Advertisement

Investigational New Drugs

, Volume 32, Issue 4, pp 644–652 | Cite as

Phase I study of carboplatin in combination with PM00104 (Zalypsis®) in patients with advanced solid tumors

  • Ramón Salazar
  • Antonio Calles
  • Marta Gil
  • Ignacio Durán
  • Margarita García
  • Manuel Hidalgo
  • Cinthya Coronado
  • Vicente Alfaro
  • Mariano Siguero
  • Carlos Fernández-Teruel
  • Raquel Prados
  • Emiliano CalvoEmail author
PHASE I STUDIES

Summary

This phase I trial determined the recommended dose for phase II trials (RD) of carboplatin 1-h intravenous (i.v.) infusion followed by PM00104 1-h i.v. infusion on Day 1 every 3 weeks (q3wk) in adult patients with advanced solid tumors. A toxicity-guided, dose-escalation design was used. Patients were stratified and divided into heavily (n = 6) or mildly pretreated (n = 14) groups. Transient grade 4 thrombocytopenia (in one heavily and three mildly pretreated patients) was the only dose-limiting toxicity (DLT) observed. Carboplatin AUC3-PM00104 2.0 mg/m2 was the RD in both groups. At this RD, the carboplatin AUC was equal to ~60 % the target AUC used in other combinations, and the PM00104 dose intensity was 56–67 % of the value achieved at the RD for single-agent PM00104 given as 1-h infusion q3wk. Most treatment-related adverse events were grade 1/2. They mainly consisted of gastrointestinal and general symptoms, such as fatigue, anorexia, mucosal inflammation or nausea. Transient neutropenia (50 % of patients) and thrombocytopenia (33–38 %) were the most common severe hematological abnormalities; their incidence was higher than with single-agent PM00104. No pharmacokinetic drug-drug alterations occurred. Partial response was found in one patient with triple negative breast cancer pretreated with paclitaxel/bevacizumab. Three patients with colorectal cancer, head and neck cancer, and tumor of unknown origin had disease stabilization for ≥3 months. In conclusion, no optimal dose was reached due to overlapping myelosuppression despite stratification according to prior treatment. Therefore, this carboplatin plus PM00104 combination was not selected for further clinical research.

Keywords

Phase I PM00104 Carboplatin Antitumor Cytotoxic Dose-limiting toxicities 

Notes

Acknowledgements

This study was supported by Pharma Mar, S.A., and presented in part at the following events:

American Society of Clinical Oncology (ASCO), 47th Annual Meeting, June 3–7, 2011. Chicago, Illinois (J Clin Oncol 29: 2011 suppl; abstr e13085). Phase I study of PM00104 in combination with carboplatin (C) in patients (pts) with advanced solid tumors. Calvo, E.; Gil, M.; Coronado, C.; Valer, A.; Duran, I.; Hidalgo, M.; Pardo, B.; Calles, A.; García, M.; Morelli, P.; Kahatt, C.M.; Prados, R.; Fernandez, C.; Salazar, R.

American Association for Cancer Research (AACR) Annual Meeting; March 31–April 4, 2012. Chicago, IL (abstract 5587). Phase I study of PM00104 in combination with carboplatin in patients (pts) with advanced solid tumors. Calvo, E.; Gil, M.; Coronado, C.; Valer, A.; Duran, I.; Hidalgo, M.; Pardo, B.; Calles, A.; Garcia, M.; Morelli, P.; Kahatt, C.; Prados, R.; Fernandez, C.; Salazar, R.

Conflict of interest

Cinthya Coronado, Vicente Alfaro, Mariano Siguero, Carlos Fernández-Teruel and Raquel Prados are employees of PharmaMar.

