Principal Investigator: Arek Dudek, MD, PhD
Study Sponsor: Hoosier Cancer Research Network
Location: Regions Cancer Care Center
Phase of Study: Phase 2
Purpose of Study:
To assess whether the combination of immunotherapy and a drug that works to block the formation of new cancer blood vessels will stop the growth of mesothelioma. The current standard treatment for mesothelioma it to receive pemetrexed with a platinum-based chemotherapy. However, there is currently no standard treatment once pemetrexed in combination with a platinum-based chemotherapy is no longer working. People who are not in a study are usually treated with a different type of chemotherapy (vinorelbine, gemcitabine, or paclitaxel), immunotherapy, or with a drug that works to block the formation of new cancer blood vessels.
The immune system functions to protect your body against “foreign” invaders such as cancer by making special cells called T-cells. Over time cancer cells have developed a way to hide or camouflage themselves from the immune system by expressing a protein on their surface called PD-L1. When PD-L1 on the cancer cells binds to PD-1 on your immune system’s T-cells the immune system is turned off and no longer works to attack cancer cells. Nivolumab is an immunotherapy drug that works by blocking PD-1 receptor on T-cells from being able to bind PD-L1 released by cancer cells. This allows your immune system’s T-cells to recognize cancer cells as “foreign” and continue to attack the cancer cells.
Cancer, including mesothelioma, needs to make new blood vessels in order to survive and grow. People with advanced mesothelioma who are not in a study are sometimes treated with a class of drugs that block the formation of new blood vessels. These drugs are termed anti-angiogenic drugs. Two drugs in this class of medications are called bevacizumab and ramucirumab. Bevacizumab has been studied in mesothelioma, while ramucirumab has not.
– 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 1.
– Adequate blood counts and renal, bone marrow, and hepatic function
– Subjects on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). Patients receiving warfarin must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy. For heparin and LMWH there should be no active bleeding (that is, no bleeding within 14 days prior to first dose of protocol therapy) or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices).
– Women of childbearing potential (WOCP) must be willing to use two methods of birth control. WOCP should begin using birth control from the screening visit, throughout the study period, and up to 161 days (about 5 months) following the last dose of study drugs.
– Men who are not surgically or medically sterile must agree to use an acceptable method of contraception. Male subjects with female sexual partners who are pregnant, possibly pregnant, or who could become pregnant during the study must agree to use condoms with spermicide from the date of the first dose of study drug, throughout the study period, and through at least 217 days (about 7 months) after the last dose of study drug. Total abstinence for the same study period is an acceptable alternative.
– Measurable disease, defined as at least 1 tumor that fulfills the criteria for a target lesion according to modified RECIST 1.1 criteria, and obtained by imaging within 28 days prior to study registration.
– Prior intra-cavity cytotoxic or sclerosing agents (including bleomycin) is acceptable.
– Radiation therapy must be completed > 28 days before study registration, and the measurable disease must be outside of the radiation port.
– Pemetrexed-containing chemotherapy must be completed > 28 days before study registration.
– All previous toxicity resolved to Grade 1 or less.
– 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.
– 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.
– Received a live vaccine within 30 days prior to the first dose of trial treatment.
– 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, Gleason ≤ grade 7 prostate cancers, or other cancer for which the subject has been disease-free for at least 5 years.
– 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.
Lisa Wahowske, RN, BSN, OCN