Clinical trial NCT01806064: Randomized Phase 2 Trial of Axitinib and TRC105 Versus Axitinib Alone in Patients Renal Cell Carcinoma
Official title: A Randomized Phase 2 Trial of Axitinib and TRC105 Versus Axitinib Alone (Including a lead-in Phase 1B Dose Escalation Portion) in Patients With Advanced or Metastatic Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Renal Cell Carcinoma
Keywords: TRC105
CD105
RCC
Renal Cell Carcinoma
Axitinib
INLYTA
Advanced Renal Cell Carcinoma
Lead sponsor: Tracon Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2013-03-07
Enrollment: 173
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Phase 1b: To evaluate safety and tolerability and determine a recommended phase 2 dose for TRC105 when added to standard dose axitinib in patients with advanced renal cell carcinoma.

Phase 2: To estimate the PFS of patients with advanced or metastatic RCC by RECIST 1.1 criteria in patients treated with axitinib and TRC105 compared to those treated with axitinib alone, following failure of one prior VEGF TKI

Detailed description: Axitinib is an oral inhibitor of multiple receptor tyrosine kinases including vascular endothelial growth factor receptor VEGFR-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. Axitinib is approved for the treatment of advanced renal cell carcinoma, following progression on one prior systemic therapy. TRC105 is an antibody to CD105, an important angiogenic target on vascular endothelial cells that is distinct from VEGFR. TRC105 inhibits angiogenesis, tumor growth and metastases in preclinical models and complements the activity of bevacizumab and multi-kinase inhibitors that target VEGFR. In a phase 1 study of advanced solid tumors,TRC105 therapy caused a global reduction in angiogenic biomarkers and reduced tumor burden at doses that were well-tolerated. By targeting a non-VEGF pathway that is upregulated following VEGF inhibition, TRC105 has the potential to complement VEGF inhibitors and could represent a major advance in cancer therapy. TRC105 potentiates bevacizumab and VEGFR tyrosine kinases (VEGFR TKI) in preclinical models. In a phase 1b study, the combination of TRC105 and bevacizumab produced radiographic reductions in tumor volume in bevacizumab refractory patients. Together, the use of TRC105 with axitinib may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with axitinib alone.

Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed advanced or metastatic renal cell carcinoma with a clear cell component that has progressed by investigator assessment following treatment with one and only one multi-targeted tyrosine kinase inhibitor (TKI) other than axitinib that targets the VEGF receptor (VEGFR) (e.g., sunitinib, pazopanib, sorafenib, tivozanib, cabozantinib). One prior immunotherapy (interleukin-2 or interferon-alpha or immune checkpoint inhibitor or tumor vaccine) and one prior mTOR inhibitor treatment are allowed.
2. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission per investigators' clinical judgment.
3. Measurable disease by RECIST 1.1 criteria
4. Age of 18 years or older
5. ECOG performance status ≤ 1
6. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade ≤ 1 or baseline (except alopecia)
7. Adequate organ function as defined by the following criteria:
8. Willingness and ability to consent for self to participate in study
9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

Exclusion Criteria:

