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Study of Nintedanib Plus Bevacizumab in Advanced Solid Tumors

Primary Purpose

Renal Cell Carcinoma, Colorectal Adenocarcinoma, Non-squamous Non-small Cell Lung Cancer

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Nintedanib
Bevacizumab
Sponsored by
University of Alabama at Birmingham
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Renal Cell Carcinoma focused on measuring advanced solid tumors, Nintedanib, Bevacizumab, dose escalation

Eligibility Criteria

19 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age >18
  2. Histologically proven advanced or metastatic solid cancer for which Bevacizumab has an indication: renal cell carcinoma, colorectal adenocarcinoma, non-squamous non-small cell lung cancer, platinum- refractory ovarian carcinoma, cervical carcinoma.
  3. Life expectancy at least 3 months
  4. ECOG performance status score 0-1
  5. Progression after at least first-line systemic therapy for metastatic disease
  6. At least one measurable lesion according to RECIST criteria or any other baseline prerequisite for the assessment of the principal judgement criteria.
  7. Signed and dated written informed consent prior to admission to the study
  8. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade less than/equal to 1 or baseline (except alopecia)
  9. Adequate organ function as defined by the following criteria

    • AST/ALT ≤ 2.5x upper limit of normal (ULN) in the case of liver metastases or AST/ALT ≤ 1.5 x ULN in patients without liver metastases
    • total serum bilirubin within normal limits regardless of liver metastases
    • absolute neutrophil count (ANC) > 1500
    • Platelets > 100k without transfusion support in the past 28 days
    • Hemoglobin > 9.0 without transfusion support in the past 28 days
    • Serum creatinine < 1.5x ULN
    • Prothrombin time/INR and partial thromboplastin time within normal limits
    • Urinalysis ≤ 1+ protein
  10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

Exclusion Criteria:

  1. Previous therapy with Bevacizumab is allowed, but patient who experienced serious dose-limiting toxicities while on prior Bevacizumab therapy are excluded
  2. Prior treatment with Nintedanib (BIBF1120). Known hypersensitivity to Nintedanib, peanut or soya or any other trial drug, their excipients or to contrast media
  3. Chemo-, hormone-, radio-(except for brain and extremities) or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug.
  4. Radiotherapy to the target lesion within the past 3 months prior to baseline imaging
  5. Persistence of clinically relevant therapy related toxicity from previous chemo and/or radiotherapy
  6. History of brain involvement with cancer, spinal cord compression, carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Patients with irradiated or resected brain lesions are permitted provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been used for at least 28 days.
  7. Leptomeningeal disease
  8. Centrally located tumours with radiographic evidence of local invasion of major blood vessels
  9. Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial
  10. Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid <325mg per day.
  11. Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.
  12. History of clinically significant hemorrhagic or thromboembolic event in the past 6 months.
  13. Known inherited predisposition to bleeding or thrombosis
  14. Significant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 6 months prior to start of study treatment, congestive heart failure >New York Heart Association II, serious cardiac arrhythmia, pericardial effusion)
  15. Proteinuria CTCAE grade 2 or greater
  16. Creatinine >1.5 ULN or GFR <45 ml/min
  17. Hepatic function: total bilirubin outside of normal limits; ALT or AST >2.5 ULN in pts without liver metastasis. For patients with liver metastasis: total bilirubin outside of normal limits, ALT or AST >5 x ULN
  18. Coagulation parameters: International normalized ratio (INR) >2, prothrombin time (PT) and partial thromboplastin time (PTT) >50% of deviation of institutional ULN
  19. Absolute neutrophil count (ANC) <1500/ml, platelets <100,000/ml, Hemoglobin <9.0 g/dl
  20. Other malignancies within the past 5 years other than basal cell skin cancer or carcinoma in situ of the cervix
  21. Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy
  22. Active or chronic hepatitis C and/or B infection
  23. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
  24. 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.
  25. Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) during the trial and for at least three months after end of active therapy.
  26. Pregnancy or breast feeding. Female patients must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment and must agree with the use of effective contraception during the study and for three months following last dose of Nintedanib.
  27. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule
  28. Active alcohol or drug abuse
  29. Minor surgical procedures such as Mediport placement or core biopsies within 7 days of study treatment
  30. Stroke, transient ischemic attack, arterial embolism, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG) within the past 6 months
  31. History of pulmonary hemorrhage or hemoptysis within 6 months of starting study treatment
  32. Open wounds or unhealed fractures within 28 days of starting study treatment
  33. Known HIV or AIDS related illness

Sites / Locations

  • University of Alabama at Birmingham Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Nintedanib 150 mg + Bevacizumab 15 mg/kg

Nintedanib 200 mg + Bevacizumab 15 mg/kg

Arm Description

The first three patients on study will be treated with 150 mg orally of Nintedanib two times daily plus 15 mg/kg of Bevacizumab administered intravenously on day one of each three week cycle. If one dose limiting toxicity occurs in the first cohort, then three more patients will be treated at that same starting dose and assessed for toxicity after cycle two. If two or more patients have dose limiting toxicity, then dose escalation will end and the maximum tolerated dose will be reached.

If no patients experience dose limiting toxicity, then three additional patients will be treated with 200 mg orally of Nintedanib two times daily plus 15 mg/kg of Bevacizumab administered intravenously on day one of each three week cycle.

Outcomes

Primary Outcome Measures

Number of participants with adverse events as a measure of safety and tolerability
Adverse event reporting will be graded following the National Cancer Institute of Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
Maximum tolerable dose of Nintedanib
The maximum dosage of drug that yields acceptable toxicity levels.

Secondary Outcome Measures

Objective tumor response rate
Response will be evaluated using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Progression-free survival
Progression-free survival is defined as the duration of time from start of treatment to the first documentation of tumor progression. Kaplan-Meier estimates will be used.
Plasma level of vascular endothelial growth factor (VEGF)
Correlative analysis will be conducted using Chi-square tests and Spearman rank correlations. Differences between responders and non-responders will utilize the Kruskal-Wallis test.
Plasma level of platelet-derived growth factor (PDGF)
Correlative analysis will be conducted using Chi-square tests and Spearman rank correlations. Differences between responders and non-responders will utilize the Kruskal-Wallis test.
Plasma level of vascular endothelial growth factor and receptor (VEGF-R)
Correlative analysis will be conducted using Chi-square tests and Spearman rank correlations. Differences between responders and non-responders will utilize the Kruskal-Wallis test.
Plasma level of phosphatidylinositol-glycan biosynthesis class F protein (PIGF)
Correlative analysis will be conducted using Chi-square tests and Spearman rank correlations. Differences between responders and non-responders will utilize the Kruskal-Wallis test.
Plasma level of fibroblast growth factor (FGF)
Correlative analysis will be conducted using Chi-square tests and Spearman rank correlations. Differences between responders and non-responders will utilize the Kruskal-Wallis test.

Full Information

First Posted
July 7, 2016
Last Updated
July 9, 2018
Sponsor
University of Alabama at Birmingham
Collaborators
Boehringer Ingelheim
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1. Study Identification

Unique Protocol Identification Number
NCT02835833
Brief Title
Study of Nintedanib Plus Bevacizumab in Advanced Solid Tumors
Official Title
Phase I Dose Escalation Study of Nintedanib Plus Bevacizumab in Advanced Solid Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
June 9, 2016 (Actual)
Primary Completion Date
April 14, 2018 (Actual)
Study Completion Date
June 14, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Alabama at Birmingham
Collaborators
Boehringer Ingelheim

