Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
NSCLC, Immunotherapy, Ramucirumab, anti-PD-1
Brief summary
This is a non-randomized, phase-II study of platinum doublet chemotherapy plus ramucirumab in patients with advanced NSCLC who have progressed on first line anti-PD-1 Immunotherapy. Up to 25 evaluable participants will be enrolled over a period of 2 years. Seven patients will be recruited at the first stage .Eligible patients would include those treated with a PD-1 inhibitor as primary therapy and exhibit evidence of disease progression, but maintain a good performance status. The investigators hypothesize that immune therapy acts as chemo-sensitizer and patients treated with standard platinum-based combination chemotherapy with the addition of the anti-angiogenic agent Ramucirumab, after immunotherapy will have higher response rates
Detailed description
OBJECTIVES: Primary Objective 1. To assess the objective response rate to a three-drug regimen (a platinum doublet plus an anti-angiogenic agent) in patients with non-small cell lung cancer who fail to respond, or progress after an initial response, to primary therapy with an immune checkpoint inhibitor. 2. To assess the toxicity profile of the three-drug regimen in this population compared to historical treatment-naïve population (as published in literature) Exploratory Objective 1. To investigate the role of peripheral blood CD 8+ T cells, absolute eosinophil count (AEC) and circulating tumor cells (CTC) as biomarkers of response to salvage chemotherapy after primary immunotherapy 2. To investigate the role of plasma carbonic anhydrase IX level as predictive biomarker of response to ramucirumab.
Interventions
DRUGRamucirumab
platinum doublets chemotherapy plus ramucirumab, intravenously(IV)
Sponsors
ROGER S KERESZTES MD
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 stage IV NSCLC per 8th IASCL (International Association for the Study of Lung Cancer) of squamous and non-squamous histology, with progression on first line anti-PD1 immunotherapy. 2. Oligo-metastatic stage IV patients who received concurrent chemotherapy with thoracic radiation, followed by durvalumab consolidation and had progression of disease. 3. Locally advanced un-resectable NSCLC patients who received concurrent chemotherapy with thoracic radiation, followed by durvalumab consolidation and had progression of disease. 4. Males or females at least 18 years of age. 5. ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. 6. Measureable disease by CT or MRI per RECIST 1.1 criteria. 7. Life expectancy of at least 3 months. 8. Resolution of all clinically significant toxic effects of prior anticancer therapy to Grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. 9. The participant must have adequate organ function, defined as: * Total bilirubin less than or equal to the upper limit of normal value (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN, or ≤5 x ULN if the transferase elevation was due to liver metastases. * Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥50 mL/min (per the Cockcroft-Gault formula or equivalent and/or 24-hour urine collection \[Cockcroft-Gault glomerular filtration rate = (140-age) \* (Wt in kg) \* (0.85 if female) / (72 \* Cr) where Cr is serum creatinine\]). * Absolute neutrophil count (ANC) ≥1.5 x 103/μL (≥1.5 x 109/L), hemoglobin ≥10.0 g/dL (≥ 6.2 mmol/L), and platelets ≥100 x 103/μL (≥100 x 109/L). * International Normalized Ratio (INR) less than or equal to 1.5, or prothrombin time and partial thromboplastin time less than or equal to 1.5 x ULN. * The participant does not have cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis. 10. Urinary protein is ≤1+ on dipstick or routine urinalysis (UA). If urine dipstick or routine analysis indicated proteinuria ≥2+, then a 24-hour urine must be collected and must demonstrate \<1000 mg of protein in 24 hours to allow participation in the study. 11. Female subjects must have a negative urine or serum pregnancy test at screening (within 72 hours of first dose of study medication) if of childbearing potential or be of non-child bearing potential. 12. If of childbearing potential, female subjects must be willing to use two adequate barrier methods throughout the study, starting with the screening visit through 180 days after last dose of chemotherapeutic agents. Note: Abstinence is acceptable if this is the established and preferred contraception. 13. Male subjects with a female partner(s) of child-bearing potential must agree to use two adequate barrier methods throughout the trial starting with the screening visit through 180 days after the last dose of chemotherapy. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner. 14. The participant has voluntarily agreed to participate by giving written informed consent for the trial.
