Alternative Dosing for CRLX101(NLG207) Alone, With Avastin and With mFOLFOX6 in Advanced Solid Tumors

Summary

The purpose of this study is to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of weekly dosing of CRLX101 (both as monotherapy; (Schedule 1) and in combination with bevacizumab every 2 weeks (Schedule 2) and weekly with a 3 week on / 1 week off schedule in combination with mFOLFOX6 (Schedule 3) to affirm the dose for future clinical studies.

Timeline

Start

2015-10

Primary completion

2017-10-17

Completion

2018-05-07

Publications

• Background Kummar S, Raffeld M, Juwara L, Horneffer Y, Strassberger A, Allen D, Steinberg SM, Rapisarda A, Spencer SD, Figg WD, Chen X, Turkbey IB, Choyke P, Murgo AJ, Doroshow JH, Melillo G. Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1alpha in advanced solid tumors. Clin Cancer Res. 2011 Aug 1;17(15):5123-31. doi: 10.1158/1078-0432.CCR-11-0682. Epub 2011 Jun 14.
• Background Eliasof S, Lazarus D, Peters CG, Case RI, Cole RO, Hwang J, Schluep T, Chao J, Lin J, Yen Y, Han H, Wiley DT, Zuckerman JE, Davis ME. Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15127-32. doi: 10.1073/pnas.1309566110. Epub 2013 Aug 26.
• Background Schluep T, Hwang J, Cheng J, Heidel JD, Bartlett DW, Hollister B, Davis ME. Preclinical efficacy of the camptothecin-polymer conjugate IT-101 in multiple cancer models. Clin Cancer Res. 2006 Mar 1;12(5):1606-14. doi: 10.1158/1078-0432.CCR-05-1566.
• Background Numbenjapon T, Wang J, Colcher D, Schluep T, Davis ME, Duringer J, Kretzner L, Yen Y, Forman SJ, Raubitschek A. Preclinical results of camptothecin-polymer conjugate (IT-101) in multiple human lymphoma xenograft models. Clin Cancer Res. 2009 Jul 1;15(13):4365-73. doi: 10.1158/1078-0432.CCR-08-2619. Epub 2009 Jun 23.
• Background Pham E, Birrer MJ, Eliasof S, Garmey EG, Lazarus D, Lee CR, Man S, Matulonis UA, Peters CG, Xu P, Krasner C, Kerbel RS. Translational impact of nanoparticle-drug conjugate CRLX101 with or without bevacizumab in advanced ovarian cancer. Clin Cancer Res. 2015 Feb 15;21(4):808-18. doi: 10.1158/1078-0432.CCR-14-2810. Epub 2014 Dec 18.
• Background Gaur S, Chen L, Yen T, Wang Y, Zhou B, Davis M, Yen Y. Preclinical study of the cyclodextrin-polymer conjugate of camptothecin CRLX101 for the treatment of gastric cancer. Nanomedicine. 2012 Jul;8(5):721-30. doi: 10.1016/j.nano.2011.09.007. Epub 2011 Oct 25.
• Background Rapisarda A, Melillo G. Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol. 2012 Apr 24;9(7):378-90. doi: 10.1038/nrclinonc.2012.64.
• Background Rapisarda A, Zalek J, Hollingshead M, Braunschweig T, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Hewitt SM, Shoemaker RH, Melillo G. Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res. 2004 Oct 1;64(19):6845-8. doi: 10.1158/0008-5472.CAN-04-2116.
• Background Conley SJ, Baker TL, Burnett JP, Theisen RL, Lazarus D, Peters CG, Clouthier SG, Eliasof S, Wicha MS. CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, targets cancer stem cells and impedes resistance to antiangiogenic therapy in mouse models of breast cancer. Breast Cancer Res Treat. 2015 Apr;150(3):559-67. doi: 10.1007/s10549-015-3349-8. Epub 2015 Apr 2.
• Background Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. doi: 10.1016/S0140-6736(07)61904-7.
