Study of Nintedanib Plus Bevacizumab in Advanced Solid Tumors

NCT02835833 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: F160202011 (UAB 15108)
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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.

  Initial dose of study drug until four weeks after the last dose or until death, whichever occurs first

• Maximum tolerable dose of Nintedanib

  The maximum dosage of drug that yields acceptable toxicity levels.

  Baseline up to three years

Secondary Outcomes (7)

• Objective tumor response rate

  up to 100 weeks

• Progression-free survival

  Baseline up to three years

• Plasma level of vascular endothelial growth factor (VEGF)

  Baseline up to two years

• Plasma level of platelet-derived growth factor (PDGF)

  Baseline up to two years

• Plasma level of vascular endothelial growth factor and receptor (VEGF-R)

  Baseline up to two years

Study Arms (2)

Nintedanib 150 mg + Bevacizumab 15 mg/kg

EXPERIMENTAL

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.

Drug: Nintedanib; Drug: Bevacizumab

Nintedanib 200 mg + Bevacizumab 15 mg/kg

EXPERIMENTAL

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.

Drug: Nintedanib; Drug: Bevacizumab

Interventions

Nintedanib DRUG

Nintedanib will be given twice daily at either 150 mg or 200 mg.

Also known as: BIBF1120

Nintedanib 150 mg + Bevacizumab 15 mg/kg; Nintedanib 200 mg + Bevacizumab 15 mg/kg

Bevacizumab DRUG

Bevacizumab will be given at 15 mg/kg

Also known as: Avastin

Nintedanib 150 mg + Bevacizumab 15 mg/kg; Nintedanib 200 mg + Bevacizumab 15 mg/kg

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• Boehringer Ingelheim: collaborator

Study Sites (1)

University of Alabama at Birmingham Comprehensive Cancer Center

Birmingham, Alabama, 35294, United States

Location

Related Publications (1)

• 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.

  PMID: 30603797 DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell; Uterine Cervical Neoplasms

Interventions

nintedanib; Bevacizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Genital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Francisco Robert, MD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 7, 2016
• First Posted: July 18, 2016
• Study Start: June 9, 2016
• Primary Completion: April 14, 2018
• Study Completion: June 14, 2018
• Last Updated: July 10, 2018

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)