Status and phase
Conditions
Treatments
About
This study will evaluate the combination of Nivolumab and Ramucirumab in patients with previously-treated mesothelioma.
Full 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.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
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.
Elective or planned major surgery to be performed during the course of the clinical trial.
Is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted.
Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: HIV testing is not required.
Known history of testing positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection. NOTE: Hepatitis B and Hepatitis C testing is not required.
Condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
o NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Received a live vaccine within 30 days prior to the first dose of trial treatment. Examples of live vaccines include, but are not limited to: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed.
History of interstitial lung disease or active, non-infectious pneumonitis.
Female subject is pregnant or breast-feeding.
Major blood vessel invasion or significant intratumor cavitation.
If they experience hemoptysis (defined as bright red blood or ≥ ½ teaspoon) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intratumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer.
Any condition that, in the opinion of the investigator, might jeopardize the safety of the subject or interfere with protocol compliance.
Any mental or medical condition that prevents the subject from giving informed consent or participating in the trial.
Any pathological condition that carries a high risk of bleeding (for example, tumor involving major vessels or known varices.)
Known hypersensitivity to nivolumab or ramucirumab or any of their components.
Known history of active tuberculosis.
Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, localized Gleason ≤ grade 7 prostate cancers. Subjects with other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to enrollment may be eligible for study after discussion with the sponsor-investigator
Treatment with any investigational agent within 28 days prior to study registration. The subject must have recovered from the acute toxic effects of the regimen.
Primary purpose
Allocation
Interventional model
Masking
34 participants in 1 patient group
Loading...
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal