A Randomised Placebo-Controlled Phase II Study of Continuous Maintenance Treatment With BIBF 1120 Following Chemotherapy in Patients With Relapsed Ovarian Cancer

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00710762
• Collaborator: (none)
• Enrollment: 89
• Locations: 11
• Arms: 2
• Duration (Months): 96
• Patients Per Site: 8.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Neoplasms	Drug: BIBF1120; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Intervention Model: Parallel Assignment
• Primary Purpose: Prevention
• Official Title: A Randomised Placebo-Controlled Phase II Study of Continuous Maintenance Treatment With BIBF 1120 Following Chemotherapy in Patients With Relapsed Ovarian Cancer
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BIBF1120	Drug: BIBF1120
Placebo Comparator: Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. Time to Death [9 months]

   This end point was not determined as no patients died during the trial.

4. 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).

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1199.9.4413 Boehringer Ingelheim Investigational Site	Burton on Trent		United Kingdom
2	1199.9.4412 Boehringer Ingelheim Investigational Site	Cambridge		United Kingdom
3	1199.9.4407 Boehringer Ingelheim Investigational Site	Creigiau, Cardiff		United Kingdom
4	1199.9.4410 St James's University Hospital	Leeds		United Kingdom
5	1199.9.4401 Boehringer Ingelheim Investigational Site	London		United Kingdom
6	1199.9.4404 Boehringer Ingelheim Investigational Site	London		United Kingdom
7	1199.9.4409 Boehringer Ingelheim Investigational Site	London		United Kingdom
8	1199.9.4411 Boehringer Ingelheim Investigational Site	London		United Kingdom
9	1199.9.4406 Boehringer Ingelheim Investigational Site	Manchester		United Kingdom
10	1199.9.4402 Boehringer Ingelheim Investigational Site	Northwood		United Kingdom
11	1199.9.4405 Boehringer Ingelheim Investigational Site	Sutton		United Kingdom

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00710762
• Other Study ID Numbers: 1199.9; EUDRACT2005-002427-14; NCT00370175
• First Posted: Jul 4, 2008
• Last Update Posted: Aug 15, 2016
• Last Verified: Jul 1, 2016

• Additional relevant MeSH terms: Ovarian Neoplasms; Nintedanib

Study Results

Participant Flow

Pre-assignment Detail	89 patients were enrolled and 84 patients were randomised for this study.

Arm/Group Title	Nintedanib	Placebo
Arm/Group Description	Patients were treated with 250mg nintedanib twice daily	Patients were treated with matching placebo twice daily
Period Title: Overall Study
STARTED	44	40
COMPLETED	5	0
NOT COMPLETED	39	40

Baseline Characteristics

Arm/Group Title	Nintedanib	Placebo	Total
Arm/Group Description	Patients were treated with 250mg nintedanib twice daily	Patients were treated with matching placebo twice daily	Total of all reporting groups
Overall Participants	43	40	83
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.4 (9.5)	61.3 (9.1)	59.8 (9.3)
Sex: Female, Male (Count of Participants)
Female	43 100%	40 100%	83 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	PFS Rate at 36 Weeks (After 9 Months)
Description	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)

Outcome Measure Data

Analysis Population Description

Treated set.

Arm/Group Title	Nintedanib	Placebo
Arm/Group Description	Patients were treated with 250mg nintedanib twice daily	Patients were treated with matching placebo twice daily
Measure Participants	43	40
Number (95% Confidence Interval) [percent probability of PFS]	15.6	2.9

2. Secondary Outcome

Title	PFS Rate at 12 Weeks (After 3 Months) and 24 Weeks ( After 6 Months)
Description	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)

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Nintedanib	Placebo
Arm/Group Description	Patients were treated with 250mg nintedanib twice daily	Patients were treated with matching placebo twice daily
Measure Participants	43	40
at 24 weeks ( after 6 months)	26.7	17.3
at 12 weeks (after 3 months)	45.3	46.2

3. Secondary Outcome

Title	Time to Tumour Progression
Description	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

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Nintedanib	Placebo
Arm/Group Description	Patients were treated with 250mg nintedanib twice daily	Patients were treated with matching placebo twice daily
Measure Participants	43	40
according to RECIST and CA-125	83.00	84.00
according to CA-125	85.00	86.00
according to RECIST	143.0	85.0

4. Secondary Outcome

Title	Time to Death
Description	This end point was not determined as no patients died during the trial.
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

This endpoint could not be calculated as no patients died.