1. Prior treatment with TRC105 or axitinib or any agent targeting the endoglin pathway (including a fusion protein that binds bone morphogenic protein)
2. Grade 3 or 4 toxicity related to prior VEGFR TKI that did not resolve to grade 1
3. Current treatment on another therapeutic clinical trial
4. Receipt of a small molecule anticancer agent, including an investigational anticancer small molecule, within 14 days of starting study treatment or receipt of a biologic anticancer agent (e.g., antibody) within 28 days of starting study treatment.
5. Prior radiation therapy within 28 days of starting the study treatment, except radiation therapy for bone metastases or radiosurgery is permitted up to 14 days of starting treatment
6. No major surgical procedure or significant traumatic injury within 6 weeks prior to study registration, and must have fully recovered from any such procedure; date of surgery (if applicable). Note: the following are not considered to be major procedures and are permitted up to 7 days before therapy initiation: Thoracentesis, paracentesis, port placement, laparoscopy, thorascopy, tube thoracostomy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided biopsy for diagnostic purposes, and routine dental procedures
7. Uncontrolled chronic hypertension defined as systolic \> 150 or diastolic \> 90 despite optimal therapy (initiation or adjustment of BP medication prior to study entry is allowed provided that the average of 3 BP readings at a visit prior to enrollment is \< 150/90 mm Hg)
8. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Patients with radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been administered for at least 28 days.
9. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, PTCA or CABG within the past 6 months. Deep venous thrombosis within 6 months unless the patient is anticoagulated without the use of warfarin for at least 2 weeks. In this situation, low molecular weight heparin is preferred.
10. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g. hereditary hemorrhagic telangiectasia).
11. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of study therapy
12. Known active viral or nonviral hepatitis or cirrhosis
13. History of hemorrhage or hemoptysis (\> ½ teaspoon bright red blood) within 3 months of starting study treatment
14. History of peptic ulcer disease within 3 months of treatment, unless treated for the condition and complete resolution has been documented by esophagogastroduodenoscopy (EGD) within 28 days of starting study treatment
15. History of gastrointestinal perforation or fistula in the past 6 months, or while previously on antiangiogenic therapy, unless underlying risk has been resolved (e.g., through surgical resection or repair)
16. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness
17. Requirement for concomitant medications that strongly induce or inhibit CYP3A4/5
18. Pregnancy or breastfeeding. Female patients must be surgically sterile (i.e.: hysterectomy) or be postmenopausal, or must agree to use effective contraception during the study and for 3 months following last dose of TRC105. All female patients of reproductive potential must have a negative pregnancy test (serum or urine) within 7 days prior to first dose. Male patients must be surgically sterile or must agree to use effective contraception during the study and for 3 months following last dose of TRC105. The definition of effective contraception will be based on the judgment of the Principal Investigator or a designated associate.
19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for this study

Primary outcomes:
measure: Phase 1b: Number of Patients With DLT
timeFrame: 12 Months
measure: Phase 2: Progression Free Survival (PFS) of Patients With RCC
timeFrame: 15 Months
Secondary outcomes:
measure: Phase 1b & 2: Response Rate of Patients With RCC
timeFrame: 15 Months
measure: Phase 2: Overall Response Rate of Patients With RCC by Choi
timeFrame: 15 Months
measure: Phase 1b & 2: Trough Concentrations of TRC105 by Dose Level in Phase 1b
timeFrame: 2.5 months (cycle 2 day 15)
measure: Phase 1b & 2: Number of Patients With Development of Immunogenicity Antibodies.
timeFrame: 12 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Fullerton
country: United States
facility: St. Joseph Heritage Healthcare
state: California
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Sacramento
country: United States
facility: University of California, Davis
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Peoria
country: United States
facility: Illinois CancerCare
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univeristy
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: Morristown
country: United States
facility: Atlantic Health System
state: New Jersey
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research & Treatment Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Brno
country: Czechia
facility: Masaryk Institute
city: Brno
country: Czechia
facility: St. Anne's
city: Brno
country: Czechia
facility: University Hospital Brno
city: Praha
country: Czechia
facility: Na Bulovce Hospital
city: Praha
country: Czechia
facility: Thomayer Hospital
city: Budapest
country: Hungary
facility: Integrated Szent Istvan and Szent Laszlo Hospital
city: Budapest
country: Hungary
facility: National Institute of Oncology
city: Debrecen
country: Hungary
facility: University of Debrecen Medical Center Institute of Oncology
city: Kaposvar
country: Hungary
facility: Kaposi Mor Teaching Hospital
city: Pecs
country: Hungary
facility: Medical Center of the University of Pecs
city: Brighton
country: United Kingdom
facility: Sussex Cancer Center, Royal Sussex County Hospital
state: East Sussex
Study officials:
affiliation: ctheuer@traconpharma.com
name: Charles Theuer, MD PhD
role: STUDY_DIRECTOR
References:
citation: Choueiri TK, Michaelson MD, Posadas EM, Sonpavde GP, McDermott DF, Nixon AB, Liu Y, Yuan Z, Seon BK, Walsh M, Jivani MA, Adams BJ, Theuer CP. An Open Label Phase Ib Dose Escalation Study of TRC105 (Anti-Endoglin Antibody) with Axitinib in Patients with Metastatic Renal Cell Carcinoma. Oncologist. 2019 Feb;24(2):202-210. doi: 10.1634/theoncologist.2018-0299. Epub 2018 Sep 6.