Pittsburgh, PA: Oncology Nursing Society. Manufactured for: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA Made in Italy 1192978A2 Rev September 2010 15 Reference ID: 3006561 Protocol ADU-CL-02-v8Aduro Biotech, Inc. CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 121 Aduro Biotech , Inc. Protocol ADU -CL-02-v8 CRS -207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 APPENDIX E CYCL OPHOSPHAMIDE Prescribing Information Page 122 page 1 of 9CYCLOPHOSPHAMIDE - cyclophosphamide injection, powder, for solution Baxter Healthcare Corporation DESCRIPTION Cyclophosphamide for Injection, USP is a sterile white powder containing cyclophosphamide monohydrate. Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. Cyclophosphamide is a white crystalline powder with the molecular formula C 7H15CI2N2O2P•H 2O and a molecular weight of 279.1. The chemical name for cyclophosphamide is 2-[bis(2- chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate. Cyclophosphamide is soluble in water, saline, orethanol and has the following structural formula: CLINICAL PHARMACOLOGY Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxi dase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA.Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than 75%. The unchanged drug has anelimination half-life of 3 to 12 hours. It is eliminated primarily in the form of metabolites, but from 5 to 25% of the dose is excreted inurine as unchanged drug. Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma. Concentrat ions of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose. Plasma protein binding of unchanged drug is lowbut some metabolites are bound to an extent greater than 60%. It has not been demonstrated that any single metabolite is respon sible for either the therapeutic or toxic effects of cyclophosphamide. Although elevated levels of metabolites of cyclophosphamide ha ve been observed in patients with renal failure, increased clinical toxicity in such patients has not been demonstrated. INDICATIONS AND USAGE Malignant Diseases Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially wi th other antineoplastic drugs. The following malignancies are often susceptible to cyclophosphamide treatment: 1. Malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma. 2.