels. For CA-125, progressive disease was defined on the basis of progressive serial elevations of CA-125 according to the following criteria: Patients with elevated CA-125 pre-treatment and normalisation of CA-125 had to show evidence of CA-125 levels ≥2 x ULN on 2 occasions at least 1 week apart. or Patients with elevated CA-125 pre-treatment that never normalised had to show evidence of CA-125 levels ≥2 x the nadir value on 2 occasions at least 1 week apart. or Patients with CA-125 in the normal range pre-treatment had to show evidence of CA-125 levels ≥2 x ULN on 2 occasions at least 1 week apart. Composite (RECIST+CA-125) endpoint is the RECIST progressive disease (PD) if it occurred or the CA-125 PD if it occurred in the absence of RECIST PD. |
| Time to Death | 9 months | This end point was not determined as no patients died during the trial. |
| Incidence and Intensity of Adverse Events With Grading According CTCAE | First drug administration until 28 days after last drug administration,up until 309 days | Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0). |
| Clinical Relevant Abnormalities for Laboratory Parameters | First drug administration until 28 days after last drug administration, up until 309 days | Clinical Relevant Abnormalities for laboratory parameters. Any new or clinically relevant worsening of baseline conditions was reported as Adverse Events. |
Countries
United Kingdom
Participant flow
Pre-assignment details
89 patients were enrolled and 84 patients were randomised for this study.
Participants by arm
| Arm | Count |
|---|---|
| Nintedanib Patients were treated with 250mg nintedanib twice daily | 43 |
| Placebo Patients were treated with matching placebo twice daily | 40 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event other disease worsening | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other Adverse Event | 7 | 7 |
| Overall Study | Progressive disease | 27 | 30 |
| Overall Study | Reason other than listed above | 2 | 2 |
Baseline characteristics
| Characteristic | Nintedanib | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.4 years STANDARD_DEVIATION 9.5 | 61.3 years STANDARD_DEVIATION 9.1 | 59.8 years STANDARD_DEVIATION 9.3 |
| Sex: Female, Male Female | 43 Participants | 40 Participants | 83 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 42 / 43 | 37 / 40 |
| serious Total, serious adverse events | 14 / 43 | 10 / 40 |
Outcome results
Primary
PFS Rate at 36 Weeks (After 9 Months)
The rate (probability) of being progression free at Week 36. Progression Free Survival (PFS) was defined according to RECIST version 1.0 from the time of first study drug administration to the first time of either objective tumour progression, the appearance of ≥1 new tumour lesion(s), occurrence or significant progression of malignant ascites, tumour related death, or the time when patients were censored at last known follow up. The rate is the Kaplan-Meier estimated percent probability.
Time frame: 36 weeks (after 9 months)
Population: Treated set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib | PFS Rate at 36 Weeks (After 9 Months) | 15.6 percent probability of PFS |
| Placebo | PFS Rate at 36 Weeks (After 9 Months) | 2.9 percent probability of PFS |
Secondary
Clinical Relevant Abnormalities for Laboratory Parameters
Clinical Relevant Abnormalities for laboratory parameters. Any new or clinically relevant worsening of baseline conditions was reported as Adverse Events.
Time frame: First drug administration until 28 days after last drug administration, up until 309 days
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Blood alkaline phosphatase increased | 7.0 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Alanine aminotransferase abnormal | 2.3 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Blood alkaline phosphatase | 0.0 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Blood lactate dehydrogenase abnormal | 2.3 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Gamma-glutamyltransferase increased | 30.2 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Gamma-glutamyltransferase abnormal | 2.3 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Blood alkaline phosphatase abnormal | 2.3 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Neutrophil count decreased | 2.3 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Alanine aminotransferase increased | 37.2 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | White blood cells urine positive | 2.3 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Lymphocyte count decreased | 0.0 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Blood pressure increased | 0.0 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Blood lactate dehydrogenase increased | 4.7 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Electrocardiogram T wave amplitude decreased | 0.0 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Vitamin B12 decreased | 0.0 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Liver function test abnormal | 2.3 Percentage of participants |
| Nintedanib | Clinical Relevant Abnormalities for Laboratory Parameters | Aspartate aminotransferase increased | 25.6 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Liver function test abnormal | 0.0 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Aspartate aminotransferase increased | 2.5 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Blood alkaline phosphatase increased | 5.0 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Alanine aminotransferase increased | 7.5 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Gamma-glutamyltransferase increased | 2.5 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Blood lactate dehydrogenase increased | 0.0 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Blood alkaline phosphatase | 2.5 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Blood alkaline phosphatase abnormal | 2.5 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Lymphocyte count decreased | 2.5 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Vitamin B12 decreased | 2.5 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Alanine aminotransferase abnormal | 0.0 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Blood lactate dehydrogenase abnormal | 0.0 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Gamma-glutamyltransferase abnormal | 0.0 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Neutrophil count decreased | 0.0 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | White blood cells urine positive | 0.0 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Blood pressure increased | 2.5 Percentage of participants |
| Placebo | Clinical Relevant Abnormalities for Laboratory Parameters | Electrocardiogram T wave amplitude decreased | 2.5 Percentage of participants |
Secondary
Incidence and Intensity of Adverse Events With Grading According CTCAE
Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).