• Background Weiss GJ, Chao J, Neidhart JD, Ramanathan RK, Bassett D, Neidhart JA, Choi CHJ, Chow W, Chung V, Forman SJ, Garmey E, Hwang J, Kalinoski DL, Koczywas M, Longmate J, Melton RJ, Morgan R, Oliver J, Peterkin JJ, Ryan JL, Schluep T, Synold TW, Twardowski P, Davis ME, Yen Y. First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies. Invest New Drugs. 2013 Aug;31(4):986-1000. doi: 10.1007/s10637-012-9921-8. Epub 2013 Feb 9.
• Background Griggs JJ, Mangu PB, Anderson H, Balaban EP, Dignam JJ, Hryniuk WM, Morrison VA, Pini TM, Runowicz CD, Rosner GL, Shayne M, Sparreboom A, Sucheston LE, Lyman GH; American Society of Clinical Oncology. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2012 May 1;30(13):1553-61. doi: 10.1200/JCO.2011.39.9436. Epub 2012 Apr 2.
• Background Viale PH. The American Cancer Society's Facts & Figures: 2020 Edition. J Adv Pract Oncol. 2020 Mar;11(2):135-136. doi: 10.6004/jadpro.2020.11.2.1. Epub 2020 Mar 1. No abstract available.
• Background Keefe, SM, Heitjan D, Hennessy M., et al. Interim results of a phase 1b/2a study evaluating the nano pharmaceutical CRLX101 with bevacizumab (bev) in the treatment of subjects (pts) with refractory metastatic renal cell carcinoma (mRCC). J Clin Oncol 32, 2014 (suppl 4; abstr 412).
• Background Yen et al, Final phase 1/2a results evaluating the cyclodextrin-containing nanoparticle CRLX101 in subjects with advanced solid tumor malignancies, 23rd EORTC-NCI-AACR, Nov 12-16, 2011: abstract A97
• Background Guichard S, Arnould S, Hennebelle I, Bugat R, Canal P. Combination of oxaliplatin and irinotecan on human colon cancer cell lines: activity in vitro and in vivo. Anticancer Drugs. 2001 Oct;12(9):741-51. doi: 10.1097/00001813-200110000-00006.
• Background Zeghari-Squalli N, Raymond E, Cvitkovic E, Goldwasser F. Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin. Clin Cancer Res. 1999 May;5(5):1189-96.
• Background Bissery MC, Vrignaud P, Lavelle F. In vivo evaluation of the irinotecan-oxaliplatin combination. Proc Am Assoc Cancer Res 1998; 39: 526.
• Background Goldwasser F, Bozec L, Zeghari-Squalli N, Misset JL. Cellular pharmacology of the combination of oxaliplatin with topotecan in the IGROV-1 human ovarian cancer cell line. Anticancer Drugs. 1999 Feb;10(2):195-201. doi: 10.1097/00001813-199902000-00008.
• Background Ychou M, Conroy T, Seitz JF, Gourgou S, Hua A, Mery-Mignard D, Kramar A. An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/ 5-fluorouracil every 2 weeks in patients with advanced solid tumors. Ann Oncol. 2003 Mar;14(3):481-9. doi: 10.1093/annonc/mdg119.
• Background Lee J, Kang WK, Kwon JM, Oh SY, Lee HR, Kim HJ, Park BB, Lim HY, Han MJ, Park JO, Park YS. Phase II trial of irinotecan plus oxaliplatin and 5-fluorouracil/leucovorin in patients with untreated metastatic gastric adenocarcinoma. Ann Oncol. 2007 Jan;18(1):88-92. doi: 10.1093/annonc/mdl317. Epub 2006 Sep 13.
• Background Long HJ 3rd, Bundy BN, Grendys EC Jr, Benda JA, McMeekin DS, Sorosky J, Miller DS, Eaton LA, Fiorica JV; Gynecologic Oncology Group Study. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol. 2005 Jul 20;23(21):4626-33. doi: 10.1200/JCO.2005.10.021. Epub 2005 May 23.
• Background Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crino L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. doi: 10.1200/JCO.2006.09.0928.
• Background Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. doi: 10.1038/sj.bjc.6603011.
• Background Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. doi: 10.1056/NEJMoa1403108.
• Background Assenat E, Desseigne F, Thezenas S, Viret F, Mineur L, Kramar A, Samalin E, Portales F, Bibeau F, Crapez-Lopez E, Bleuse JP, Ychou M. Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial. Oncologist. 2011;16(11):1557-64. doi: 10.1634/theoncologist.2011-0141. Epub 2011 Oct 20.
