1. BIBF 1120 (Nintedanib) in platinum-resistant ovarian cancer:
A phase I/II of pegylated liposomal doxorubicin (Doxil®) in combination with
BIBF 1120 (Nintedanib) in platinum-resistant ovarian cancer:
Hoosier Cancer Research Network GYN10-149
M. de Leon, A. Arnold, E. Rossi, J. Schilder, J. Case, Y. Zeng, C. Johnson, D. Matei
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN
Background
Methods
Results
Results
The median survival of patients with recurrent platinum refractory
or resistant ovarian cancer (OC) is ~12 months (Gordon, JCO
2001).
Pegylated liposomal doxorubicin Doxil® is FDA-approved for
platinum resistant/refractory OC. Overall response rate is 20%
and median PFS is 5.5 months (Gordon, JCO, 2001).
BIBF 1120 is a triple oral angiokinase inhibitor that blocks
PDGFRa/b, VEGFR1-3 and FGFR1-3 and has single agent
activity in ovarian cancer.
This phase I/II trial evaluates tolerability and efficacy of BIBF
1120 combined with Doxil® in platinum-resistant OC.
Doxil®
Dose Limiting Toxicities
Responses
28 days = 1 cycle
BIBF 1120 PO BID
Week 2
Week 3
Week 4
Week 1
Dose level
Doxil® (mg/m2)
BIBF 1120 (mg) BID
Pts
treated
DLT 1 40
150 4 2§
-1#
100 7 1*
Best Response
Number (%) SD
5(45.5%)
PR (RECIST)#
2 (18.2%) PD
3 (27.3%)
Not Evaluable
1 (9.0%)
Total 11
C1D1 blood draw for CHSPCs, repeated at C2D1 and at
treatment discontinuation
§Gr 3 fatigue on one pt and Gr 2 diarrhea on another pt causing
treatment interruption
*Gr 4 neutropenia and Gr 3 thrombocytopenia (prior hx of
chemotherapy induced myelosupression)
# One patient developed allergic reaction to doxil and was not
evaluable
Dose escalation
BIBF Dose level 1: 150 mg po bid
2: 200 mg po bid
-1: 100 mg po bid
Doxil Dose level 1: 40mg/m2
-2: 30mg/m2
Methods
Grade 3-4 toxicities
# not confirmed by second scan but with 66%
decreased in CA 125 in one of the two patient
Median time to progression = 3.7 months
Adverse Event
Grade 3
Grade 4
N (%)
Neutropenia 1
2 (18%)
Thrombocytopenia
1 (9%)
Fatigue
Oral pain
Allergic reaction
Study Design
- Multiple institution phase I/II study
- Open label
Key Eligibility Criteria
- Recurrent or persistent epithelial ovarian, primary peritoneal
and fallopian tube cancer. Patients with uterine cancer were
eligible for phase I portion only.
- Measurable disease:  1 target lesion (RECIST 1.1)
- Prior cytotoxic therapy
At least 1 platinum-based regimen
PFI < 6 months
Up to 5 prior cytotoxic regimens
- ECOG Performance Status (PS) 0-1
- Adequate hematologic, hepatic and renal functions
Study Objectives
1. Primary Objectives:
Phase I: To determine the maximum tolerated dose (MTD) and evaluate the safety and toxicity of the combination
Phase II: To assess objective response rate (RECIST 1.1)
2. Secondary Objectives:
- To determine PFS
- To determine the rate of clinical benefit defined as:
1. The number of patients experiencing an objective
response or
2. CA125 response in the absence of disease progression
by clinical or radiographic criteria
3. Translational Objectives:
- To determine treatment effects on circulating hematopoietic
stem and progenitor cells (CHSPCs) which contains two
phenotypically distinct populations:
1. Pro-angiogenic CHSPCs (ViViD-CD14-glyA-
CD34+AC133+CD45dimCD31+ cells)
2. Non-angiogenic CHSPCs (ViViD-CD14-glyA-
CD34+AC133-CD45dimCD31+ cells)
Treatment Schema
- Doxil® : 40 mg/m2 IV every 28 days
- BIBF 1120: For the phase I portion, a dose escalation
design was used, starting with 150 mg po BID given starting at
C1D2
Results
Patient Characteristics
Effect on CHSPCs
Pro-angiogenic CHSPCs (ViViD-CD14-glyA- CD34+AC133+CD45dimCD31+)
Non-angiogenic CHSPCs (ViViD-CD14-glyA- CD34+AC133-CD45dimCD31+)
Patients Characteristics
Phase I
Patients Enrolled 11
Age (years)
Median (Range)
61 (26-82)
ECOG PS
11 (100%)
Origin
Epithelial Ovarian Cancer
8 (73.0%)
Uterine Cancer
2 (18.0%)
Primary Peritoneal Cancer
1 (9.0% )
Histology
Serous Papillary Carcinoma
Endometrioid Carcinoma
Mucinous Carcinoma
1 (9.0%)
Disease Stage at diagnosis I
1 (9.1%) IB
IIIB
IIIC
7 (63.6%) IV
CA-125 at Enrollment
144 (19-776)
Total number of prior chemotherapies 1
3 (27.3%) 2 3 4 5
Toxicities (all) ocurring in > 1 pt.
Adverse Event G1 G2 G3 G4
Total
Diarrhea 2 3 5
Fatigue 1 4
Headache
Anorexia
Skin and subcutaneous disorder
Vomiting
Abdominal pain
Constipation
Dizziness
Mucositis
Pain in extremity
Rash Maculo-Papular
Skin Hyperpigmentation
End of study
Ratio: 1.84 (N=7)
C1D1 Ratio: 1.68
N=10
C2D1 Ratio: 1.58
N=8
Conclusions
The combination of BIBF 1120 and Doxil ® is tolerated at 100mg po BID and 40mg/m 2
7 of 11 patients had PR or SD as best response
iii An expanded cohort using generic liposomal
doxorubicin and BIBF 1120 at level -1 is planned
before starting phase II cohort.
Number of Cycles Administered (Ph I )
N=11
Acknowledgments
This study was funded by Boehringer Ingelheim and conducted at the IU Simon Cancer Center. We thank the IUSCC Angio BioCore for processing the PB samples for this study, and the Hoosier Cancer Research Network staff for management of the trial.