Skip to main content

Advertisement

SpringerLink
Log in

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

  • Clinical Trial Report
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Background

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.

Design

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.

Results

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.

Conclusion

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 10:211–215

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 9:457–459

    Article  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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 6:104–110

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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. 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

    Article  CAS  PubMed  Google Scholar 

  24. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153–166. doi:10.1038/nrc2602

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

  1. Drug Development Department (DITEP), Gustave Roussy Cancer Centre, Université Paris-Saclay, 114 Rue Eduard Vaillant, 94805, Villejuif, France

    Sandrine Aspeslagh, Rastilav Bahleda, Anas Gazzah, Andréa Varga, Antoine Hollebecque, Christophe Massard & Jean-Charles Soria

  2. Tiziana Life Sciences Plc, 55 Park Lane, London, W1K 1NA, UK

    Kunwar Shailubhai

  3. Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy

    Anna Spreafico & Michele Reni

Authors
  1. Sandrine Aspeslagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kunwar Shailubhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rastilav Bahleda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anas Gazzah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andréa Varga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antoine Hollebecque
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christophe Massard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anna Spreafico
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michele Reni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean-Charles Soria
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sandrine Aspeslagh.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aspeslagh, S., Shailubhai, K., Bahleda, R. et al. Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors. Cancer Chemother Pharmacol 79, 1257–1265 (2017). https://doi.org/10.1007/s00280-017-3303-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-017-3303-z

Keywords

Search

Navigation