Open Label Dose-Finding Study of TRC105 Plus Capecitabine for Metastatic Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the recommended phase 2 dose and overall safety and tolerability of TRC105 when given in combination with capecitabine for the treatment of patients with progressive or recurrent metastatic breast cancer.

Detailed Description
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All patients were required to sign a consent form prior to undertaking any study-related procedures. Prospective patients were screened to determine if they qualified for the study within 28 days of enrollment. Patients who qualified received TRC105 i.v. over 1 to 4 hours on Day 1, Day 4, Day 8 and Day 15 of the initial 21-day cycle and Day 1, Day 8 and Day 15 of every subsequent 21-day cycle in combination with 1000 mg/m2 capecitabine BID for 14 days of each 21-day cycle. Those who tolerated TRC105 without any infusion reactions were eligible for reduced infusion durations. After 3 cycles of treatment, patients who demonstrated a response of complete response (CR), partial response (PR) or stable disease (SD) were eligible for additional treatment for up to six months (9 total cycles). Upon discussion with TRACON, patients judged by the Principal Investigator to be benefiting from treatment were able to continue treatment on this protocol beyond six months. Toxicities were graded according to the NCI CTCAE Version 4.0. Patients who exited the study for reasons other than drug-related toxicity prior to completion of the first 21-day cycle were replaced. Intra-patient dose escalation was not allowed.

Official Title
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An Open Label Phase 1B Dose-Finding Study of TRC105 in Combination With Capecitabine for Progressive or Recurrent Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: TRC105
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven advanced solid cancer for which curative therapy is not available (Part 1 only) Histologically proven metastatic Her-2-negative breast cancer (Part 2 only) Measurable disease by RECIST 1.1 criteria (Part 2 only) Willing and able to consent for self to participate in study Progressive or recurrent disease after prior systemic chemotherapy regimen Age ≥ 18 years ECOG performance status of 0 or 1 Resolution of all acute toxic effects of prior therapy to NCI CTCAE Grade ≤ 1 or baseline (except alopecia) Adequate organ function Exclusion Criteria: Prior treatment with more than one systemic chemotherapy regimen for metastatic disease. Prior treatment with TRC105 History of hypersensitivity reaction to antimetabolite therapy Receipt of an investigational agent within 28 days of starting study treatment Prior surgery (including open biopsy), radiation therapy or systemic therapy within 28 days of starting study treatment Minor surgical procedures within 14 days prior to first dose of TRC105 History of brain metastasis, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, DVT, PTCA or CABG within the past 6 months Uncontrolled chronic hypertension defined as systolic > 140 or diastolic > 90 despite optimal therapy Past medical history of acquired or inherited coagulopathy including patients with known hereditary hemorrhagic telangiectasia Thrombolytic or anticoagulant use (except to maintain i.v. catheters) within 10 days prior to first dose with TRC105 Cardiac dysrhythmias of NCI CTCAE Grade ≥ 2 within the last month Hemorrhage within 28 days of starting study treatment Unhealed wounds within 28 days of starting study treatment History of peptic ulcer disease or gastritis within the past 6 months, unless treated for the condition and complete resolution has been documented by esophagogastroduodenoscopy (EGD) within 28 days of starting study treatment Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness Known active viral or nonviral hepatitis History of hypersensitivity reaction to human or mouse antibody products Lung cancer with central chest lesions Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single<br>All patients received TRC105 + capecitabine | Drug: TRC105<br>* IV<br>* Other names: carotuximab;Drug: Capecitabine<br>* oral<br>* Other names: xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Maximum Tolerated Dose of TRC105 in Combination With Capecitabine | Assess safety and dose limiting toxicity by dose cohort and coding all terms utilized MedDRA version 14.1. | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TRC105 Steady State Pharmacokinetic Trough Concentration at the RP2D | Mean trough concentration for patients dosed at 10 mg/kg at cycle 2 day 1 | Cycle 2 day 1 (3 weeks) | 
| Number of Patients With Positive Immune Response to TRC105 | Serial blood samples will be tested for anti-drug antibody (ADA) immune response to TRC105. Patients who are positive at baseline (prior to receiving TRC105) are excluded from analysis. | 1.5 years | 
| Number of Patients With Objective Response According to RECIST 1.1 | The best response according to RECIST 1.1 for each patient with measurable disease who received at least one dose of study drug will be listed by cohort and tumor type | 1.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TRC105, Breast Cancer, CD105, Endoglin, TRACON Pharma, Roswell Park Cancer Institute, Department of Defense