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Angiogenesis, the development of new blood vessels, plays an important role in the disease development and tumor growth in many solid organ malignancies. Bevacizumab was the first anti-angiogenic drug to be approved in solid tumors and has shown advantageous activity with multiple tumor types. However, the responses from Bevacizumab are often transient due to the tumor's manipulative abilities to circumvent the usual pathways to find salvage pathways instead. Nintedanib has demonstrated anti-tumor activity in non-squamous non-small cell lung cancer, colorectal cancer, ovarian cancer, and renal cell cancer. The combination of Bevacizumab and Nintedanib are being proposed to target the tumor's manipulation processes to generate alternate pathways for angiogenesis thus creating a potential benefit to delay tumor growth.
Detailed Description
This is an open-label, phase I dose-escalation study of Nintedanib combined with standard-dose Bevacizumab for advanced solid tumors in which Bevacizumab has an indication. The primary endpoints will be safety and tolerability of the drug combination and a determination of recommended Phase II dose for Nintedanib in combination with standard dose Bevacizumab. The first three patients will be treated with Nintedanib daily plus Bevacizumab on day one of each three week cycle. If there are no dose limiting toxicities, then three additional patients will be treated with the same drugs with Nintedanib at a slightly higher level. Finally, a third cohort of three patients will be dosed at an even higher level. Once the maximum tolerated dose of Nintedanib is reached, then an additional six patients will be treated at that dose in combination with Bevacizumab until disease progression or unacceptable toxicities.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Cell Carcinoma, Colorectal Adenocarcinoma, Non-squamous Non-small Cell Lung Cancer, Platinum-refractory Ovarian Carcinoma, Cervical Carcinoma
Keywords
advanced solid tumors, Nintedanib, Bevacizumab, dose escalation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
21 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nintedanib 150 mg + Bevacizumab 15 mg/kg
Arm Type
Experimental
Arm Description
The first three patients on study will be treated with 150 mg orally of Nintedanib two times daily plus 15 mg/kg of Bevacizumab administered intravenously on day one of each three week cycle. If one dose limiting toxicity occurs in the first cohort, then three more patients will be treated at that same starting dose and assessed for toxicity after cycle two. If two or more patients have dose limiting toxicity, then dose escalation will end and the maximum tolerated dose will be reached.
Arm Title
Nintedanib 200 mg + Bevacizumab 15 mg/kg
Arm Type
Experimental
Arm Description
If no patients experience dose limiting toxicity, then three additional patients will be treated with 200 mg orally of Nintedanib two times daily plus 15 mg/kg of Bevacizumab administered intravenously on day one of each three week cycle.
Intervention Type
Drug
Intervention Name(s)
Nintedanib
Other Intervention Name(s)
BIBF1120
Intervention Description
Nintedanib will be given twice daily at either 150 mg or 200 mg.
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin
Intervention Description
Bevacizumab will be given at 15 mg/kg
Primary Outcome Measure Information:
Title
Number of participants with adverse events as a measure of safety and tolerability
Description
Adverse event reporting will be graded following the National Cancer Institute of Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.
Time Frame
Initial dose of study drug until four weeks after the last dose or until death, whichever occurs first
Title
Maximum tolerable dose of Nintedanib
Description
The maximum dosage of drug that yields acceptable toxicity levels.
Time Frame
Baseline up to three years
Secondary Outcome Measure Information:
Title
Objective tumor response rate
Description
Response will be evaluated using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Time Frame
up to 100 weeks
Title
Progression-free survival
Description
Progression-free survival is defined as the duration of time from start of treatment to the first documentation of tumor progression. Kaplan-Meier estimates will be used.
Time Frame
Baseline up to three years
Title
Plasma level of vascular endothelial growth factor (VEGF)
Description
Correlative analysis will be conducted using Chi-square tests and Spearman rank correlations. Differences between responders and non-responders will utilize the Kruskal-Wallis test.
Time Frame
Baseline up to two years
Title
Plasma level of platelet-derived growth factor (PDGF)
Description
Correlative analysis will be conducted using Chi-square tests and Spearman rank correlations. Differences between responders and non-responders will utilize the Kruskal-Wallis test.
Time Frame
Baseline up to two years
Title
Plasma level of vascular endothelial growth factor and receptor (VEGF-R)
Description
Correlative analysis will be conducted using Chi-square tests and Spearman rank correlations. Differences between responders and non-responders will utilize the Kruskal-Wallis test.
Time Frame
Baseline up to two years
Title
Plasma level of phosphatidylinositol-glycan biosynthesis class F protein (PIGF)
Description
Correlative analysis will be conducted using Chi-square tests and Spearman rank correlations. Differences between responders and non-responders will utilize the Kruskal-Wallis test.
Time Frame
Baseline up to two years
Title
Plasma level of fibroblast growth factor (FGF)
