Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Nivolumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Carotuximab (TRC105)

OPDIVO

Charles Theuer, MD, PhD

This is a multi-center, open-label, nonrandomized, dose-escalation, Phase 1b study of carotuximab in combination with standard dose nivolumab in patients with NSCLC that has progressed on or after platinum-based chemotherapy or PD-1/PD-L1 checkpoint inhibition, as a single agent or with chemotherapy.

Study of Carotuximab (TRC105) Plus Nivolumab in Patients With Metastatic NSCLC

A Phase 1b Dose-Escalation Study of Carotuximab (TRC105) in Combination With Nivolumab in Patients With Metastatic Non-Small Cell Lung Cancer

For DLT evaluation, severity (grade) was classified according to common terminology criteria for adverse events version 4.03 (CTCAE v4.03). DLTs were defined as grade 4 neutropenia persisting for ≥ 5 days, Febrile neutropenia: Grade 4 neutropenia with fever \>38.5ºC both sustained over a ≥24-hour period, neutropenic infection (grade ≥ 3 neutropenia with grade ≥ 3 infection), anemia ≥ grade 4, Grade ≥4 thrombocytopenia or Grade ≥3 thrombocytopenia with Grade ≥3 hemorrhage, or grade 3 or 4 nonhematologic toxicity with the following exceptions: asymptomatic electrolyte abnormality that is corrected to Grade 1 or better in \<72 hours, grade 3 headache lasting \<48 hours. See protocol for Immune related DLT criteria.

Preliminary evidence of antitumor activity of carotuximab (TRC105) plus nivolumab will be evaluated, by assessing response rate and progression-free survival. The best response was measured to iRECIST by MRI or CT scans for each patient with measurable disease who received at least 1 dose of study drug.

Trough (pre-dose) serum carotuximab (TRC105) concentrations will be measured using validated ELISA methods.

Number of Participants with carotuximab (TRC105) anti-product antibodies (APA)

Trough (pre-dose) serum nivolumab concentrations will be measured using validated ELISA methods.

Tracon Pharmaceuticals Inc.

Dose Level 1 8 mg/kg TRC105 + Nivolumab

Carotuximab (TRC105): Anti Endoglin Antibody

OPDIVO (Nivolumab): Programmed Death Receptor-1

8 mg/kg TRC105 + Nivolumab

Dose Level 2 10 mg/kg TRC105 + Nivolumab

Carotuximab (TRC105): Anti Endoglin Antibody

OPDIVO (Nivolumab): Programmed Death Receptor-1

10 mg/kg TRC105 + Nivolumab

Dose Level 1 8 mg/kg TRC105 + Nivolumab Carotuximab (TRC105): Anti Endoglin Antibody OPDIVO (Nivolumab): Programmed Death Receptor-1

8 mg/kg TRC105 Plus Nivolumab

Dose Level 2 10 mg/kg TRC105 + Nivolumab Carotuximab (TRC105): Anti Endoglin Antibody OPDIVO (Nivolumab): Programmed Death Receptor-1

10 mg/kg TRC105 Plus Nivolumab

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Medical Monitor

All patients who received at least a portion of a dose of any study drug (TRC105, Nivolumab)

Number of Participants With Dose Limiting Toxicity (DLT)

iSD (Immune Stable Disease) Best Response

iPR (Immune Partial Response) Best Response

iPD (Immune Progressive Disease) Best Response

iCR (Immune Complete Response) Best Response

iUPD (Unconfirmed Immune PD) Best Response

Number of patients with a baseline scan and at least 1 on study scan were evaluable for response rate determination. Patients were scanned at baseline and every 8 weeks to determine disease status.

Response Rate

All patients who received at least a portion of a dose of TRC105 with PK samples collected at baseline and at least 1 time point on study. 6 patients had PK analysis completed.

Trough Carotuximab (TRC105) Concentrations

Anti-product antibody concentrations will be measured using validated ELISA methods. Anti-product antibody concentrations will be evaluated in the context of pharmacokinetic parameters and AE profiles.

Development of Immunogenicity Antibodies

All patients who received at least a portion of a dose of TRC105 with PK samples collected at baseline and at least 1 time point on study. Only Cycle 2 Day 1 trough mean serum TRC105 concentrations were analyzed before study closure.

