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(12) Patent Application Publication (10) Pub. No.: US 2011/0160159 A1 Ryan (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2011/0160159 A1 Ryan (43) Pub US 2011 016O159A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0160159 A1 Ryan (43) Pub. Date: Jun. 30, 2011 (54) TREATMENT OF CANCER 61/381.851, filed on Sep. 10, 2010, provisional appli cation No. 61/332,150, filed on May 6, 2010. (76) Inventor: John Ryan, Philadelphia, PA (US) Publication Classification 21) Appl. No.: 12/883,084 (51) Int. Cl. (21) Appl. No 9 A63L/724 (2006.01) 22) Filed: Sep.15, 2010 A6IP35/00 (2006.01) (22) File ep. 15, (52) U.S. Cl. .......................................................... 514/58 Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 61/242,752, filed on Sep. Provided are methods relating to compositions that include a 15, 2009, provisional application No. 61/317,039, CDP-topoisomerase inhibitor, e.g., a CDP-camptothecin or filed on Mar. 24, 2010, provisional application No. camptothecin derivative conjugate, e.g., CRLX101. Structure and description of CDP-camptothecin conjugate "CRLX101." O ) Oi O O Y v/OH 4 HO O O HO O O HNS O OH O N t H N-SS- HO -S o/). N-), O O OHIOO O O YO O In the above structure: n = about 77 or the molecular weight of the PEG moiety is from about 3060 to about 3740 (e.g., about 3400) Da; m at is from about 10 to about 18 (e.g., about 14), the molecular weight of the polymer backbone (i.e., the polymer minus the CPT-gly, which results in the Cysteine moieties having a free-C(O)CH) is from about 48 to about 85 kDa, the polydispersity of the polymer backbone is less than about 2.2, and the loading of the CPT onto the polymer backbone is from about 6 to about 13% by weight, wherein 13% is theoretical maximum, meaning, in some instances, one or more of the cysteine residues has a free-C(O)OH (i.e., it lacks the CPT-gly). Patent Application Publication Jun. 30, 2011 Sheet 1 of 4 US 2011/O16O159 A1 FIG. 1A FIG. 1 B Patent Application Publication Jun. 30, 2011 Sheet 2 of 4 US 2011/O16O159 A1 F.G. 2A FIG. 2B A B 30 es S. s So 220 X S c s c s 3 O 10 SS 0 25 50 75 100 125 150. 175 O 0-24 hrs 24-48 hrs Time (hr) Patent Application Publication Jun. 30, 2011 Sheet 3 of 4 US 2011/O16O159 A1 F.G. 3A FIG. 3B 250 ng total protein 500 ng total protein SC DNA Wock rx Pre Day 2 Day 25 Pe. Day 2 Day 25 relaxed Relaxed Relaxed form form Supercoiled DNA --> F.G. 3C Patent Application Publication Jun. 30, 2011 Sheet 4 of 4 US 2011/O16O159 A1 Figure 4: Structure and description of CDP-camptothecin conjugate "CRLX101." O O OH O O- O ()- O HHO O O O O O in the above structure: n = about 77 or the molecular weight of the PEG moiety is from about 3060 to about 3740 (e.g., about 3400) Da; m F is from about 10 to about 18 (e.g., about 14); the molecular weight of the polymer backbone (i.e., the polymer minus the CPT-gly, which results in the cysteine moieties having a free -C(O)OH) is from about 48 to about 85 kDa, the polydispersity of the polymer backbone is less than about 2.2, and the loading of the CPT onto the polymer backbone is from about 6 to about 13% by weight, wherein 13% is theoretical maximum, meaning, in Some instances, one or more of the cysteine residues has a free -C(O)OH (i.e., it lacks the CPT-gly). US 2011/O160 159 A1 Jun. 30, 2011 TREATMENT OF CANCER 0011. In an embodiment, the drug is provided at 18-60 mg/m/month, e.g., 18-30 mg/m/month, 24-30 mg/m2/ CLAIM OF PRIORITY month or 36-60 mg/m/month. 0012. In an embodiment, the conjugate includes a topoi 0001. This application claims priority to U.S. Ser. No. somerase I inhibitor and/or a topoisomerase II inhibitor. In an 61/242,752, filed Sep. 15, 2009; U.S. Ser. No. 61/317,039, embodiment, the conjugate includes atopoisomerase I inhibi filed Mar. 24, 2010; U.S. Ser. No. 61/332,150, filed May 6, tor or combination of topoisomerase I inhibitors, e.g., camp 2010; and U.S. Ser. No. 61/381,851, filed Sep. 10, 2010, the tothecin, irinotecan, SN-38, topotecan, lamellarin D and contents of each of which are incorporated herein by refer derivatives thereof. In an embodiment, the conjugate includes CCC. a topoisomerase II inhibitor or a combination of topoi Somerase II inhibitors, e.g., eptoposide, tenoposide, doxoru BACKGROUND OF THE INVENTION bicin and derivatives thereof. In one embodiment, the conju 0002 Drug delivery and dosing of small molecule thera gate includes a combination of one or more topoisomerase I peutic agents, such as camptothecin, can be problematic due inhibitors and one or more topoisomerase II inhibitors. In an to a number issues including half-life, toxicity, distribution embodiment, the CDP-topoisomerase inhibitor conjugate is a etc. CDP-camptothecin or camptothecin derivate conjugate, e.g., a CDP-camptothecin or camptothecin derivative conjugate SUMMARY OF THE INVENTION described herein, e.g., CRLX101. 