Cancer Chemotherapy and Pharmacology

, Volume 60, Issue 4, pp 523–533 | Cite as

Phase I and pharmacokinetic trial of AP5346, a DACH–platinum–polymer conjugate, administered weekly for three out of every 4 weeks to advanced solid tumor patients

  • Mario Campone
  • Jeany M. Rademaker-Lakhai
  • Jaafar Bennouna
  • Stephen B. Howell
  • David P. Nowotnik
  • Jos H. Beijnen
  • Jan H. M. Schellens
Original Article



To determine the maximum tolerated dose (MTD) safety and pharmacokinetics of AP5346, a copolymer-linked 1,2-diaminocyclohexane(DACH)-platinum compound, in advanced solid tumor patients.

Experimental design

AP5346 was administered as a 1-hour IV infusion on days 1, 8, 15 of a 28-day cycle. Seven dose levels (DL) were explored: DL1: 40 mg platinum (Pt)/m² (1 patient); DL2: 80 (1); DL3: 160 (3); DL4: 320 (3); DL5: 640 (6); DL6: 850 (6); DL7: 1280 (6) mg Pt/m2. Dose-limiting toxicity (DLT) included infusion omission and cycle delay >2 weeks.


Twenty-six patients received 41 cycles (median 1/patient, range 1–4). No DLT occurred in DL 1–4; 1 DLT in DL5 (RD; renal insufficiency), two in DL6 (MTD; vomiting; fatigue) and 5 in DL7 (neutropenic infection with diarrhea; neutropenia with vomiting; vomiting with fatigue; renal insufficiency; and fatigue). Two deaths occurred due to renal insufficiency (DL5); in both cases patients had disease in or surrounding genitourinary tract whose contribution could not be accurately discerned. Grade 1-2 creatinine abnormalities occurred in seven patients. Nausea/emesis was frequent (92%), reaching grade 3-4 (23%), but controlled by antiemetics. Grade 2-4 allergic reactions occurred in 4 patients. C max and AUC increased linearly with dose for total plasma platinum and ultrafiltrate platinum. Antitumor activity included two partial responses in metastatic melanoma and ovarian cancer, and an additional CA-125 normalization (from 133 IU/l) in a suspected ovarian cancer.


AP5346 administered weekly for 3 weeks out of every four is tolerated up to a dose of 640 mg Pt/m² on the first cycle when given with antiemetic prophylaxis. The pharmacokinetics of AP5346 indicates a prolonged half-life, and evidence of antitumor activity was observed at this dose level.


AP5346 Phase I trial Pharmacokinetics Drug delivery 



The authors wish to thank Dr. Alejandro Yovine, Mr. Ronan Fougeray and Dr. Maria Mavris (CAC Oncology, Kremlin-Bicêtre, France) for their aid in the analysis of the study and preparation of the manuscript. This study was sponsored by ACCESS Pharmaceuticals Inc., Dallas, TX.