Arm/Group Title	Nintedanib	Placebo
Arm/Group Description	Patients were treated with 250mg nintedanib twice daily	Patients were treated with matching placebo twice daily
Measure Participants	0	0

5. Secondary Outcome

Title	Incidence and Intensity of Adverse Events With Grading According CTCAE
Description	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

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Nintedanib	Placebo
Arm/Group Description	Patients were treated with 250mg nintedanib twice daily	Patients were treated with matching placebo twice daily
Measure Participants	43	40
CTCAE grade 1	2.3 5.3%	25.0 62.5%
CTCAE grade 2	34.9 81.2%	42.5 106.3%
CTCAE grade 3	53.5 124.4%	25.0 62.5%
CTCAE grade 4	7.0 16.3%	2.5 6.3%
CTCAE grade 5	0.0 0%	0.0 0%

6. Secondary Outcome

Title	Clinical Relevant Abnormalities for Laboratory Parameters
Description	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

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Nintedanib	Placebo
Arm/Group Description	Patients were treated with 250mg nintedanib twice daily	Patients were treated with matching placebo twice daily
Measure Participants	43	40
Alanine aminotransferase increased	37.2 86.5%	7.5 18.8%
Gamma-glutamyltransferase increased	30.2 70.2%	2.5 6.3%
Aspartate aminotransferase increased	25.6 59.5%	2.5 6.3%
Blood alkaline phosphatase increased	7.0 16.3%	5.0 12.5%
Blood lactate dehydrogenase increased	4.7 10.9%	0.0 0%
Blood alkaline phosphatase	0.0 0%	2.5 6.3%
Blood alkaline phosphatase abnormal	2.3 5.3%	2.5 6.3%
Lymphocyte count decreased	0.0 0%	2.5 6.3%
Vitamin B12 decreased	0.0 0%	2.5 6.3%
Alanine aminotransferase abnormal	2.3 5.3%	0.0 0%
Blood lactate dehydrogenase abnormal	2.3 5.3%	0.0 0%
Gamma-glutamyltransferase abnormal	2.3 5.3%	0.0 0%
Neutrophil count decreased	2.3 5.3%	0.0 0%
White blood cells urine positive	2.3 5.3%	0.0 0%
Blood pressure increased	0.0 0%	2.5 6.3%
Electrocardiogram T wave amplitude decreased	0.0 0%	2.5 6.3%
Liver function test abnormal	2.3 5.3%	0.0 0%