Exclusion criteria
1. Participant has received prior cytotoxic therapy or targeted oral agents for the treatment of their stage IV NSCLC. Participants with oligo-metastatic stage IV disease who received concurrent chemotherapy with thoracic radiation, followed by durvalumab consolidation with disease progression were eligible. 2. Participant has an EGFR (epidermal growth factor receptor) sensitizing mutation, ALK translocation and/or an ROS-1 gene rearrangement. 3. Participant has undergone major surgery within 28 days prior to screening, or subcutaneous venous access device placement within 7 days prior to screening. Furthermore, any partcipant with postoperative bleeding complications or wound complications from a surgical procedure performed in the last 2 months will be excluded. 4. Participant has untreated CNS (central nervous system) metastases. Participants with treated brain metastases were eligible if they were clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to screening, or after surgical resection performed at least 28 days prior to screening. No evidence of Grade ≥1 CNS hemorrhage based on pretreatment MRI or IV contrast CT scan (performed within 21 days before screening). 5. There is radiologically documented evidence of major blood vessel invasion or encasement by cancer. 6. There is radiographic evidence of intra-tumor cavitation, regardless of tumor histology. 7. Participant has a history of uncontrolled hereditary or acquired thrombotic disorder. 8. Participant has a history of gross hemoptysis (defined as bright red blood or ≥1/2 teaspoon) within 2months prior to screening. 9. Participant has clinically relevant congestive heart failure (CHF; NYHA II-IV) or symptomatic or poorly controlled cardiac arrhythmia. 10. Participant has experienced any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to screening. 11. Participant has uncontrolled arterial hypertension ≥150 / ≥90 mm Hg despite standard medical management. 12. Participant has a serious or non-healing wound, ulcer, or bone fracture within 28 days prior to screening. 13. Participant has significant bleeding disorders, vasculitis, or experienced Grade 3-4 gastrointestinal (GI) bleeding within 3 months prior to screening. 14. History of GI perforation and/or fistulae within 6 months prior to screening. 15. Participant has bowel obstruction,history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea. 16. Participant has peripheral neuropathy ≥Grade 2 (NCI-CTCAE v 4.0). 17. Participant has a serious illness or medical condition(s) including, but not limited to, the following: * Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness. * Active or uncontrolled clinically serious infection. * Previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumours treated curatively and without evidence of recurrence for at least 3 years prior to screening. * Uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induced a high medical risk and/or made assessment of survival uncertain. * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that might increase the risk associated with study participation or study drug administration, or might interfere with the interpretation of study results, and in the judgment of the investigator made the patient ineligible for entry into this study. * Participant has significant third-space fluid retention (for example, ascites or pleural effusion), and is not amenable for required repeated drainage. * Known allergy or hypersensitivity reaction to any of the treatment components. * Participant has a known history of active drug abuse.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Objective Response Per RECIST 1.1 as Assessed by Central Imaging | ≥18 weeks, up to maximum of 12 months | Objective response (OR) is the occurrence of CR or PR as the best overall response. OR will be based on responses confirmed using the subsequent 6-weekly scan. OR is based on the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) 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. |
| Number of Participants With Treatment Related Dose Delay or Treatment Discontinuation | Through study completion, up to a maximum of 12 months. Serious AEs: Up to 90 days after last dose of study treatment, Other AEs: Up to 30 days after last dose of study treatment | Adverse events will be recorded in relation to each cycle of treatment and graded according to CTCAE criteria. The toxicity co-primary outcome measure for the trial is defined as the occurrence of a treatment-related dose delay or treatment discontinuation due to toxicity |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab Ramucirumab 10 mg/kg IV day 1, every 3 weeks for 4 cycles
Ramucirumab: platinum doublets chemotherapy plus ramucirumab, intravenously(IV) | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Ramucirumab |
|---|---|
| Age, Customized Age Range 58-66 years | 3 participants |
| Race/Ethnicity, Customized white,non-Hispanic | 3 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 3 / 3 |
Outcome results
Primary
Number of Participants With Objective Response Per RECIST 1.1 as Assessed by Central Imaging
Objective response (OR) is the occurrence of CR or PR as the best overall response. OR will be based on responses confirmed using the subsequent 6-weekly scan. OR is based on the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) 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.
Time frame: ≥18 weeks, up to maximum of 12 months
Population: Data were not collected
Primary
Number of Participants With Treatment Related Dose Delay or Treatment Discontinuation
Adverse events will be recorded in relation to each cycle of treatment and graded according to CTCAE criteria. The toxicity co-primary outcome measure for the trial is defined as the occurrence of a treatment-related dose delay or treatment discontinuation due to toxicity
Time frame: Through study completion, up to a maximum of 12 months. Serious AEs: Up to 90 days after last dose of study treatment, Other AEs: Up to 30 days after last dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ramucirumab | Number of Participants With Treatment Related Dose Delay or Treatment Discontinuation | 3 Participants |