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Investigational New Drugs

, Volume 35, Issue 2, pp 198–206 | Cite as

Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors

  • Luis Paz-Ares
  • Martin Forster
  • Valentina Boni
  • Sergio Szyldergemajn
  • Jesús Corral
  • Samantha Turnbull
  • Antonio Cubillo
  • Carlos Fernandez Teruel
  • Iker López Calderero
  • Mariano Siguero
  • Patrick Bohan
  • Emiliano CalvoEmail author
PHASE I STUDIES

Summary

Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m2 was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m2); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m2, which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12–40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7–6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m2)/gemcitabine 800 mg/m2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.

Keywords

PM01183 Lurbinectedin Gemcitabine Combination Solid tumor 

Notes

Acknowledgements

Support was provided to Martin Forster by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre, and the Cancer Research UK University College London Experimental Cancer Medicine Centre.

Compliance with ethical standards

Conflict of interest

Emiliano Calvo, Martin Forster, Valentina Boni, Jesús Corral, Samantha Turnbull, Antonio Cubillo, and Iker López Calderero declare that they have no conflict of interest. Luis Paz-Ares reports honoraria from Pharma Mar, S.A. outside the submitted work. Sergio Szyldergemajn, Carlos Fernandez Teruel and Patrick Bohan are employees of Pharma Mar, S.A. Mariano Siguero is an employee and shareholder of Pharma Mar, S.A.

