Phase II Study of Nivolumab and Ramucirumab for Patients With Previously-Treated Mesothelioma:Hoosier Cancer Research Network LUN15-299
Overview
- Phase
- Phase 2
- Intervention
- Nivolumab
- Conditions
- Mesothelioma, Malignant
- Sponsor
- Arkadiusz Z. Dudek, MD
- Enrollment
- 34
- Locations
- 4
- Primary Endpoint
- Response Rate
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This study will evaluate the combination of Nivolumab and Ramucirumab in patients with previously-treated mesothelioma.
Detailed Description
The programmed death ligand 1 (PD-L1) \[16\] and VEGFR2 \[34\] are highly-expressed on mesothelioma cells, and are therefore attractive options for this cancer. We chose to study the combination of ramucirumab with nivolumab because of the potential efficacy of these two agents in mesothelioma and because of the potential synergistic activity between them \[30\]. As previously discussed, immunotherapies such as anti-PD-1 inhibitors must contend with a hostile, immunosuppressive tumor microenvironment due to angiogenesis that results in hypoxia. This hypoxia decreases the ability of antibodies to infiltrate the tumor. We hypothesize that the normalization of tumor vasculature (by reducing the area of the tumor that is hypoxic) with an anti-VEGF strategy (i.e., ramucirumab) used in synergy with a PD-1 inhibitor will facilitate the infiltration of T-lymphocytes into tumor parenchyma. We will conduct a phase II study based on this premise using nivolumab and ramucirumab as second-line therapy in patients with malignant mesothelioma who have failed standard doublet platinum and anti-folate therapy.
Investigators
Arkadiusz Z. Dudek, MD
Sponsor-Investigator
Hoosier Cancer Research Network
Eligibility Criteria
Inclusion Criteria
- •Male or female ≥ 18 years of age at time of consent.
- •Histologically-confirmed malignant mesothelioma not amenable to curative surgery and who have received at least one pemetrexed-containing chemotherapy regimen.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •total bilirubin \< 1.5 mg/dL (25.65 μmol/L) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 mg/dL (except subject with Gilbert's Syndrome, who can have total bilirubin \< 3.0 mg/dl)
- •aspartate aminotransferase (AST) ≤ 3 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
- •alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
- •hemoglobin ≥ 8 g/dL, subjects requiring transfusion will not be eligible to start study
- •absolute neutrophil count (ANC) ≥ 1.5 × 109/L
- •platelet count ≥ 100 × 109/L
- •serum creatinine ≤1.5 times the ULN, or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute (that is, if serum creatinine is \>1.5 times the ULN, a 24-hour urine collection to calculate creatinine clearance must be performed)
Exclusion Criteria
- •Any Grade 3-4 GI bleeding within 3 months prior to study registration.
- •History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to study registration.
- •Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to study registration.
- •Cirrhosis at a level of Child-Pugh B (or worse), or cirrhosis (any degree) with a history of hepatic encephalopathy, or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.
- •Uncontrolled or poorly-controlled hypertension (\>160 mmHg systolic or \> 100 mmHg diastolic for \>4 weeks) despite standard medical management.
- •Prior history of GI perforation/fistula (within 6 months of study registration) or risk factors for perforation.
- •Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to study registration.
- •Active brain metastases or carcinomatous meningitis. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of study drugs and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to study registration. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
- •Major surgery within 28 days prior to study registration
- •Subcutaneous venous access device placement within 7 days prior to study registration.
Arms & Interventions
Nivolumab + Ramucirumab
Nivolumab 240mg IV + Ramucirumab 8mg/kg IV
Intervention: Nivolumab
Nivolumab + Ramucirumab
Nivolumab 240mg IV + Ramucirumab 8mg/kg IV
Intervention: Ramucirumab
Outcomes
Primary Outcomes
Response Rate
Time Frame: Up to a maximum of 23 months
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Response rate will be defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1.
Secondary Outcomes
- Overall Survival(Time of treatment start until death or date of last contact, up to a maximum of 32 months.)
- Adverse Event Assessment(AE had been recorded from time of consent until 100 days after discontinuation of study drug or until a new anti-cancer treatment starts, whichever occurs first; up to a maximum of 28 months.)
- Progression-free Survival (PFS)(Time of treatment start until the criteria for disease progression or death, up to a maximum of 23 months.)