Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 6, pp 1257–1265 | Cite as

Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors

  • Sandrine Aspeslagh
  • Kunwar Shailubhai
  • Rastilav Bahleda
  • Anas Gazzah
  • Andréa Varga
  • Antoine Hollebecque
  • Christophe Massard
  • Anna Spreafico
  • Michele Reni
  • Jean-Charles Soria
Clinical Trial Report



This phase I trial evaluated the safety and tolerability of milciclib, an inhibitor of multiple cyclin-dependent kinases and tropomycin receptor kinase A, in combination with gemcitabine in patients with refractory solid tumors.


Sixteen patients were enrolled and treated with milciclib at three dose levels (45 mg/m2/day, n = 3; 60 mg/m2/day, n = 3; and 80 mg/m2/day, n = 10) with a fixed dose of gemcitabine (1000 mg/m2/day). Milciclib was administered orally once daily for 7 days on/7 days off in a 4-week cycle, and gemcitabine was administered intravenously on days 1, 8 and 15 in a 4-week cycle.


All 16 enrolled patients were evaluable for safety and toxicity. Dose-limiting toxicities, which occurred in only one out of nine patients treated at the maximum dose tested (milciclib 80 mg/m2/day and gemcitabine 1000 mg/m2/day), consisted of Grade 4 thrombocytopenia, Grade 3 ataxia and Grade 2 tremors in the same patient. Most frequent treatment-related AEs were neutropenia and thrombocytopenia. Among 14 evaluable patients, one NSCLC patient showed partial response and 4 patients (one each with thyroid, prostatic, pancreatic carcinoma and peritoneal mesothelioma) showed long-term disease stabilization (>6–14 months). Pharmacokinetics of the orally administered milciclib (~t1/2 33 h) was not altered by concomitant treatment with gemcitabine.


The combination treatment was well tolerated with manageable toxicities. The recommended phase II dose was 80 mg/m2/day for milciclib and 1000 mg/m2/day for gemcitabine. This combination treatment regimen showed encouraging clinical benefit in ~36% patients, including gemcitabine refractory patients. These results support further development of combination therapies with milciclib in advanced cancer patients.


Milciclib Gemcitabine Cyclin-dependent kinase inhibitors Advanced cancer patient 



The authors would like to thank patients and their families for their participation and Nelly Hainault for writing support. Funding was provided by Nerviano (Grant No. ID0E2GAE300).

Compliance with ethical standards

Conflict of interest

Sandrine Aspeslagh received speaker’s fee from BMS, Astra Zeneca and Roche. Kunwar Shailubhai is a member of the board of Tiziana Life Sciences. Antoine Hollebecque received honoraria from Merck Serono, had an advisory role for AMGEN and Lilly, and received travel and accommodation expenses from Amgen and Servier. Christophe Massard received honoraria/consultancy fees from Sanofi Genzyme, Janssen, Astellas, Genentech, Orion, Medimmune and Ipsen. Michele Reni: Celgene, Boehringer, Genentech, Lilly, Merck-Serono, Baxalta, Shire, Pfizer, Novocure, Halozyme, Novartis. Jean-Charles Soria: AstraZeneca, Astex, Clovis, GSK, Gammamabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, Pharmamar, Pierre Fabre, Roche-Genentech, Sanofi, Servier, Symphogen, Takeda. Rastilav Bahleda, Anna Spreafico, Anas Gazzah, Andréa Varga: none.