0013. In one embodiment, the CDP-topoisomerase inhibi 0003. In one aspect, the disclosure features, a method of tor conjugate, particle or composition, e.g., a CDP-camptoth treating a proliferative disorder, e.g., a cancer, in a subject. ecin or camptothecin derivative, a CDP-camptothecin or The method comprises: camptothecin derivative conjugate, particle or composition 0004 providing an initial administration of a CDP-topoi described herein, e.g., CRLX101, is administered by intrave Somerase inhibitor conjugate, particle or composition, e.g., a nous administration over a period equal to or less than about CDP-camptothecin conjugate, particle or composition or 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, camptothecin derivative conjugate, particle or composition, 150 minutes, or 180 minutes. In one embodiment, the CDP e.g., a CDP-camptothecin conjugate, particle or composition topoisomerase inhibitor conjugate, particle or composition, or camptothecin derivative conjugate, particle or composition e.g., a CDP-camptothecin or camptothecin derivative conju described herein, e.g., CRLX101, to said subject at a dosage gate, particle or composition, e.g., the CDP-camptothecin or of 6 mg/m, 7 mg/m, 8 mg/m, 9 mg/m, 10 mg/m, 11 camptothecin derivative conjugate, particle or composition mg/m, 12 mg/m, 13 mg/m, 14 mg/m, 15 mg/m, 16 described herein, e.g. CRLX101, is administered at a dosage mg/m, 17 mg/m, 18 mg/m, 19 mg/m, 20 mg/m, 21 of 6 mg/m, 7 mg/m, 8 mg/m, 9 mg/m, 10 mg/m, 11 mg/m, 22 mg/m, 23 mg/m, 24 mg/m, 25 mg/m, 26 mg/m, 12 mg/m, 13 mg/m, 14 mg/m, 15 mg/m, 16 mg/m, 27 mg/m, 28 mg/m, 29 mg/m or 30 mg/m. mg/m, 17 mg/m, 18 mg/m. 19 mg/m. 20 mg/m, 21 (wherein said dosage is expressed in mg of drug, as opposed mg/m, 22 mg/m, 23 mg/m, 24 mg/m, 25 mg/m, 26 to mg of conjugate) and mg/m, 27 mg/m, 28 mg/m, 29 mg/m or 30 mg/m by 0005 optionally, providing one or more subsequent intravenous administration over a period equal to or less than administrations of said CDP-topoisomerase inhibitor conju about 30 minutes, 45 minutes, 60 minutes or 90 minutes, e.g., gate, particle or composition, e.g., a CDP-camptothecin con a period equal to or less than 30 minutes, 45 minutes or 60 jugate, particle or composition or camptothecin derivative minutes. conjugate, particle or composition, e.g., a CDP-camptothecin 0014. In one embodiment, the CDP-topoisomerase inhibi conjugate, particle or composition or camptothecin derivative tor conjugate, particle or composition, e.g., a CDP-camptoth conjugate, particle or composition described herein, e.g., ecin or camptothecin derivative, a CDP-camptothecin or CRLX101, at a dosage of 6 mg/m, 7 mg/m, 8 mg/m, 9 camptothecin derivative conjugate, particle or composition mg/m, 10 mg/m, 11 mg/m, 12 mg/m, 13 mg/m, 14 described herein, e.g., CRLX101, is administered by intrave mg/m, 15 mg/m, 16 mg/m, 17 mg/m, 18 mg/m, 19 nous administration overa period of about 12 hours, 15 hours, mg/m. 20 mg/m, 21 mg/m, 22 mg/m, 23 mg/m, 24 18 hours, 21 hours, 24 hours, 27 hours, or 30 hours. In one mg/m, 25 mg/m, 26 mg/m, 27 mg/m, 28 mg/m, 29 embodiment, the CDP-topoisomerase inhibitor conjugate, mg/m or 30 mg/m, wherein each subsequent administration particle or composition, e.g., a CDP-camptothecin or camp is provided, independently, between 9, 10, 11, 12, 13, 14, 15 tothecin derivative conjugate, particle or composition, e.g., or 16 days after the previous, e.g., the initial, administration, the CDP-camptothecin or camptothecin derivative conjugate, to thereby treat the proliferative disorder. particle or composition described herein, e.g. CRLX101, is 0006. In an embodiment, the dosage of at least 2, 3, 4, 5, 6, administered at a dosage of 6 mg/m, 7 mg/m, 8 mg/m, 9 7, 8, 9, 10, 12, 15 or 20 administrations is the same.
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