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

• Carotuximab (TRC105) (Drug), also known as TRC105: Anti Endoglin Antibody
• OPDIVO (Drug), also known as Nivolumab: Programmed Death Receptor-1

Primary outcomes

• Number of Participants With Dose Limiting Toxicity (DLT) [Approximately 2-8 months]: 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.

Secondary outcomes

• Response Rate [Approximately 2-8 months]: 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 Carotuximab (TRC105) Concentrations [8 weeks]: Trough (pre-dose) serum carotuximab (TRC105) concentrations will be measured using validated ELISA methods.
• Development of Immunogenicity Antibodies [Approximately 2-8 months]: Number of Participants with carotuximab (TRC105) anti-product antibodies (APA)
• Trough Nivolumab Concentrations [Approximately 2-8 months]: Trough (pre-dose) serum nivolumab concentrations will be measured using validated ELISA methods.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Histologically confirmed metastatic non-small cell lung cancer (NSCLC) with disease recurrence or progression during or after prior platinum-containing doublet chemotherapy regimen
2. Histologically confirmed metastatic non-small cell lung cancer (NSCLC) that has relapsed following prior PD-1/PD-L1 checkpoint inhibitor therapy without Grade 3 immune-related toxicity, which may or may not have included concurrent chemotherapy. Relapse following prior PD-1 checkpoint therapy is defined as confirmed progressive disease following stable disease or better (e.g., iSD, iPR, iCR) on at least 1 tumor assessment.
3. Patients with an active oncogenic driver (e.g., epidermal growth factor \[EGFR\], activin-receptor-like kinase 1 \[ALK1\], or the proto-oncogene tyrosine-protein kinase ROS-1) must have progressed on or after a US Food and Drug Administration (FDA)-approved therapy for that aberration
4. Patients who received adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery and/or radiation therapy) and developed recurrent or metastatic disease within 6 months of completing therapy are eligible.
5. Patients with recurrent disease > 6 months after adjuvant or neoadjuvant platinum-based chemotherapy, who also subsequently progressed during or after a platinum- doublet regimen given to treat the recurrence, are eligible.
6. Formalin fixed, paraffin-embedded (FFPE) tumor tissue block that permits the preparation of 20 unstained slides of tumor sample (archival) - Biopsy must be excisional, incisional, or core. Needle aspiration is insufficient. In cases where archival tumor tissue is unavailable, tumor biopsy will be required prior to treatment initiation.
7. Programmed death ligand 1 (PD-L1) determination by validated immunohistochemistry assay
8. Measurable disease by iRECIST
9. Age ≥ 18 years
10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
11. Resolution of all acute adverse events resulting from prior cancer therapies to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤ 1 or baseline (except alopecia or neuropathy)
12. Adequate organ function
13. Willingness and ability to consent for self to participate in study
14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

Exclusion Criteria:

1. Autoimmune disease requiring treatment within the past twelve months.
2. Condition requiring systemic treatment with either corticosteroids
3. History or active interstitial lung disease
4. Prior therapy with T-cell therapy, including an immune checkpoint inhibitor. Patients who received prior immune checkpoint inhibitor therapy are allowed in Expansion Cohort 2 in the absence of recurrent grade 2 (except skin, endocrine and constitutional symptoms), or ≥ 3 immune-related toxicity).
5. Prior treatment with carotuximab
6. Current treatment on another therapeutic clinical trial
7. Receipt of systemic anticancer therapy, including investigational agents, within 28 days prior to study treatment (Note: If anticancer therapy was given within 28 days prior to starting study treatment, patients are not excluded if ≥ 5 times the elimination half-life of the drug has elapsed.)
8. Major surgical procedure or significant traumatic injury within 4 weeks prior to study treatment, and must have fully recovered from any such procedure; and no date of surgery (if applicable) or anticipated need for a major surgical procedure planned within the next 6 months
9. Chest radiotherapy ≤ 28 days, 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 study treatment - Such patients must have recovered adequately from any side effects of such therapy.
10. Hypertension defined as blood pressure (BP) systolic > 150 or diastolic > 90 mm Hg (Note: Initiation or adjustment of antihypertensive medication prior to study entry is allowed provided that the average of 3 BP readings prior to study treatment is ≤150/90 mm Hg.)
11. Ascites or pericardial effusion that required intervention within 3 months prior to study treatment
12. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease
13. Angina, myocardial infarction (MI), symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack TIA), arterial embolism, pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG) within 6 months prior to study treatment
14. Deep venous thrombosis within 6 months prior to study treatment, unless the patient is anti-coagulated without the use of warfarin for ≥2 weeks prior to study treatment; in this situation, low molecular weight heparin is preferred
15. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g., hereditary hemorrhagic telangiectasia)
16. Thrombolytic use (except to maintain IV catheters) within 10 days prior study treatment
17. Known active viral or nonviral hepatitis or cirrhosis
18. Any active infection requiring systemic treatment
19. History of hemorrhage or hemoptysis (> ½ teaspoon bright red blood) within 3 months prior to study treatment
20. History of peptic ulcer within the past 3 months prior to study treatment, unless treated for the condition and complete resolution has been documented by esophagogastroduodenoscopy (EGD) within 28 days prior to study treatment
21. History of gastrointestinal perforation or fistula in the 6 months prior to study treatment, or while previously on antiangiogenic therapy, unless underlying risk has been resolved (e.g., through surgical resection or repair)
22. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness
23. Pregnancy or breastfeeding - Female patients must be surgically sterile (i.e., ≥6 weeks following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) or be postmenopausal, or must agree to use effective contraception during the study and for 3 months following last dose of carotuximab. All female patients of reproductive potential must have a negative pregnancy test (serum or urine) within 7 days prior to study treatment. Male patients must be surgically sterile or must agree to use effective contraception during the study and for at least 180 days following last dose of study drug (carotuximab or nivolumab, whichever occurs later).
24. 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.

Participant flow

Outcome results

• Number of Participants With Dose Limiting Toxicity (DLT) (Primary), Count of participants, Participants: 8 mg/kg TRC105 + Nivolumab 0; 10 mg/kg TRC105 + Nivolumab 0
• Response Rate (Secondary), Number, participants: 8 mg/kg TRC105 + Nivolumab 0; 10 mg/kg TRC105 + Nivolumab 4
• Trough Carotuximab (TRC105) Concentrations (Secondary), Mean, ng/ml: 8 mg/kg TRC105 + Nivolumab 65233 (46400 to 82700); 10 mg/kg TRC105 + Nivolumab 93600 (72600 to 121000)
• Development of Immunogenicity Antibodies (Secondary), Count of participants, Participants: 8 mg/kg TRC105 + Nivolumab 0; 10 mg/kg TRC105 + Nivolumab 0
• Trough Nivolumab Concentrations (Secondary), Mean, ng/ml: 8 mg/kg TRC105 + Nivolumab 65233 (46400 to 82700); 10 mg/kg TRC105 + Nivolumab 93600 (72600 to 121000)

Adverse events

Time frame: From screening until completion of follow-up, on average 6 months

Serious adverse events by term

Other adverse events by term

14 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2018-04-05)

• Charles Theuer, MD, PhD, Study director, Medical Monitor