References

  1. 1.
    Rinehart KL, Holt TG, Fregeau NL, Stroh JG, Keifer PA, Sun F, Li LH, Martin DG (1990) Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata. J Org Chem 55:4512–4515CrossRefGoogle Scholar
  2. 2.
    Fontana A, Cavaliere P, Wahidulla S, Naik CG, Cimino G (2000) A new antitumor isoquinoline alkaloid from the marine nudibranch Jorunna funebris. Tetrahedron 56:7305–7308CrossRefGoogle Scholar
  3. 3.
    Oku N, Matsunaga S, van Soest RW, Fusetani N (2003) Renieramycin J, a highly cytotoxic tetrahydroisoquinoline alkaloid, from a marine sponge Neopetrosia sp. J Nat Prod 66:1136–1139CrossRefPubMedGoogle Scholar
  4. 4.
    Leal JF, Garcia-Hernandez V, Moneo V, Domingo A, Bueren-Calabuig JA, Negri A, Gago F, Guillen-Navarro MJ, Aviles P, Cuevas C, Garcia-Fernandez LF, Galmarini CM (2009) Molecular pharmacology and antitumor activity of Zalypsis in several human cancer cell lines. Biochem Pharmacol 78:162–170CrossRefPubMedGoogle Scholar
  5. 5.
    Guirouilh-Barbat J, Antony S, Pommier Y (2009) Zalypsis (PM00104) is a potent inducer of gamma-H2AX foci and reveals the importance of the C ring of trabectedin for transcription-coupled repair inhibition. Mol Cancer Ther 8:2007–2014CrossRefPubMedGoogle Scholar
  6. 6.
    Herrero A, Botet J, Cuevas C, Gago F, Moreno S (2007) Genome-wide screen reveals antitumor Zalypsis(R) as a strong inducer of DNA double strand breaks. AACR Meeting Abstracts 2007:5733Google Scholar
  7. 7.
    Ocio EM, Maiso P, Chen X, Garayoa M, Alvarez-Fernandez S, San-Segundo L, Vilanova D, Lopez-Corral L, Montero JC, Hernandez-Iglesias T, de Alava E, Galmarini C, Aviles P, Cuevas C, San-Miguel JF, Pandiella A (2009) Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks. Blood 113:3781–3791CrossRefPubMedGoogle Scholar
  8. 8.
    LePage D, Sasak H, Guillen MJ, Grant W, Cuevas C, Aviles P (2007) Antitumor activity of Zalypsis® (PM00104) in experimental models of bladder, gastric and liver cancer. In: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; San Francisco, CA. p. Abstract C62Google Scholar
  9. 9.
    LePage D, Sasak H, Cheney L, Oyama S, Cuevas C, Avilés P, Maxuitenko Y, Faircloth G (2007) Antitumor activity of Zalypsis® in human pancreas tumors. In: AACR American Association for Cancer Research; Annual Meeting; Los Angeles, CA. p. Abstract 1519Google Scholar
  10. 10.
    Greiner T, Maier A, Bausch N, Fiebig HH, LePage D, Guillén MJ, Cuevas C, Avilés P (2007) Preclinical evaluation of PM00104 to support the selection of tumor indications for clinical studies. In: 19th AACR-NCI-EORTC International Conference on “Molecular Targets and Cancer Therapeutics: Discovery, Biology and Clinical Applications”. San Francisco, CA. p. Abstract C60Google Scholar
  11. 11.
    Elices MJ, Grant W, Guillen MJ, Cuevas Marchante C, Aviles P, Faircloth GT (2005) The novel compound PM00104 exhibits significant in vivo activity againts breast tumors. In: AACR American Association for Cancer Research; 96th Annual Meeting; Anaheim, CA. p. Abstract 623Google Scholar
  12. 12.
    Elices M, LePage D, Grant W, Sasak H, Caylor T, Martin J, Guillén MJ, Cuevas Marchante C, Avilés P, Faircloth G (2005) Profile of ZalypsisTM (PM00104) against various human solid tumors. In: 17th AACR-NCI-EORTC International Conference on “ Molecular Targets and Cancer Therapeutics: Discovery, Biology and Clinical Applications”.Clin Cancer Res; Philadelphia, PA. p. 9085s-9086s (Abstract B9216)Google Scholar
  13. 13.
    Guillen MJ, Lepage D, Grant W, Cuevas C, Aviles P (2009) Abstract #2018: Antitumor activity of PM00104 in hepatocellular carcinoma (HCC) experimental models. AACR Meeting Abstracts 2009:2018Google Scholar
  14. 14.
    Yin J, Avilés P, Guillén MJ, Ly C, Lee W, Munt S, Cuevas C, Faircloth GT (2005) Pharmacokinetic evaluation of a novel anti-tumor agent, zalypsis (PM00104), in mice and dogs. 17th AACR-NCI-EORTC International Conference on “ Molecular Targets and Cancer Therapeutics: Discovery, Biology and Clinical Applications”. Filadelfia, EEUU, 14–18 Noviembre, 2005. Clin Cancer Res 11:9072s (Abstract B9163)Google Scholar
  15. 15.
    Yin J, Aviles P, Wright T, Guillen MJ, Ly C, Lee W, Munt S, Cuevas C, Faircloth GT (2006) Toxicokinetic evaluation of a novel anti-tumor agent, Zalypsis(R) (PM00104), in dogs. AACR Meeting Abstracts 2006:728-bGoogle Scholar
  16. 16.
