SAINT: A Phase I/Expanded Phase II Study Using Safe Amounts of Ipilimumab, Nivolumab and Trabectedin as First-Line Treatment of Advanced Soft Tissue Sarcoma

Erlinda Maria Gordon, Sant P Chawla, Walter Andree Tellez, Elan Younesi, Sonu Thomas, Victoria S Chua-Alcala, Hripsime Chomoyan, Chrysler Valencia, Don Arlen Brigham, Ania Moradkhani, Doris Quon, Amornchit Srikureja, Steven G Wong, William Tseng, Noah Federman, Erlinda Maria Gordon, Sant P Chawla, Walter Andree Tellez, Elan Younesi, Sonu Thomas, Victoria S Chua-Alcala, Hripsime Chomoyan, Chrysler Valencia, Don Arlen Brigham, Ania Moradkhani, Doris Quon, Amornchit Srikureja, Steven G Wong, William Tseng, Noah Federman

Abstract

Background: This Phase 1/2 study is based on the hypothesis that immune checkpoint inhibitors are more effective when given earlier in the course of the disease for advanced soft tissue sarcoma.

Methods: Phase I endpoints-maximum tolerated dose in previously treated patients; Phase II endpoints-best response, progression free survival and overall survival and incidence of adverse events in previously untreated patients; Phase I treatments-escalating doses of trabectedin (1.0, 1.2, 1.5 mg/m2) as continuous intravenous infusion over 24 h every 3 weeks, 1 mg/kg of ipilimumab given intravenously every 12 weeks, and 3 mg/kg of nivolumab given intravenously every 2 weeks; Phase II treatments-maximum tolerated dose of trabectedin and defined doses of ipilimumab and nivolumab.

Results: Phase I (n = 9)-the maximum tolerated dose of trabectedin was 1.2 mg/m2; Phase II (n = 79)-6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median progression-free survival, 6.7 months (CI 95%: 4.4-7.9), median overall survival, 24.6 months (CI 95%: 17.0-.); Grade 3/4 therapy-related adverse events (n = 92)-increased ALT (25%), fatigue (8.7%), increased AST (8.7%), decreased neutrophil count (5.4%) and anemia (4.6%).

Conclusion: SAINT is a safe and effective first-line treatment for advanced soft tissue sarcoma.

Keywords: alkylating agent; chemotherapy; immune checkpoint inhibitor; immunotherapy; ipilimumab; nivolumab and trabectedin; soft tissue sarcoma.

Conflict of interest statement

The authors E.M.G., S.P.C., W.A.T., E.Y., S.T., V.S.C.-A., H.C., C.V., D.A.B., A.M., S.G.W., D.Q., A.S., N.F., W.T. have no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Graphic illustration of the mechanism of action of Ipilimumab, Nivolumab and Trabectedin in the tumor microenvironment. Ipilimumab (I) blocks the CTLA 4 receptor and nivolumab (N) blocks the PD-1 receptor on T cells which then block the PD1- PD-L1 interaction on tumor cells. Trabectedin (T) not only kills cancer cells but depletes the tumor microenvironment of growth promoting or M2 macrophages. The combined effect of these three drugs is sustained T cell activation, resulting in tumor lysis, inhibition of tumor growth or tumor eradication.
Figure 2
Figure 2
Kaplan–Meier graphs of overall survival and progression free survival for the mITT patients in Phase II of the study. (A,B) Percent survival is plotted on the vertical axis as a function of time from treatment initiation (months) plotted on the horizontal axis.