Trough Nivolumab Concentrations

Overall Study

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Recurrence

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Ovarian Cancer

Ovarian Epithelial Cancer

Fallopian Tube Cancer

Antibodies, Monoclonal

Immunologic Factors

Single arm, open label Carotuximab (TRC105) alone therapy dosed at 10 mg/kg administered intravenously over 1 to 4 hours on days 1, 8, 15 and 22 of each 28 day cycle

Carotuximab (TRC105) 10 mg/kg weekly by intravenous administration on Days 1, 8, 15 and 22 of each 28-day cycle

Charles P Theuer, MD

The purpose of this study is to evaluate the safety and efficacy of TRC105 in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.

Angiogenesis plays a central role in the progression of epithelial ovarian cancer. In mouse models, VEGF-inhibitors diminish ovarian tumor growth, metastasis and malignant ascites formation. Independent Phase 2 trials have demonstrated single-agent activity for bevacizumab in recurrent ovarian cancer, and randomized controlled Phase 3 trials are ongoing in the first-line setting (GOG 0218 and ICON-7) and for recurrent disease (GOG 0213, OCEANS).

TRC105 is an antibody to CD105, an important non-VEGF angiogenic target on vascular endothelial cells. TRC105 inhibits angiogenesis, tumor growth and metastases in preclinical models. 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. We hypothesize that TRC105 will have single-agent activity in recurrent ovarian cancer. By targeting a non-VEGF pathway, TRC105 has the potential to complement VEGF inhibitors which could represent a major advance in ovarian cancer therapy.

Evaluation of TRC105 in the Treatment of Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma

A Phase 2 Evaluation of TRC105 in the Treatment of Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma

Number of patients ongoing within the study who have not progressed after 6 months of treatment

Proportion of patients who have objective tumor response (complete or partial) by RECIST 1.1

Frequency of adverse events as assessed by NCI CTCAE (Version 4.0)

Median peak and trough concentration of TRC105 by ELISA in ug/mL

TRC105 Anti-Drug Antibody (ADA) Immunogenicity by ELISA

Chimeric monoclonal antibody (TRC105) to CD105: 10 mg/kg weekly by intravenous administration on Days 1, 8, 15 and 22 of each 28-day cycle

TRC105

Age, Categorical

Total number of patients enrolled in the trial who received at least a portion of a dose of TRC105. Screen-failure patients are not included in the overall baseline analysis population.

Charles Theuer, Medical Monitor

This population will include all patients enrolled in the study who receive at least 1 dose of TRC105 study medication and who undergo at least one on study efficacy assessment or expire due to progressive disease prior to the first efficacy assessment.

Progression-free Survival Rate After 6 Months of Treatment on Study

Proportion of Patients Who Have Objective Tumor Response

Anemia (Grade 3 Suspected Reaction)

Fatigue (Grade 3 Suspected Reaction)

Headache (Grade 3 Suspected Reaction)

Migraine (Grade 3 Suspected Reaction)

Epistaxis (Grade 3 Suspected Reaction)

All patients who received at least a portion of a dose of TRC105.

Adverse Events

CA-125 Decrease

CA-125 Increase

All patients who received at least a portion of a dose of TRC105

CA-125 Response Rate

Median Trough Concentration Cycle 1 Day 15

Median Peak Concentration Cycle 1 Day 15

All patients who received at least a portion of a TRC105 dose

Serum Concentrations of TRC105

Patients with Positive Treatment Emergent ADA

Patients with Negative Treatment Emergent ADA

All patients that received at least a portion of TRC105

TRC105 Immunogenicity

Serious Adverse Events

TRC105 Related Serious Adverse Events

No Serious Adverse Events

Severity of Adverse Events

Overall Survival

Digestive System Diseases

Carcinoma, Hepatocellular

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Amino Acids

Angiogenesis Inhibitors

Tyrosine Kinase Inhibitors

Sorafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Carotuximab (TRC105) in combination with standard dose Sorafenib.

Bi-weekly iv TRC105 (15 mg/kg) will be given with 400mg sorafenib twice daily in the phase 1B portion of the study. Weekly iv TRC105 (10 mg/kg) will be given with 400mg sorafenib twice daily in the phase 2 portion of the study.

400 mg of sorafenib will be given twice daily.

The purpose of the phase 1b portion is to evaluate safety and tolerability and determine a recommended phase 2 dose for TRC105 when added to standard dose sorafenib in patients with hepatocellular carcinoma. Up to 18 patients will be treated.

The purpose of the phase 2 portion is to estimate the ORR of patients with hepatocellular carcinoma by RECIST 1.1. Up to 21 patients will be treated in phase 2.