Description
Correlative analysis will be conducted using Chi-square tests and Spearman rank correlations. Differences between responders and non-responders will utilize the Kruskal-Wallis test.
Time Frame
Baseline up to two years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age >18 Histologically proven advanced or metastatic solid cancer for which Bevacizumab has an indication: renal cell carcinoma, colorectal adenocarcinoma, non-squamous non-small cell lung cancer, platinum- refractory ovarian carcinoma, cervical carcinoma. Life expectancy at least 3 months ECOG performance status score 0-1 Progression after at least first-line systemic therapy for metastatic disease At least one measurable lesion according to RECIST criteria or any other baseline prerequisite for the assessment of the principal judgement criteria. Signed and dated written informed consent prior to admission to the study Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade less than/equal to 1 or baseline (except alopecia) Adequate organ function as defined by the following criteria AST/ALT ≤ 2.5x upper limit of normal (ULN) in the case of liver metastases or AST/ALT ≤ 1.5 x ULN in patients without liver metastases total serum bilirubin within normal limits regardless of liver metastases absolute neutrophil count (ANC) > 1500 Platelets > 100k without transfusion support in the past 28 days Hemoglobin > 9.0 without transfusion support in the past 28 days Serum creatinine < 1.5x ULN Prothrombin time/INR and partial thromboplastin time within normal limits Urinalysis ≤ 1+ protein Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Exclusion Criteria: Previous therapy with Bevacizumab is allowed, but patient who experienced serious dose-limiting toxicities while on prior Bevacizumab therapy are excluded Prior treatment with Nintedanib (BIBF1120). Known hypersensitivity to Nintedanib, peanut or soya or any other trial drug, their excipients or to contrast media Chemo-, hormone-, radio-(except for brain and extremities) or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug. Radiotherapy to the target lesion within the past 3 months prior to baseline imaging Persistence of clinically relevant therapy related toxicity from previous chemo and/or radiotherapy History of brain involvement with cancer, spinal cord compression, carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Patients with irradiated or resected brain lesions are permitted provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been used for at least 28 days. Leptomeningeal disease Centrally located tumours with radiographic evidence of local invasion of major blood vessels Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid <325mg per day. Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period. History of clinically significant hemorrhagic or thromboembolic event in the past 6 months. Known inherited predisposition to bleeding or thrombosis Significant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 6 months prior to start of study treatment, congestive heart failure >New York Heart Association II, serious cardiac arrhythmia, pericardial effusion) Proteinuria CTCAE grade 2 or greater Creatinine >1.5 ULN or GFR <45 ml/min Hepatic function: total bilirubin outside of normal limits; ALT or AST >2.5 ULN in pts without liver metastasis. For patients with liver metastasis: total bilirubin outside of normal limits, ALT or AST >5 x ULN Coagulation parameters: International normalized ratio (INR) >2, prothrombin time (PT) and partial thromboplastin time (PTT) >50% of deviation of institutional ULN Absolute neutrophil count (ANC) <1500/ml, platelets <100,000/ml, Hemoglobin <9.0 g/dl Other malignancies within the past 5 years other than basal cell skin cancer or carcinoma in situ of the cervix Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy Active or chronic hepatitis C and/or B infection Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug 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. Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) during the trial and for at least three months after end of active therapy. Pregnancy or breast feeding. Female patients must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment and must agree with the use of effective contraception during the study and for three months following last dose of Nintedanib. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule Active alcohol or drug abuse Minor surgical procedures such as Mediport placement or core biopsies within 7 days of study treatment Stroke, transient ischemic attack, arterial embolism, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG) within the past 6 months History of pulmonary hemorrhage or hemoptysis within 6 months of starting study treatment Open wounds or unhealed fractures within 28 days of starting study treatment Known HIV or AIDS related illness
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francisco Robert, MD
Organizational Affiliation
University of Alabama at Birmingham
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham Comprehensive Cancer Center
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30603797
Citation
Paluri R, Madan A, Li P, Jones B, Saleh M, Jerome M, Miley D, Keef J, Robert F. Phase 1b trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2019 Mar;83(3):551-559. doi: 10.1007/s00280-018-3761-y. Epub 2019 Jan 2.
Results Reference
derived

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Study of Nintedanib Plus Bevacizumab in Advanced Solid Tumors

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