A Phase 1B Dose-escalation and Phase 2a Study of TRC105 in Combination With Pazopanib in Patients With Advanced Soft Tissue Sarcoma
Rochester, Minn., Jacksonville, Fla.
Trial status: Open for Enrollment
Why is this study being done?
Pazopanib 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. Pazopanib is approved for the treatment of advanced soft tissue sarcoma, following progression on one prior systemic therapy, based on improved progression free survival. 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 the 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. In a phase 1b study, the combination of TRC105 and bevacizumab produced radiographic reductions in tumor volume in bevacizumab-refractory patients, and was well tolerated. TRC105 potentiates bevacizumab and VEGFR tyrosine kinases (VEGFR TKI) in preclinical models. By targeting a non-VEGF pathway that is upregulated following VEGF inhibition, TRC105 has the potential to complement VEGFR TKIs and could represent a major advance in cancer therapy. Together, the use of TRC105 with pazopanib may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with pazopanib alone.
Who is eligible to participate?
1. Histologically confirmed unresectable soft tissue sarcoma (i.e., non-GIST, non-adipocytic) that has progressed following treatment with chemotherapy. Prior pazopanib is allowed if the drug was not discontinued for toxicity ( Phase 1 only)
2. Histologically confirmed metastatic soft tissue sarcoma (i.e., non-GIST, non-adipocytic) that has progressed by RECIST following treatment with anthracycline chemotherapy. Patients may have received up to four lines of systemic therapy for metastatic disease and no more than two lines of combination treatment ( Phase 2 only)
3. Measurable disease by RECIST
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 or neuropathy)
7. Adequate organ function
8. Willingness and ability to consent for self and to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
9. Available archival tumor specimen of the soft tissue sarcoma that meets inclusion criterion #1 or #2.
1. Prior treatment with TRC105
2. Prior treatment with a VEGFR TKI (including pazopanib) (Part 2 only)
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
5. Receipt of a biologic anticancer agent (e.g., antibody), including an investigational anticancer antibody, within 28 days of starting study 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. Patients who have received wide field radiotherapy ≤ 28 days (defined as > 50% of volume of pelvic bones or equivalent) or limited field radiation for palliation < 14 days prior to cycle 1 day 1 or those patients who have not recovered adequately from side effects of such therapy
8. 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)
9. Symptomatic ascites or symptomatic pericardial or symptomatic pleural effusion
10. 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.
11. 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 anti-coagulated without the use of warfarin for at least 2 weeks. In this situation, low molecular weight heparin is preferred.
12. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g. hereditary hemorrhagic telangiectasia). Patients who have been uneventfully anti-coagulated with low molecular weight heparin are eligible.
13. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of study therapy
14. Known active viral or nonviral hepatitis or cirrhosis
15. History of hemorrhage or hemoptysis (> ½ teaspoon bright red blood) within 3 months of starting study treatment
16. History of peptic ulcer within the past 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
17. 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)
18. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness
19. Receipt of a strong CYP3A4 inducer within 12 days prior to cycle 1 day 1 or a strong CYP3A4 inhibitor within 7 days prior to cycle 1 day 1 (Table 8)
20. Pregnancy or breastfeeding.