Sorafenib is an oral multikinase inhibitor targeting several receptor tyrosine kinases, including the VEGF receptor (VEGFR), implicated in pathologic angiogenesis, tumor growth, and cancer progression. Sorafenib is approved for the treatment of unresectable hepatocellular carcinoma (HCC). TRC105 is an antibody to endoglin, an important angiogenic target on proliferating endothelial cells that is distinct from VEGFR. TRC105 inhibits angiogenesis, tumor growth and metastases and complements the activity of bevacizumab and multi-kinase inhibitors that target the VEGFR in preclinical models. Together, the use of TRC105 with sorafenib may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with sorafenib alone.

Trial of TRC105 and Sorafenib in Patients With HCC

An Open Label Phase 1B/2 Trial of TRC105 and Sorafenib in Patients With Hepatocellular Carcinoma (HCC)

If 1 of 3 patients experienced a DLT, the dose level was expanded to 6 patients. The maximum tolerated dose (MTD) would have been exceeded if ≥ 33% of patients experience DLT at a given dose level. DLT occurred when a patient had 1 or more toxicities outlined in the protocol that was considered at least possibly related to TRC105 during the first 4 months of participation in the trial. The number of DLTs by dose cohort have been presented.

Number of patients with a response (PR or CR) are included by dose level. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Patients must have had a screening scan and at least 1 on study scan to be eligible for RECIST 1.1 evaluation.

Steady state mean trough serum concentrations by dose level of TRC105 after 5 weeks of dosing were measured using validated methods after 5 weeks of dosing.

Number of patients who tested positive for antibodies to TRC105 by dose level. Anti-Product Antibody (APA) concentrations were measured using validated ELISA methods.

Only patients who received at least a portion of a dose of TRC105 or sorafenib were included in the safety population. Both dose groups received 10 mg/kg TRC105 for the first month. Patients assigned to the 10 mg/kg weekly (cycle 1) then 15 mg/kg every two weeks (cycle 2+) dose group who discontinued the study prior to initiating cycle 2 dosing were counted in the 10 mg/kg weekly adverse event group.

Carotuximab (TRC105) given weekly (10 mg/kg) for 2 cycles then bi-weekly iv TRC105 (15 mg/kg) with 400mg sorafenib twice daily

Carotuximab (10 mg/kg wk to 15 mg/kg Bi-wk) Plus Sorafenib

Carotuximab (TRC105) given weekly iv (10 mg/kg) with 400mg sorafenib twice daily

Carotuximab (10 mg/kg Weekly) Plus Sorafenib

Asian

White

Black or African American

Unknown

Race/Ethnicity, Customized

United States

Region of Enrollment

Patients who received at least a portion of a dose of Carotuximab

TRC105 development has been discontinued due to lack of efficacy. Secondary endpoints including PFS, OS, duration of response, sorafenib PK, circulating angiogenic biomarkers and assessment of IGF-1-modified Child-Pugh score were not performed.

Charles Theuer

Patients must have received at least a portion of a dose of TRC105 or sorafenib to be evaluable for assessment of DLT.

Number of Patients Who Experience Dose Limiting Toxicities by Dose Level

Patients must have had a screening scan and at least 1 on study scan to be eligible for RECIST 1.1 evaluation.

Overall Response Rate (ORR)

Steady state mean trough serum concentration by dose level after 5 weeks of dosing. Patients must have received all protocol required TRC105 doses to be included in the analysis. Additional analysis were not performed as TRC105 development overall was canceled due to lack of efficacy.

Pharmacokinetic Profile of TRC105 When Given With Sorafenib

Number of patients who tested positive for antibodies to TRC105. Patients must have tested negative for TRC105 antibodies at baseline and have had an on study test performed to be included in the analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Carotuximab (TRC105) Plus Nivolumab in Patients With Metastatic NSCLC	NCT03181308	Carcinoma, Non-...	Carotuximab (TR... OPDIVO	18 Years -	Tracon Pharmaceuticals Inc.
Evaluation of TRC105 in the Treatment of Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma	NCT01381861	Recurrent Ovari... Fallopian Tube ... Primary Periton...	Carotuximab (TR...	18 Years -	Tracon Pharmaceuticals Inc.
Trial of TRC105 and Sorafenib in Patients With HCC	NCT02560779	Hepatocellular ...	Carotuximab (TR... Sorafenib	18 Years -	Tracon Pharmaceuticals Inc.
Evaluation of TRC105 in the Treatment of Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma	NCT01381861	Recurrent Ovari... Fallopian Tube ... Primary Periton...	Carotuximab (TR...	18 Years -	Tracon Pharmaceuticals Inc.

Spots Global Cancer Trial Database for carotuximab (trc105)