    Yap TA, Cortes-Funes H, Shaw H, Rodriguez R, Olmos D, Lal R, Fong PC, Tan DS, Harris D, Capdevila J, Coronado C, Alfaro V, Soto-Matos A, Fernandez-Teruel C, Siguero M, Tabernero JM, Paz-Ares L, de Bono JS, Lopez-Martin JA (2012) First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours. Br J Cancer 106:1379–1385PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Capdevila J, Clive S, Tabernero J, Lardelli P, Soto-Matos A, Baselga J, Piera A, Pardos I, Rye R, Smyth JF (2009) Phase I study of the novel anticancer drug PM00104 as a 24-hour IV infusion every 3 weeks (q3w) in patients (pts) with advanced solid tumors or lymphoma. J Clin Oncol 27:Abstract 2568Google Scholar
  18. 18.
    Massard C, Margetts J, Amellal N, Drew Y, Bahleda R, Stevens P, Armand JP, Calvert H, Soria JC, Coronado C, Kahatt C, Alfaro V, Siguero M, Fernandez-Teruel C, Plummer R (2013) Phase I study of PM00104 (Zalypsis(R)) administered as a 1-hour weekly infusion resting every fourth week in patients with advanced solid tumors. Invest New Drugs 31:623–630CrossRefPubMedGoogle Scholar
  19. 19.
    Martin LP, Krasner C, Rutledge T, Ibanes ML, Fernandez-Garcia EM, Kahatt C, Gomez MS, McMeekin S (2013) Phase II study of weekly PM00104 (ZALYPSIS((R))) in patients with pretreated advanced/metastatic endometrial or cervical cancer. Med Oncol 30:627CrossRefPubMedGoogle Scholar
  20. 20.
    Jones RL, Ferrari S, Blay JY, Navid F, Lardelli P, Alfaro V, Siguero M, Soman N, Chawla SP (2013) A Phase II multicenter, open-label, clinical and pharmokinetic trial of PM00104 in patients with advanced Ewing Family of Tumors. Invest New Drugs. doi: 10.1007/s10637-013-0037-6 PubMedCentralGoogle Scholar
  21. 21.
    Guillén MJ, LePage D, Grant W, Cuevas C, Avilés P (2009) Evaluation of antitumor activity of PM00104 combined with cisplatin in experimental models of bladder and gastric tumors. AACR American Association for Cancer Research; 100th Annual Meeting; April 18–22, 2009. Denver, CO:Abstract #2682Google Scholar
  22. 22.
    Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME, Wiltshaw E (1989) Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748–1756PubMedGoogle Scholar
  23. 23.
    National Cancer Institute (2006) Common Terminology Criteria for Adverse Events (CTCAE) v.3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf:1–72
  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. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
  25. 25.
    Yin J, Aviles P, Lee W, Ly C, Guillen MJ, Munt S, Cuevas C, Faircloth G (2005) Development of a liquid chromatography/tandem mass spectrometry assay for the quantification of PM00104, a novel antineoplastic agent, in mouse, rat, dog, and human plasma. Rapid Commun Mass Spectrom 19:689–695CrossRefPubMedGoogle Scholar
  26. 26.
    Alberts DS, Dorr RT (1998) New perspectives on an old friend: optimizing carboplatin for the treatment of solid tumors. Oncologist 3:15–34PubMedGoogle Scholar
  27. 27.
    Sessa C, Cresta S, Noberasco C, Capri G, Gallerani E, De Braud F, Zucchetti M, D’Incalci M, Locatelli A, Marsoni S, Corradino I, Minoia C, Zintl P, Gianni L (2009) Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours. Eur J Cancer 45:2116–2122CrossRefPubMedGoogle Scholar
  28. 28.
    Sessa C, Del Conte G, Christinat A, Cresta S, Perotti A, Gallerani E, Lardelli P, Kahatt C, Alfaro V, Iglesias JL, Fernandez-Teruel C, Gianni L (2013) Phase I clinical and pharmacokinetic study of trabectedin and cisplatin given every three weeks in patients with advanced solid tumors. Invest New Drugs 31:1236–1243CrossRefPubMedGoogle Scholar
  29. 29.
    Vidal L, Magem M, Barlow C, Pardo B, Florez A, Montes A, Garcia M, Judson I, Lebedinsky C, Kaye SB, Salazar R (2012) Phase I clinical and pharmacokinetic study of trabectedin and carboplatin in patients with advanced solid tumors. Invest New Drugs 30:616–628CrossRefPubMedGoogle Scholar
  30. 30.
    Perez-Ruixo C, Valenzuela B, Fernandez Teruel C, Gonzalez-Sales M, Miguel-Lillo B, Soto-Matos A, Perez-Ruixo JJ (2012) Population pharmacokinetics of PM00104 (Zalypsis((R))) in cancer patients. Cancer Chemother Pharmacol 69:15–24CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ramón Salazar
    • 1
  • Antonio Calles
    • 2
  • Marta Gil
    • 1
  • Ignacio Durán
    • 2
  • Margarita García
    • 1
  • Manuel Hidalgo
    • 2
  • Cinthya Coronado
    • 3
  • Vicente Alfaro
    • 3
  • Mariano Siguero
    • 3
  • Carlos Fernández-Teruel
    • 3
  • Raquel Prados
    • 3
  • Emiliano Calvo
    • 2
    Email author
  1. 1.Instituto Catalán de OncologíaL’Hospitalet de LlobregatBarcelonaSpain
  2. 2.START Madrid, Centro Integral Oncológico Clara CampalHospital Universitario Madrid Norte SanchinarroMadridSpain
  3. 3.PharmaMar, Clinical R&DColmenar ViejoSpain

Personalised recommendations