  1. 1.
    Aebi S, Kurdi-Haidar B, Gordon R, Cenni B, Zheng H, Fink D, Christen R, Boland CR, Koi M, Fishel R, Howell SB (1996) Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res 56:3087PubMedGoogle Scholar
  2. 2.
    de Gramont A, Figer A, Seymour M, et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938PubMedGoogle Scholar
  3. 3.
    De Vita F, Orditura M, Matano E, Bianco R, Carlomagno C, Infusino S, Damiano V, Simeone E, Diadema MR, Lieto E, Castellano P, Pepe S, De Placido S, Galizia G, Di Martino N, Ciardiello F, Catalano G, Bianco AR (2005) A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients. Br J Cancer 92:1644PubMedCrossRefGoogle Scholar
  4. 4.
    Droz JP, Muracciole X, Mottet N, Ould Kaci M, Vannetzel JM, Albin N, Culine S, Rodier JM, Misset JL, Mackenzie S, Cvitkovic E, Benoit G (2003) Phase II study of oxaliplatin versus oxaliplatin combined with infusional 5-fluorouracil in hormone refractory metastatic prostate cancer patients. Ann Oncol 14:1291PubMedCrossRefGoogle Scholar
  5. 5.
    Duncan R (1997) Polymer therapeutics for tumour specific delivery. Chem Ind 7:262Google Scholar
  6. 6.
    Extra JM, Espie M, Calvo F, Ferme C, Mignot L, Marty M (1990) Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol 25:299PubMedCrossRefGoogle Scholar
  7. 7.
    Gowda A, Goel R, Berdzik J, Leichman CG, Javle M (2004) Hypersensitivity Reactions to oxaliplatin: incidence and management. Oncology (Williston Park) 18:1671Google Scholar
  8. 8.
    Kavanagh T, Tresukosol D, Edwards C, Freedman R, Aagaard L, Gonzalez de Leon C, Fishman A, Mante R, Hord M, Kudelka A (1995) Carboplatin reinduction after taxane in patients with platinum-refractory epithelial ovarian cancer. J Clin Oncol 13:1584PubMedGoogle Scholar
  9. 9.
    Krishnan AV, Goldstein D, Friedlander M, Kiernan MC (2005) Oxaliplatin-induced neurotoxicity and the development of neuropathy. Muscle Nerve 32:51PubMedCrossRefGoogle Scholar
  10. 10.
    Markman M, Kennedy A, Webster K, Elson P, Peterson G, Kulp B, Belinson J (1999) Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol 17:1141PubMedGoogle Scholar
  11. 11.
    Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387PubMedGoogle Scholar
  12. 12.
    Misset JL (1998) Oxaliplatin in practice. Br J Cancer 77 Suppl 4:4Google Scholar
  13. 13.
    Monnet I, de CH, Soulie P, Saltiel-Voisin S, Bekradda M, Saltiel JC, Brain E, Rixe O, Yataghene Y, Misset JL, Cvitkovic E (2002) Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study. Ann Oncol 13:103Google Scholar
  14. 14.
    Muggia FM (1996) Dose intensity: not the only path to clinical dose optimization. J Infus Chemother 6:57PubMedGoogle Scholar
  15. 15.
    Mukherjee S, Ghosh RN, Maxfield FR (1997) Endocytosis. Physiol Rev 77:759PubMedGoogle Scholar
  16. 16.
    Nichols CR, Williams SD, Loehrer PJ, Greco FA, Crawford ED, Weetlaufer J, Miller ME, Bartolucci A, Schacter L, Einhorn LH (1991) Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer study group and Southwest oncology group protocol. J Clin Oncol 9:1163PubMedGoogle Scholar
  17. 17.
    Rademaker-Lakhai JM, Terret C, Howell SB, Baud CM, De Boer RF, Pluim D, Beijnen JH, Schellens JH, Droz JP (2004) A Phase I and pharmacological study of the platinum polymer AP5280 given as an intravenous infusion once every 3 weeks in patients with solid tumors. Clin Cancer Res 10:3386PubMedCrossRefGoogle Scholar
  18. 18.
    Rice JR, Gerberich JL, Nowotnik DP, Howell SB (2006) Preclinical efficacy and pharmacokinetics of AP5346, a novel diaminocyclohexane-platinum tumor-targeting drug delivery system. Clin Cancer Res 12:2248PubMedCrossRefGoogle Scholar
  19. 19.
    Rice JR, Howell SB (2004) AP-5346. Polymer-delivered platinum complex. Drugs Future 29:561CrossRefGoogle Scholar
  20. 20.
    Rixe O, Ortuzar W, Alvarez M, Parker R, Reed E, Paull K, Fojo T (1996) Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the national cancer institute’s anticancer drug screen panel. Biochem Pharmacol 52:1855PubMedCrossRefGoogle Scholar
  21. 21.
    Saris CP, van de Vaart PJ, Rietbroek RC, Blommaert FA (1996) In vitro formation of DNA adducts by cisplatin, lobaplatin and oxaliplatin in calf thymus DNA in solution and in cultured human cells. Carcinogenesis 17:2763PubMedCrossRefGoogle Scholar
  22. 22.
    Seymour LW (1992) Passive tumor targeting of soluble macromolecules and drug conjugates. Crit Rev Ther Drug Carrier Sys 6:135Google Scholar
  23. 23.
    Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC (1997) Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138PubMedCrossRefGoogle Scholar
  24. 24.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New Guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205PubMedCrossRefGoogle Scholar
  25. 25.
    Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22:229PubMedCrossRefGoogle Scholar
  26. 26.
    Vaisman A, Varchenko M, Umar A, Kunkel TA, Risinger JI, Barrett JC, Hamilton TC, Chaney SG (1998) The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: correlation with replicative bypass of platinum-DNA adducts. Cancer Res 58:3579PubMedGoogle Scholar
  27. 27.
    Viens P, Petit T, Yovine A, Bougnoux P, Deplanque G, Cottu PH, Delva R, Lotz JP, Belle SV, Extra JM, Cvitkovic E (2006) A phase II study of a paclitaxel and oxaliplatin combination in platinum-sensitive recurrent advanced ovarian cancer patients. Ann Oncol 17:429PubMedCrossRefGoogle Scholar
  28. 28.
    Woynarowski JM, Faivre S, Herzig MC, Arnett B, Chapman WG, Trevino AV, Raymond E, Chaney SG, Vaisman A, Varchenko M, Juniewicz PE (2000) Oxaliplatin-induced damage of cellular DNA. Mol Pharmacol 58:920PubMedGoogle Scholar
  29. 29.
    Zelek L, Cottu P, Tubiana-Hulin M, Vannetzel JM, Chollet P, Misset JL, Chouaki N, Marty M, Gamelin E, Culine S, Dieras V, Mackenzie S, Spielmann M (2002) Phase II study of oxaliplatin and fluorouracil in taxane–and anthracycline-pretreated breast cancer patients. J Clin Oncol 20:2551PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Mario Campone
    • 1
  • Jeany M. Rademaker-Lakhai
    • 2
  • Jaafar Bennouna
    • 1
  • Stephen B. Howell
    • 3
    • 4
  • David P. Nowotnik
    • 5
  • Jos H. Beijnen
    • 2
    • 5
  • Jan H. M. Schellens
    • 2
    • 5
  1. 1.Centre René GauducheauNantesFrance
  2. 2.Netherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Moores UCSD Cancer CenterUniversity of CaliforniaSan DiegoUSA
  4. 4.ACCESS Pharmaceuticals Inc.DallasUSA
  5. 5.Faculty of Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands

Personalised recommendations