Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
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.
Interventions
Anti Endoglin Antibody
DRUGOPDIVO
Programmed Death Receptor-1
Sponsors
Tracon Pharmaceuticals Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 8 mg/kg TRC105 Plus Nivolumab Dose Level 1 8 mg/kg TRC105 + Nivolumab Carotuximab (TRC105): Anti Endoglin Antibody OPDIVO (Nivolumab): Programmed Death Receptor-1 | 3 |
| 10 mg/kg TRC105 Plus Nivolumab Dose Level 2 10 mg/kg TRC105 + Nivolumab Carotuximab (TRC105): Anti Endoglin Antibody OPDIVO (Nivolumab): Programmed Death Receptor-1 | 8 |
| Total | 11 |
Baseline characteristics
| Characteristic | 10 mg/kg TRC105 Plus Nivolumab | Total | 8 mg/kg TRC105 Plus Nivolumab |
|---|---|---|---|
| Age, Continuous | 59 years | 59 years | 58 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 11 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 9 Participants | 3 Participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 8 |
| other Total, other adverse events | 3 / 3 | 8 / 8 |
| serious Total, serious adverse events | 0 / 3 | 4 / 8 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicity (DLT)
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.
Time frame: Approximately 2-8 months
Population: All patients who received at least a portion of a dose of any study drug (TRC105, Nivolumab)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 8 mg/kg TRC105 + Nivolumab | Number of Participants With Dose Limiting Toxicity (DLT) | Patients with DLT at 8 mg/kg | 0 Participants |
| 8 mg/kg TRC105 + Nivolumab | Number of Participants With Dose Limiting Toxicity (DLT) | Patients with DLT at 10 mg/kg | 0 Participants |
| 8 mg/kg TRC105 + Nivolumab | Number of Participants With Dose Limiting Toxicity (DLT) | Patients without DLT at 8 mg/kg | 3 Participants |
| 8 mg/kg TRC105 + Nivolumab | Number of Participants With Dose Limiting Toxicity (DLT) | Patients without DLT at 10 mg/kg | 0 Participants |
| 10 mg/kg TRC105 + Nivolumab | Number of Participants With Dose Limiting Toxicity (DLT) | Patients without DLT at 8 mg/kg | 0 Participants |
| 10 mg/kg TRC105 + Nivolumab | Number of Participants With Dose Limiting Toxicity (DLT) | Patients with DLT at 8 mg/kg | 0 Participants |
| 10 mg/kg TRC105 + Nivolumab | Number of Participants With Dose Limiting Toxicity (DLT) | Patients without DLT at 10 mg/kg | 8 Participants |
| 10 mg/kg TRC105 + Nivolumab | Number of Participants With Dose Limiting Toxicity (DLT) | Patients with DLT at 10 mg/kg | 0 Participants |
Secondary
Development of Immunogenicity Antibodies
Number of Participants with carotuximab (TRC105) anti-product antibodies (APA)
Time frame: Approximately 2-8 months
Population: 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.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 8 mg/kg TRC105 + Nivolumab | Development of Immunogenicity Antibodies | Ptn without treatment emergent ADA | 3 Participants |
| 8 mg/kg TRC105 + Nivolumab | Development of Immunogenicity Antibodies | Ptn with low titer treatment emergent ADA | 0 Participants |
| 10 mg/kg TRC105 + Nivolumab | Development of Immunogenicity Antibodies | Ptn with low titer treatment emergent ADA | 0 Participants |
| 10 mg/kg TRC105 + Nivolumab | Development of Immunogenicity Antibodies | Ptn without treatment emergent ADA | 3 Participants |
Secondary
Response Rate
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.
Time frame: Approximately 2-8 months
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 8 mg/kg TRC105 + Nivolumab | Response Rate | iPR (Immune Partial Response) Best Response | 1 participants |
| 8 mg/kg TRC105 + Nivolumab | Response Rate | iCR (Immune Complete Response) Best Response | 0 participants |
| 8 mg/kg TRC105 + Nivolumab | Response Rate | iPD (Immune Progressive Disease) Best Response | 0 participants |
| 8 mg/kg TRC105 + Nivolumab | Response Rate | iUPD (Unconfirmed Immune PD) Best Response | 2 participants |
| 8 mg/kg TRC105 + Nivolumab | Response Rate | iSD (Immune Stable Disease) Best Response | 0 participants |
| 10 mg/kg TRC105 + Nivolumab | Response Rate | iUPD (Unconfirmed Immune PD) Best Response | 3 participants |
| 10 mg/kg TRC105 + Nivolumab | Response Rate | iSD (Immune Stable Disease) Best Response | 4 participants |
| 10 mg/kg TRC105 + Nivolumab | Response Rate | iPR (Immune Partial Response) Best Response | 0 participants |
| 10 mg/kg TRC105 + Nivolumab | Response Rate | iPD (Immune Progressive Disease) Best Response | 0 participants |
| 10 mg/kg TRC105 + Nivolumab | Response Rate | iCR (Immune Complete Response) Best Response | 0 participants |
Secondary
Trough Carotuximab (TRC105) Concentrations
Trough (pre-dose) serum carotuximab (TRC105) concentrations will be measured using validated ELISA methods.
Time frame: 8 weeks
Population: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 8 mg/kg TRC105 + Nivolumab | Trough Carotuximab (TRC105) Concentrations | 65233 ng/ml |
| 10 mg/kg TRC105 + Nivolumab | Trough Carotuximab (TRC105) Concentrations | 93600 ng/ml |
Secondary
Trough Nivolumab Concentrations
Trough (pre-dose) serum nivolumab concentrations will be measured using validated ELISA methods.
Time frame: Approximately 2-8 months
Population: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 8 mg/kg TRC105 + Nivolumab | Trough Nivolumab Concentrations | 65233 ng/ml |
| 10 mg/kg TRC105 + Nivolumab | Trough Nivolumab Concentrations | 93600 ng/ml |