Adverse Events

Time Frame	First drug administration until 28 days after last drug administration, up until 309 days
Arm/Group Title	Nintedanib		Placebo
Arm/Group Description	Patients were treated with 250mg nintedanib twice daily.		Patients were treated with matching placebo twice daily.
All Cause Mortality
	Nintedanib		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nintedanib		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/43 (32.6%)		10/40 (25%)
Blood and lymphatic system disorders
Pancytopenia	0/43 (0%)		1/40 (2.5%)
Gastrointestinal disorders
Abdominal distension	1/43 (2.3%)		0/40 (0%)
Abdominal pain	4/43 (9.3%)		2/40 (5%)
Ascites	6/43 (14%)		5/40 (12.5%)
Constipation	1/43 (2.3%)		0/40 (0%)
Diarrhoea	3/43 (7%)		0/40 (0%)
Intestinal obstruction	2/43 (4.7%)		1/40 (2.5%)
Nausea	1/43 (2.3%)		0/40 (0%)
Rectal haemorrhage	1/43 (2.3%)		0/40 (0%)
Small intestinal obstruction	1/43 (2.3%)		1/40 (2.5%)
Vomiting	10/43 (23.3%)		0/40 (0%)
General disorders
Pyrexia	1/43 (2.3%)		0/40 (0%)
Infections and infestations
Catheter related infection	0/43 (0%)		1/40 (2.5%)
Lower respiratory tract infection	1/43 (2.3%)		0/40 (0%)
Investigations
Alanine aminotransferase increased	1/43 (2.3%)		0/40 (0%)
Aspartate aminotransferase increased	1/43 (2.3%)		0/40 (0%)
Blood alkaline phosphatase increased	1/43 (2.3%)		0/40 (0%)
Gamma-glutamyltransferase increased	1/43 (2.3%)		0/40 (0%)
Metabolism and nutrition disorders
Anorexia	1/43 (2.3%)		0/40 (0%)
Dehydration	0/43 (0%)		1/40 (2.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm	0/43 (0%)		1/40 (2.5%)
Neuroendocrine tumour	0/43 (0%)		1/40 (2.5%)
Psychiatric disorders
Abnormal behaviour	1/43 (2.3%)		0/40 (0%)
Agitation	1/43 (2.3%)		0/40 (0%)
Confusional state	1/43 (2.3%)		0/40 (0%)
Delusion	1/43 (2.3%)		0/40 (0%)
Depression	0/43 (0%)		1/40 (2.5%)
Mood altered	0/43 (0%)		1/40 (2.5%)
Respiratory, thoracic and mediastinal disorders
Pleuritic pain	1/43 (2.3%)		0/40 (0%)
Pulmonary embolism	0/43 (0%)		1/40 (2.5%)
Vascular disorders
Deep vein thrombosis	1/43 (2.3%)		0/40 (0%)
Other (Not Including Serious) Adverse Events
	Nintedanib		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/43 (97.7%)		37/40 (92.5%)
Ear and labyrinth disorders
Tinnitus	3/43 (7%)		1/40 (2.5%)
Gastrointestinal disorders
Abdominal distension	3/43 (7%)		1/40 (2.5%)
Abdominal pain	23/43 (53.5%)		15/40 (37.5%)
Constipation	9/43 (20.9%)		11/40 (27.5%)
Diarrhoea	33/43 (76.7%)		14/40 (35%)
Dyspepsia	3/43 (7%)		1/40 (2.5%)
Flatulence	5/43 (11.6%)		4/40 (10%)
Nausea	32/43 (74.4%)		13/40 (32.5%)
Rectal haemorrhage	3/43 (7%)		1/40 (2.5%)
Stomatitis	5/43 (11.6%)		1/40 (2.5%)
Vomiting	23/43 (53.5%)		9/40 (22.5%)
General disorders
Fatigue	12/43 (27.9%)		11/40 (27.5%)
Oedema peripheral	1/43 (2.3%)		3/40 (7.5%)
Infections and infestations
Infection	3/43 (7%)		1/40 (2.5%)
Nasopharyngitis	6/43 (14%)		2/40 (5%)
Upper respiratory tract infection	4/43 (9.3%)		3/40 (7.5%)
Urinary tract infection	4/43 (9.3%)		4/40 (10%)
Investigations
Alanine aminotransferase increased	16/43 (37.2%)		3/40 (7.5%)
Aspartate aminotransferase increased	10/43 (23.3%)		1/40 (2.5%)
Gamma-glutamyltransferase increased	12/43 (27.9%)		1/40 (2.5%)
Metabolism and nutrition disorders
Anorexia	11/43 (25.6%)		6/40 (15%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/43 (11.6%)		6/40 (15%)
Back pain	2/43 (4.7%)		8/40 (20%)
Muscle spasms	2/43 (4.7%)		4/40 (10%)
Pain in extremity	4/43 (9.3%)		2/40 (5%)
Nervous system disorders
Dizziness	4/43 (9.3%)		4/40 (10%)
Headache	6/43 (14%)		4/40 (10%)
Lethargy	4/43 (9.3%)		4/40 (10%)
Neuropathy peripheral	0/43 (0%)		3/40 (7.5%)
Paraesthesia	1/43 (2.3%)		4/40 (10%)
Psychiatric disorders
Anxiety	2/43 (4.7%)		4/40 (10%)
Insomnia	0/43 (0%)		3/40 (7.5%)
Respiratory, thoracic and mediastinal disorders
Cough	6/43 (14%)		1/40 (2.5%)
Dyspnoea	5/43 (11.6%)		3/40 (7.5%)
Skin and subcutaneous tissue disorders
Alopecia	2/43 (4.7%)		4/40 (10%)
Pruritus	0/43 (0%)		6/40 (15%)
Rash	3/43 (7%)		5/40 (12.5%)
Vascular disorders
Hot flush	3/43 (7%)		3/40 (7.5%)
Hypertension	5/43 (11.6%)		2/40 (5%)

Limitations/Caveats

Data from all randomised patients collected upto NOV'08 were included in all above sections,unless stated otherwise.5 patients continued on BIBF1120 after database lock(DBL)-NOV'08 upto Mar'14,but due to limited data no further analyses were done.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.