Funding

This work was funded by a grant from Pharma Mar, S.A.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Leal JF, Martinez-Diez M, 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 (2010) PM01183, a new DNA minor groove covalent binder with potent in vitro and in vivo anti-tumour activity. Br J Pharmacol 161(5):1099–1110CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bueren-Calabuig JA, Giraudon C, Galmarini CM, Egly JM, Gago F (2011) Temperature-induced melting of double-stranded DNA in the absence and presence of covalently bonded antitumour drugs: insight from molecular dynamics simulations. Nucleic Acids Res 39(18):8248–8257. doi: 10.1093/nar/gkr512 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Santamaria G, Martínez-Leal JF, Cuevas C, Garcia-Fernandez LF, Galmarini CM Lurbinectedin (PM01183) specifically targets RNA Pol II for degradation via the proteasome pathway in a transcription and TC-NER dependent fashion. Eur J Cancer 50:20. doi: 10.1016/S0959-8049(14)70173-x
  4. 4.
    Soares DG, Machado MS, Rocca CJ, Poindessous V, Ouaret D, Sarasin A, Galmarini CM, Henriques JA, Escargueil AE, Larsen AK (2011) Trabectedin and its C subunit modified analogue PM01183 attenuate nucleotide excision repair and show activity toward platinum-resistant cells. Mol Cancer Ther 10(8):1481–1489. doi: 10.1158/1535-7163.MCT-11-0252 CrossRefPubMedGoogle Scholar
  5. 5.
    Santamaria Nunez G, Robles CM, Giraudon C, Martinez-Leal JF, Compe E, Coin F, Aviles P, Galmarini CM, Egly JM (2016) Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells. Mol Cancer Ther. doi: 10.1158/1535-7163.mct-16-0172 PubMedGoogle Scholar
  6. 6.
    Guillen MJ, Cataluña O, Palomares M, Lopez R, Cuevas C, Aviles P (2011) In vivo combination studies of PM01183 with alkylating, antimetabolites, DNA-topoisomerase inhibitors and tubulin binding agents. Cancer Res 71 (8 Suppl):Abstract 3538Google Scholar
  7. 7.
    Soares DG, Larsen AK, Escargueil AE (2012) The DNA damage response to monofunctional anticancer DNA binders. Drug Discov Today 9(2):59–67Google Scholar
  8. 8.
    Aviles P, Galmarini C, Cuevas C, Guillen MJ, Frapolli R, Uboldi S, Romano M, Tavecchio M, Erba E, Bello E, D'Incalci M (2009) Mechanism of action and antitumor activity of PM01183. Cancer Res 69(9 Suppl):Abstract 2679Google Scholar
  9. 9.
    Mangues R, Céspedes MV, Guillén MJ, Alamo P, López R, Gallardo A, Nuñez P, Cuevas C, Aviles P 223 Lurbinectedin (PM01183) Synergizes with Gemcitabine in NSCLC, Ovarian and Pancreas Tumor Xenografts. Eur J Cancer 48:67–68. doi: 10.1016/S0959-8049(12)72021-X
  10. 10.
    Cespedes MV, Guillen MJ, Lopez-Casas PP, Sarno F, Gallardo A, Alamo P, Cuevas C, Hidalgo M, Galmarini CM, Allavena P, Aviles P, Mangues R (2016) Lurbinectedin induces depletion of tumor-associated macrophages (TAM), an essential component of its in vivo synergism with gemcitabine. Dis Model Mech. doi: 10.1242/dmm.026369 PubMedPubMedCentralGoogle Scholar
  11. 11.
    Heusinkveld M, van der Burg SH (2011) Identification and manipulation of tumor associated macrophages in human cancers. J Transl Med 9:216. doi: 10.1186/1479-5876-9-216 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Elez ME, Tabernero J, Geary D, Macarulla T, Kang SP, Kahatt C, Pita AS, Teruel CF, Siguero M, Cullell-Young M, Szyldergemajn S, Ratain MJ (2014) First-in-human phase I study of Lurbinectedin (PM01183) in patients with advanced solid tumors. Clin Cancer Res: an Off J Am Assoc Cancer Res 20(8):2205–2214. doi: 10.1158/1078-0432.CCR-13-1880 CrossRefGoogle Scholar
  13. 13.
    Ratain MJ, Gore L, Szyldergemajn S, Diamond J, Geary D, Fernandez-Teruel C, Soto-Matos A, Sharma M, Jimeno A 23 Phase I study of lurbinectedin (PM01183) administered on days (D) 1 & 8 every 3 weeks (q3wk) in patients (pts) with solid tumors. Eur J Cancer 50:13–14. doi: 10.1016/S0959-8049(14)70149-2
  14. 14.
    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 (2015) Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. doi: 10.1200/jco.2015.62.3488 Google Scholar
  15. 15.
    Yilmaz B, Kadioglu YY, Aksoy Y (2004) Investigation of the pharmacokinetics of gemcitabine and 2',2'-difluorodeoxyuridine in human plasma by liquid chromatography. Anal Biochem 332(2):234–237. doi: 10.1016/j.ab.2004.05.059 CrossRefPubMedGoogle Scholar
  16. 16.
