ALDOXORUBICIN-P3-STS-01 Aldoxorubicin Clinical Reconstitution Procedure

Introduction The following procedure is for the reconstitution of aldoxorubicin drug product for use in the ALDOXORUBICIN-P3-STS-01 study. The reconstitution should be performed at room temperature. The total time allotted for reconstitution and patient infusion is not to exceed 120 minutes. This procedure requires that an initial volume is removed from the IV infusion bag prior to the injection of the reconstituted drug product. Required Materials: 1x 60 mL syringe (to remove Lactated Ringers solution) 2x 20 mL syringe (to transfer diluent and drug product) 1x timer (to record total time from reconstitution to infusion completion)

Steps 1-2 Step 1. Calculate patient Body Surface Area (BSA). Step 2. See Table 1 to determine the number of drug product vials and diluent vials required for reconstitution in order to deliver the targeted dose based on the patient’s BSA. Each lyophilized drug product vial requires one vial of diluent. Remove vials from -20˚C freezer and allow to equilibrate to room temperature for 20 minutes prior to reconstitution. Example: A 350 mg/m2 dose for a patient with a BSA of 1.5 requires 3 vials per cycle. This will require 3 vials of lyophilized drug product and 3 vials of diluent.

Step 3 Step 3: From the 250 mL Lactated Ringer’s IV infusion bag remove the volume of solution indicated in Table 1 for the respective dose and discard. Set the IV bag aside once the appropriate volume has been removed. Example: A 350 mg/m2 dose for a patient with a BSA of 1.5 requires 53 mL of reconstituted aldoxorubicin be injected into a 250 mL Lactated Ringer’s IV bag. According to Table 1; 53 mL must first be removed from the IV bag prior to injecting the reconstituted aldoxorubicin for a final infusion volume of 250 mL, yielding a final concentration of 2.1 mg/mL. Prepare the IV Bag

Reconstituting the Drug Product Step 4 Reconstituting the Drug Product Step 4: Remove 20 mL of aldoxorubicin diluent from the diluent vial using a syringe. Transfer the diluent into the vial of dried aldoxorubicin drug product. Each lyophilized vial of aldoxorubicin (200 mg) requires 20 mL of diluent for reconstitution for a final concentration of 10.0 mg/mL.

Step 5 Step 5: Gently swirl the vial of drug product and diluent to obtain a homogeneous mixture. Inspect the reconstituted solution of drug product to assure the drug is completely dissolved and there is no foreign matter present. Record time at start of reconstitution. Total time from the start of reconstitution to the end of infusion must be less than 120 minutes.

Steps 6-7 Step 6: Withdraw the required volume of reconstituted solution (according to Table 1) from the vials and transfer the solution into the IV infusion bag using a suitably sized syringe. Step 7: Gently mix the contents of the IV infusion solution completely to obtain a homogeneous mixture.

Steps 8-10 Step 8: Store the IV infusion solution at room temperature. Step 9: Begin patient infusion. Infusion must be completed no more than 120 minutes from the start of reconstitution procedure. Step 10: Retain all vials until the next monitoring visit.

Table 1. ALDOXORUBICIN-P3-STS-01 RECONSTITUTION GUIDE   Total Dose (mg) # of Aldoxorubicin Vials Per Cycle/# of Diluent Vials Per Cycle Volume of Aldoxorubicin for IV Bag Injection (mL)  Lactated Ringer's IV Bag (mL)  Volume to Remove from IV Bag (mL) Final Infusion Volume (mL) 200 2/2 20 250 220 22 240 24 260 26 280 28 300 30 320 32 340 34 360 36 380 38 400 3/3 40 420 42 440 44 460 46 480 48 500 50 520 52 540 54 560 56 580 58 600 4/4 60 620 62

Table 1. ALDOXORUBICIN-P3-STS-01 RECONSTITUTION GUIDE   Total Dose (mg) # of Aldoxorubicin Vials Per Cycle/# of Diluent Vials Per Cycle Volume of Aldoxorubicin for IV Bag Injection (mL)  Lactated Ringer's IV Bag (mL)  Volume to Remove from IV Bag (mL) Final Infusion Volume (mL) 640 4/4 64 250 660 66 680 68 700 70 720 72 740 74 760 76 780 78 800 5/5 80 820 82 840 84 860 86 880 88 900 90 920 92 940 94 960 96 980 98 1000 6/6 100 1020 102 1040 104