Time frame: First drug administration until 28 days after last drug administration,up until 309 days
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 2 | 34.9 percentage of participants |
| Nintedanib | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 4 | 7.0 percentage of participants |
| Nintedanib | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 3 | 53.5 percentage of participants |
| Nintedanib | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 5 | 0.0 percentage of participants |
| Nintedanib | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 1 | 2.3 percentage of participants |
| Placebo | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 5 | 0.0 percentage of participants |
| Placebo | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 1 | 25.0 percentage of participants |
| Placebo | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 2 | 42.5 percentage of participants |
| Placebo | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 3 | 25.0 percentage of participants |
| Placebo | Incidence and Intensity of Adverse Events With Grading According CTCAE | CTCAE grade 4 | 2.5 percentage of participants |
Secondary
PFS Rate at 12 Weeks (After 3 Months) and 24 Weeks ( After 6 Months)
The rate (probability) of being progression free at Week 12 and Week 24. Progression Free Survival (PFS) was defined according to RECIST version 1.0 from the time of first study drug administration to the first time of either objective tumour progression, the appearance of ≥1 new tumour lesion(s), occurrence or significant progression of malignant ascites, tumour related death, or the time when patients were censored at last known follow up. The rate is the Kaplan-Meier estimated percent probability.
Time frame: 12 weeks (after 3 months) and 24 weeks ( after 6 months)
Population: Treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib | PFS Rate at 12 Weeks (After 3 Months) and 24 Weeks ( After 6 Months) | at 24 weeks ( after 6 months) | 26.7 percent probability of PFS |
| Nintedanib | PFS Rate at 12 Weeks (After 3 Months) and 24 Weeks ( After 6 Months) | at 12 weeks (after 3 months) | 45.3 percent probability of PFS |
| Placebo | PFS Rate at 12 Weeks (After 3 Months) and 24 Weeks ( After 6 Months) | at 24 weeks ( after 6 months) | 17.3 percent probability of PFS |
| Placebo | PFS Rate at 12 Weeks (After 3 Months) and 24 Weeks ( After 6 Months) | at 12 weeks (after 3 months) | 46.2 percent probability of PFS |
Secondary
Time to Death
This end point was not determined as no patients died during the trial.
Time frame: 9 months
Population: This endpoint could not be calculated as no patients died.
Secondary
Time to Tumour Progression
Time to Tumour Progression according to RECIST version 1.0 , CA-125 (ovarian tumour marker) levels and RECIST + CA-125 levels. For CA-125, progressive disease was defined on the basis of progressive serial elevations of CA-125 according to the following criteria: Patients with elevated CA-125 pre-treatment and normalisation of CA-125 had to show evidence of CA-125 levels ≥2 x ULN on 2 occasions at least 1 week apart. or Patients with elevated CA-125 pre-treatment that never normalised had to show evidence of CA-125 levels ≥2 x the nadir value on 2 occasions at least 1 week apart. or Patients with CA-125 in the normal range pre-treatment had to show evidence of CA-125 levels ≥2 x ULN on 2 occasions at least 1 week apart. Composite (RECIST+CA-125) endpoint is the RECIST progressive disease (PD) if it occurred or the CA-125 PD if it occurred in the absence of RECIST PD.
Time frame: 9 months
Population: Treated set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nintedanib | Time to Tumour Progression | according to RECIST | 143.0 days |
| Nintedanib | Time to Tumour Progression | according to RECIST and CA-125 | 83.00 days |
| Nintedanib | Time to Tumour Progression | according to CA-125 | 85.00 days |
| Placebo | Time to Tumour Progression | according to CA-125 | 86.00 days |
| Placebo | Time to Tumour Progression | according to RECIST and CA-125 | 84.00 days |
| Placebo | Time to Tumour Progression | according to RECIST | 85.0 days |