    Messersmith WA, Jimeno A, Ettinger D, Laheru D, Brahmer J, Lansey D, Khan Y, Donehower RC, Elsayed Y, Zannikos P, Hidalgo M (2008) Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors. Cancer Chemother Pharmacol 63(1):181–188. doi: 10.1007/s00280-008-0733-7 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Faivre S, Le Chevalier T, Monnerat C, Lokiec F, Novello S, Taieb J, Pautier P, Lhomme C, Ruffie P, Kayitalire L, Armand JP, Raymond E (2002) Phase I-II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma. Ann Oncol: Off J Eur Soc Med Oncol/ ESMO 13(9):1479–1489CrossRefGoogle Scholar
  18. 18.
    Lee M-Y, Jung KS, Kim HS, Lee JY, Lim SH, Kim M, Jung HA, Kim SM, Sun JM, Ahn M-J, Lee J, Park SH, Yi SY, Hwang IG, Lee S-C, Ahn HK, Lim DH, Lee SI, Park KW (2015) Weekly docetaxel and gemcitabine in previously treated metastatic esophageal squamous cell carcinoma. World J Gastroenterol 21(14):4268–4274. doi: 10.3748/wjg.v21.i14.4268 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Seidman AD (2004) Gemcitabine and docetaxel in metastatic breast cancer. Oncology (Williston Park) 18(14 Suppl 12):13–16Google Scholar
  20. 20.
    Johnson DH (2001) Gemcitabine for the treatment of non-small-cell lung cancer. Oncology (Williston Park) 15(3 Suppl 6):33–39Google Scholar
  21. 21.
    Blackstein M, Vogel CL, Ambinder R, Cowan J, Iglesias J, Melemed A (2002) Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial. Oncology 62(1):2–8CrossRefPubMedGoogle Scholar
  22. 22.
    Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, Stahle A, Stuart G, Kimmig R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, Jackisch C, Luck HJ, Rochon J, Zimmermann AH, Eisenhauer E, Ago O, Ncic CTG, Eortc GCG (2006) Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24(29):4699–4707. doi: 10.1200/JCO.2006.06.0913 CrossRefPubMedGoogle Scholar
  23. 23.
    Bria E, Milella M, Gelibter A, Cuppone F, Pino MS, Ruggeri EM, Carlini P, Nistico C, Terzoli E, Cognetti F, Giannarelli D (2007) Gemcitabine-based combinations for inoperable pancreatic cancer: have we made real progress? A meta-analysis of 20 phase 3 trials. Cancer 110(3):525–533. doi: 10.1002/cncr.22809 CrossRefPubMedGoogle Scholar
  24. 24.
    Stinchcombe TE, Socinski MA (2008) Considerations for second-line therapy of non-small cell lung cancer. Oncologist 13(Suppl 1):28–36. doi: 10.1634/theoncologist.13-S1-28 CrossRefPubMedGoogle Scholar
  25. 25.
    He J, Hu Y, Hu M, Li B (2015) Development of PD-1/PD-L1 Pathway in Tumor Immune Microenvironment and Treatment for Non-Small Cell Lung Cancer. Sci Rep 5:13110. doi: 10.1038/srep13110 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Cameron L, Solomon B (2015) Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: Recent Progress and Future Directions. Drugs 75(10):1059–1070. doi: 10.1007/s40265-015-0415-9 CrossRefPubMedGoogle Scholar
  27. 27.
    Poveda A, Berton-Rigaud D, Ray-Coquard IL, Alexandre J, Provansal M, Soto A, Kahatt CM, Szyldergemajn SA, Nieto A, Fernandez C, Guerra Alia E, Casado A, Gonzalez-Martin A, Del Campo JM (2014) Lurbinectedin (PM01183), an active compound in platinum-resistant/refractory ovarian cancer (PRROC) patients: Results of a two-stage, controlled phase II study. ASCO Meeting Abstracts 32(15_suppl):5505Google Scholar
  28. 28.
    Balmaña J, Cruz C, Garber J, Perez Fidalgo JA, Lluch A, Tung N, Antolin S, Fernandez C, Kahatt C, Szyldergemajn S, Soto Matos A, Extremera S, Baselga J, Isakoff SJ (2015) Abstract P3–13-01: Lurbinectedin (PM01183) activity in BRCA1/2-associated or unselected metastatic breast cancer. Interim results of an ongoing phase II trial. Cancer Res 75(9 Supplement):P3–13-01. doi: 10.1158/1538-7445.sabcs14-p3-13-01 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Luis Paz-Ares
    • 1
    • 2
  • Martin Forster
    • 3
  • Valentina Boni
    • 4
  • Sergio Szyldergemajn
    • 5
  • Jesús Corral
    • 1
  • Samantha Turnbull
    • 3
    • 6
  • Antonio Cubillo
    • 4
  • Carlos Fernandez Teruel
    • 5
  • Iker López Calderero
    • 1
    • 7
  • Mariano Siguero
    • 5
  • Patrick Bohan
    • 5
  • Emiliano Calvo
    • 4
    Email author
  1. 1.Hospital Universitario Virgen del RocíoSevilleSpain
  2. 2.Chair of the Medical Oncology DepartmentHospital Universitario 12 de OctubreMadridSpain
  3. 3.University College of London HospitalLondonUK
  4. 4.START Madrid, Centro Integral Oncológico Clara CampalHospital Universitario Madrid SanchinarroMadridSpain
  5. 5.Pharma Mar, S.AMadridSpain
  6. 6.Clinical Research Fellow and SpR in Medical Oncology, Leeds Immunotherapy Team (LIT) at the Leeds Institute of Cancer and PathologyUniversity of LeedsLeedsUK
  7. 7.Consultant Clinical Oncologist in Can Misses HospitalIbizaSpain

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