  1. 1.
    O’Leary B, Finn RS, Turner NC (2016) Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 13:417–430. doi: 10.1038/nrclinonc.2016.26 CrossRefPubMedGoogle Scholar
  2. 2.
    Otto T, Sicinski P (2017) Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer 17:93–115. doi: 10.1038/nrc.2016.138 CrossRefPubMedGoogle Scholar
  3. 3.
    Nakagawara A (2001) Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 169:107–114. doi: 10.1016/S0304-3835(01)00530-4 CrossRefPubMedGoogle Scholar
  4. 4.
    Amatu A, Sartore-Bianchi A, Siena S (2016) NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 1:1–10. doi: 10.1136/esmoopen-2015-000023 CrossRefGoogle Scholar
  5. 5.
    Ardini E, Menichincheri M, Banfi P et al (2016) Entrectinib, a pan-TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indications. Mol Cancer Ther 15:628–639. doi: 10.1158/1535-7163.MCT-15-0758 CrossRefPubMedGoogle Scholar
  6. 6.
    Albanese C, Alzani R, Amboldi N et al (2010) Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy. Mol Cancer Ther 9:2243–2254. doi: 10.1158/1535-7163.MCT-10-0190 CrossRefPubMedGoogle Scholar
  7. 7.
    Weiss GJ, Hidalgo M, Borad MJ et al (2012) Phase I study of the safety, tolerability and pharmacokinetics of PHA-848125AC, a dual tropomyosin receptor kinase A and cyclin-dependent kinase inhibitor, in patients with advanced solid malignancies. Invest New Drugs 30:2334–2343. doi: 10.1007/s10637-011-9774-6 CrossRefPubMedGoogle Scholar
  8. 8.
    Spielmann M, Llombart-Cussac A, Kalla S et al (2001) Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology 60:303–307. doi: 10.1159/000058524 CrossRefPubMedGoogle Scholar
  9. 9.
    Fossella FV, Lippman SM, Shin DM et al (1997) Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer. J Clin Oncol 15:310–316. doi: 10.1200/jco.1997.15.1.310 CrossRefPubMedGoogle Scholar
  10. 10.
    Mavroudis D, Malamos N, Alexopoulos A et al (1999) Salvage chemotherapy in anthracycline-pretreated metastatic breast cancer patients with docetaxel and gemcitabine: a multicenter phase II trial. Ann Oncol Off J Eur Soc Med Oncol 10:211–215CrossRefGoogle Scholar
  11. 11.
    Kose MF, Sufliarsky J, Beslija S et al (2005) A phase II study of gemcitabine plus carboplatin in platinum-sensitive, recurrent ovarian carcinoma. Gynecol Oncol 96:374–380. doi: 10.1016/j.ygyno.2004.10.011 CrossRefPubMedGoogle Scholar
  12. 12.
    Castellano D, Lianes P, Paz-Ares L et al (1998) A phase II study of a novel gemcitabine plus cisplatin regimen administered every three weeks for advanced non-small-cell lung cancer. Ann Oncol Off J Eur Soc Med Oncol 9:457–459CrossRefGoogle Scholar
  13. 13.
    von der Maase H, Sengelov L, Roberts JT et al (2005) Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 23:4602–4608. doi: 10.1200/JCO.2005.07.757 CrossRefPubMedGoogle Scholar
  14. 14.
    Karnitz LM, Flatten KS, Wagner JM et al (2005) Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival. Mol Pharmacol 68:1636–1644. doi: 10.1124/mol.105.012716 PubMedGoogle Scholar
  15. 15.
    Matthews DJ, Yakes FM, Chen J et al (2007) Pharmacological abrogation of S-phase checkpoint enhances the anti-tumor activity of gemcitabine in vivo. Cell Cycle 6:104–110CrossRefPubMedGoogle Scholar
  16. 16.
    Parsels LA, Morgan MA, Tanska DM et al (2009) Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells. Mol Cancer Ther 8:45–54. doi: 10.1158/1535-7163.MCT-08-0662 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Therasse P, Arbuck S, Eisenhauer E et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 87:881–886. doi: 10.1093/jnci/92.3.205 Google Scholar
  18. 18.
    Lee HW, Chung MJ, Kang H et al (2014) Gemcitabine-induced hemolytic uremic syndrome in pancreatic cancer: a case report and review of the literature. Gut Liver 8:109–112. doi: 10.5009/gnl.2014.8.1.109 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zupancic M, Shah PC, Shah-Khan F, Nagendra S (2007) Gemcitabine-associated thrombotic thrombocytopenic purpura. Lancet Oncol 8:634–641. doi: 10.1016/S1470-2045(07)70203-6 CrossRefPubMedGoogle Scholar
  20. 20.
    Delaloge S, Llombart A, Di Palma M et al (2004) Gemcitabine in patients with solid tumors and renal impairment: a pharmacokinetic phase I study. Am J Clin Oncol 27:289–293. doi: 10.1097/01.COC.0000071382.14174.C5 CrossRefPubMedGoogle Scholar
  21. 21.
    Brasca MG, Amboldi N, Ballinari D et al (2009) Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem 52:5152–5163. doi: 10.1021/jm9006559 CrossRefPubMedGoogle Scholar
  22. 22.
    Besse B, Garassino MC, Rajan A et al (2014) A phase II study of milciclib (PHA-848125AC) in patients (pts) with thymic carcinoma (TC). J Clin Oncol 32:5s (suppl; abstr 7526) Google Scholar
  23. 23.
    Sherr CJ, Beach D, Shapiro GI (2016) Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov 6:353–367. doi: 10.1158/2159-8290.CD-15-0894 CrossRefPubMedGoogle Scholar
  24. 24.
    Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153–166. doi: 10.1038/nrc2602 CrossRefPubMedGoogle Scholar
  25. 25.
    Sidle A, Palaty C, Dirks P et al (1996) Activity of the retinoblastoma family proteins, pRB, p107, and p130, during cellular proliferation and differentiation. Crit Rev Biochem Mol Biol 31:237–271. doi: 10.3109/10409239609106585 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Sandrine Aspeslagh
    • 1
  • Kunwar Shailubhai
    • 2
  • Rastilav Bahleda
    • 1
  • Anas Gazzah
    • 1
  • Andréa Varga
    • 1
  • Antoine Hollebecque
    • 1
  • Christophe Massard
    • 1
  • Anna Spreafico
    • 3
  • Michele Reni
    • 3
  • Jean-Charles Soria
    • 1
  1. 1.Drug Development Department (DITEP), Gustave Roussy Cancer CentreUniversité Paris-SaclayVillejuifFrance
  2. 2.Tiziana Life Sciences PlcLondonUK
  3. 3.Department of Medical OncologyIRCCS Ospedale San RaffaeleMilanItaly

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