References

    1. Wagner M.J., Ismaila L., Duh M., Korves C., Solleza F., Manson S., Diaz J., Neary M., Demetri G. A retrospective chart review of drug treatment patterns and clinical outcomes among patients with metastatic or recurrent soft tissue sarcoma refractory to one or more prior chemotherapy treatments. BMC Cancer. 2015;15:175. doi: 10.1186/s12885-015-1182-4.
    1. Mocellin S., Rossi C., Brandes A., Nitti D. Adult soft tissue sarcomas: Conventional therapies and molecularly targeted approaches. Cancer Treat. Rev. 2006;32:9–27. doi: 10.1016/j.ctrv.2005.10.003.
    1. Sharma S., Takyar S., Manson S., Powell S., Penel N. Efficacy and safety of pharmacological interventions in second- or later-line treatment of patients with advanced soft tissue sarcoma: A systematic review. BMC Cancer. 2013;13:385. doi: 10.1186/1471-2407-13-385.
    1. Petek B.J., Loggers E.T., Pollack S.M., Jones R.L. Trabectedin in Soft Tissue Sarcomas. Mar. Drugs. 2015;13:974–983. doi: 10.3390/md13020974.
    1. Judson I., Verweij J., Gelderblom H., Hartmann J.T., Schöffski P., Blay J.Y., Kerst J.M., Sufliarsky J., Whelan J., Hohenberger P., et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for firstline treatment of advanced or metastatic soft-tissue sarcoma: A randomised controlled phase 3 trial. Lancet Oncol. 2014;15:415–423. doi: 10.1016/S1470-2045(14)70063-4.
    1. Nagar S.P., Mytelka D.S., Candrilli S.D., D’yachkova Y., Lorenzo M., Kasper B., Lopez-Martin J.A., Kaye J.A. Treatment Patterns and Survival among Adult Patients with Advanced Soft Tissue Sarcoma: A Retrospective Medical Record Review in the United Kingdom, Spain, Germany, and France. Sarcoma. 2018;2018:5467057. doi: 10.1155/2018/5467057.
    1. Demetri G.D., von Mehren M., Jones R.L., Hensley M.L., Schuetze S.M., Staddon A., Milhem M., Elias A., Ganjoo K., Tawbi H., et al. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J. Clin. Oncol. 2016;34:786–793. doi: 10.1200/JCO.2015.62.4734.
    1. Coens C., van der Graaf W.T.A., Blay J.-Y., Chawla S.P., Judson I., Sanfilippo R., Manson S.C., Hodge R.A., Marreaud S., Prins J.B., et al. Health-related quality-of-life results from PALETTE: A randomized, double-blind, phase 3 trial of pazopanib versus placebo in patients with soft tissue sarcoma whose disease has progressed during or after prior chemotherapy-a European Organization for research and treatment of cancer soft tissue and bone sarcoma group global network study (EORTC 62072) Cancer. 2015;121:2933–2934. doi: 10.1002/cncr.29426.
    1. Schoffski P., Chawla S., Maki R.G., Italiano A., Gelderblom H., Choy E., Grignani G., Camargo V., Bauer S., Rha S.Y., et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: A randomised, open-label, multicentre, phase III trial. Lancet. 2016;387:1629–1637. doi: 10.1016/S0140-6736(15)01283-0.
    1. In G.K., Hu J.S., Tseng W.W. Treatment of advanced, metastatic soft tissue sarcoma: Latest evidence and clinical considerations. Ther. Adv. Med. Oncol. 2017;9:533–550. doi: 10.1177/1758834017712963.
    1. Ferre A., Álvarez R.Á., Herráez A.C., Jurado J.C., González A.E., Martin-Broto J., Marín V.M., Vega A.M., García A.S., Morales C.V., et al. SEOM Clinical Guideline of management of soft-tissue sarcoma. Clin. Transl. Oncol. 2021;23:922–930. doi: 10.1007/s12094-020-02534-0.
    1. Blay J.-Y., Le Cesne A., Demetri G.D. The current reality of soft tissue sarcomas: Advances, controversies, areas for improvement, and promising new treatments. Expert. Rev. Anticancer Ther. 2020;20:29–39. doi: 10.1080/14737140.2020.1753511.