• Background Conroy T, Paillot B, Francois E, Bugat R, Jacob JH, Stein U, Nasca S, Metges JP, Rixe O, Michel P, Magherini E, Hua A, Deplanque G. Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer--a Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer study. J Clin Oncol. 2005 Feb 20;23(6):1228-36. doi: 10.1200/JCO.2005.06.050.
• Background Ychou M, Desseigne F, Guimbaud R et al. Randomized phase II trial comparing folfirinox (5FU/leucovorin [LV], irinotecan [I] and oxaliplatin [O] vs gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA). First results of the ACCORD 11 trial [abstract]. J Clin Oncol 2007;25(June 20 Suppl):4516.
• Background Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. doi: 10.1056/NEJMoa1011923.
• Background Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, Mezi S, Tomasello G, Ronzoni M, Zaniboni A, Tonini G, Carlomagno C, Allegrini G, Chiara S, D'Amico M, Granetto C, Cazzaniga M, Boni L, Fontanini G, Falcone A. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015 Oct;16(13):1306-15. doi: 10.1016/S1470-2045(15)00122-9. Epub 2015 Aug 31.
• Background Marsh Rde W, Talamonti MS, Katz MH, Herman JM. Pancreatic cancer and FOLFIRINOX: a new era and new questions. Cancer Med. 2015 Jun;4(6):853-63. doi: 10.1002/cam4.433. Epub 2015 Feb 19.
• Background Lowery MA, Yu KH, Adel NG et al. Activity of front-line FOLFIRINOX (FFX) in stage III/IV pancreatic adenocarcinoma (PC) at Memorial Sloan-Kettering Cancer Center (MSKCC) [abstract]. ASCO Meeting Abstracts 2012;30:4057.
• Background Clark AJ, Wiley DT, Zuckerman JE, Webster P, Chao J, Lin J, Yen Y, Davis ME. CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing. Proc Natl Acad Sci U S A. 2016 Apr 5;113(14):3850-4. doi: 10.1073/pnas.1603018113. Epub 2016 Mar 21.
• Background Castells MC, Tennant NM, Sloane DE, Hsu FI, Barrett NA, Hong DI, Laidlaw TM, Legere HJ, Nallamshetty SN, Palis RI, Rao JJ, Berlin ST, Campos SM, Matulonis UA. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol. 2008 Sep;122(3):574-80. doi: 10.1016/j.jaci.2008.02.044. Epub 2008 May 27.
• Background Leong S, Eckhardt SG, Chan E, Messersmith WA, Spratlin J, Camidge DR, Diab S, Khosravan R, Lin X, Chow Maneval E, Lockhart AC. A phase I study of sunitinib combined with modified FOLFOX6 in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2012 Jul;70(1):65-74. doi: 10.1007/s00280-012-1880-4. Epub 2012 May 24.
• Background Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO; American Society of Clinical Oncology. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015 Oct 1;33(28):3199-212. doi: 10.1200/JCO.2015.62.3488. Epub 2015 Jul 13.
• Background Sriram D, Yogeeswari P, Thirumurugan R, Bal TR. Camptothecin and its analogues: a review on their chemotherapeutic potential. Nat Prod Res. 2005 Jun;19(4):393-412. doi: 10.1080/14786410412331299005.
• Background Rouch JA, Burton B, Dabb A, Brown V, Seung AH, Kinsman K, Holdhoff M. Comparison of enteral and parenteral methods of urine alkalinization in patients receiving high-dose methotrexate. J Oncol Pharm Pract. 2017 Jan;23(1):3-9. doi: 10.1177/1078155215610914. Epub 2016 Jun 23.
• Background Sharma S, Abhyankar V, Burgess RE, Infante J, Trowbridge RC, Tarazi J, Kim S, Tortorici M, Chen Y, Robles RL. A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors. Ann Oncol. 2010 Feb;21(2):297-304. doi: 10.1093/annonc/mdp489. Epub 2009 Nov 25.

Drugs

Indications