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Clinical Trial 19694

Cancer Type: Thoracic
Study Type: Treatment
NCT#: NCT03502746

Phase: Phase II
Principal Investigator: Chiappori, Alberto

Call 813-745-6100
or 1-800-679-0775 Learn More

Overview

Study Title

Phase II Study of Nivolumab and Ramucirumab for Patients with Previously-Treated Mesothelioma

Summary

This study will evaluate the combination of Nivolumab and Ramucirumab in patients with previously-treated mesothelioma.

Objective

PRIMARY OBJECTIVES: Evaluate response rate [complete response (CR) + partial response (PR)] of nivolumab in combination with ramucirumab in subjects with previously-treated mesothelioma. Response assessment will be performed using modified RECIST 1.1 criteria as described by Byrne et al. SECONDARY OBJECTIVE(S): Characterize adverse effects (AE) of nivolumab in combination with ramucirumab in subjects with previously-treated mesothelioma. Measure progression-free survival (PFS) rate at 24 weeks with the combination of the anti-Programmed Death 1 (PD-1) agent, nivolumab and the anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody, ramucirumab in subjects with previously-treated mesothelioma. Measure overall survival (OS) at 2 years after treatment with nivolumab in combination with ramucirumab in subjects with previously-treated mesothelioma. CORRELATIVES OBJECTIVES: Correlate programmed death-ligand 1 (PD-L1) expression in tumor tissue (from biopsy before treatment) with best clinical response (modified RECIST 1.1 criteria) in subjects with previously-treated mesothelioma. Correlate change in PD-L1 expression in tumor tissue from before therapy (assessed within 14 days before treatment) to after 4 cycles (8 weeks) of therapy with best clinical response (modified RECIST 1.1 criteria) at the end of Cycle 4 (Week 8) in subjects with previously-treated mesothelioma. Correlate cytokine genes expressions and change in tumor tissue (such as IL-1, IL-2, IL-6, GM-CSF, IL-10, IL-12, T-bet, IRF1, IFNã, CXCL1, CXCL9, CXCL10, CCL2 and 5) from before therapy (assessed within 14 days before treatment) to after 4 cycles (8 weeks) of therapy with best clinical response (modified RECIST 1.1 criteria) at the end of Cycle 4 (Week 8) in subjects with previously-treated mesothelioma. Correlate change in soluble PD-L1 level in plasma during therapy (assessed pre-dose Cycles 1 and 5 [Days 1 and 57 of treatment period, respectively]), with best clinical response (modified RECIST 1.1 criteria) at the end of Cycle 4 (Week 8) in subjects with previously-treated mesothelioma. Correlate change in number of CD8+, Granzyme B+ T cells in tumor tissue from before therapy (assessed within 14 days before treatment) to after 4 cycles (8 weeks) of therapy with best clinical response (modified RECIST 1.1 criteria) at the end of Cycle 4 (Week 8) in subjects with previously-treated mesothelioma.

Treatments

Therapies

Immunotherapy; Therapy (NOS)

Medications

BMS-936558 (Nivolumab); IMC-1121B (Ramucirumab); Nivolumab (Opdivo); Ramucirumab ()

Inclusion Criteria

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 organ 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. The two birth control methods can be either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 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 intracavity 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.

Must provide written informed consent

All previous toxicity resolved to Grade 1 or less.

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 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 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, 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.

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.

Any condition that, in the opinion of the investigator, might jeopardize the safety of the subject or interfere with protocol compliance.

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).

Other exclusions apply

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