    1. Lee A., Huang P., DeMatteo R.P., Pollack S.M. Immunotherapy for Soft Tissue Sarcoma: Tomorrow Is Only a Day Away. Am. Soc. Clin. Oncol. Educ. Book. 2016;35:281–290. doi: 10.1200/EDBK_157439.
    1. Clemente O., Ottaiano A., Di Lorenzo G., Bracigliano A., Lamia S., Cannella L., Pizzolorusso A., Di Marzo M., Santorsola M., Chiara D., et al. Is immunotherapy in the future of therapeutic management of sarcomas? J. Transl. Med. 2021;19:173. doi: 10.1186/s12967-021-02829-y.
    1. Yervoy pi [(accessed on 6 June 2017)]; Available online: .
    1. Opdivo pi [(accessed on 6 June 2017)]; Available online: .
    1. Yervoy [(accessed on 6 June 2017)]; Available online: .
    1. Schreiber R.D., Old L.J., Smyth M.J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–1570. doi: 10.1126/science.1203486.
    1. Storer B.E. Design and analysis of phase I clinical trials. Biometrics. 1989;45:925–937. doi: 10.2307/2531693.
    1. Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., Dancey J., Arbuck S., Gwyther S., Mooney M., et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur. J. Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Park H., Kim G., Kim K., Lee C., Yoon S., Chae Y., Tirumani S., Ramaiya N. Comparison of RECIST 1.1 and iRECIST in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis. Cancers. 2021;13:120. doi: 10.3390/cancers13010120.
    1. NCI Common Terminology Criteria for Adverse Events Version 4.03. [(accessed on 6 June 2017)];2010 :1–78. Available online: .
    1. Kaplan E.L., Meier P. Nonparametric Estimation from Incomplete Observations. J. Am. Stat. Assoc. 1958;53:457–481. doi: 10.1080/01621459.1958.10501452.
    1. Selby M.J., Engelhardt J.J., Johnston R.J., Lu L.S., Han M., Thudium K., Yao D., Quigley M., Valle J., Wang C., et al. Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology. PLoS ONE. 2016;11:e0161779.
    1. Tawbi H.A., Burgess M., Bolejack V., Van Tine B.A., Schuetze S.M., Hu J., D’Angelo S., Attia S., Riedel R.F., Priebat D.A., et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017;18:1493–1501. doi: 10.1016/S1470-2045(17)30624-1. Erratum in: Lancet Oncol. 2018, 19, e8.
    1. D’Angelo S.P., Mahoney M.R., Van Tine B.A., Atkins J., Milhem M.M., Jahagirdar B.N., Antonescu C.R., Horvath E., Tap W.D., Schwartz G.K., et al. A non-comparative multi-center randomized phase II study of nivolumab +/− ipilimumab for patients with metastatic sarcoma (Alliance A091401) Lancet Oncol. 2018;19:416–426. doi: 10.1016/S1470-2045(18)30006-8.
    1. Dunn G.P., Old L.J., Schreiber R.D. The Immunobiology of Cancer Immunosurveillance and Immunoediting. Immunity. 2004;21:137–148. doi: 10.1016/j.immuni.2004.07.017.
    1. Chawla S.P., Sankhala K., Ravicz J., Kang G., Liu S., Stumpf N., Leong B., Kim S., Arasheben S., Tseng W., et al. Clinical Experience with Combination Chemo-/Immunotherapy using Trabectedin and Nivolumab for Advanced Soft Tissue Sarcoma. J. Sarcoma Res. 2018;2:1009. doi: 10.1200/JCO.2018.36.15_suppl.e23568.
    1. Birdi H.K., Jirovec A., Cortés-Kaplan S., Werier J., Nessim C., Diallo J.S., Ardolino M. Immunotherapy for sarcomas: New frontiers and unveiled opportunities. J. Immunother. Cancer. 2021;9:e001580. doi: 10.1136/jitc-2020-001580.
    1. Pautier P., Italiano A., Piperno-Neumann S., Chevreau C., Penel N., Firmin N., Boudou-Rouquette P., Bertucci F., Balleyguier C., Lebrun-Ly V., et al. Doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma (LMS-04): A randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2022;23:1044–1054. doi: 10.1016/S1470-2045(22)00380-1.

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