Pazopanib in Patients with Osteosarcoma Metastatic to the Lung: Phase 2 Study Results and the Lessons for Tumor Measurement

Paul Frankel, Chris Ruel, An Uche, Edwin Choy, Scott Okuno, Neeta Somiah, Warren A Chow, Paul Frankel, Chris Ruel, An Uche, Edwin Choy, Scott Okuno, Neeta Somiah, Warren A Chow

Abstract

Background: This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable, pulmonary metastatic osteosarcoma. Patients and Methods. Patients with pulmonary metastatic osteosarcoma unresponsive to chemotherapy were eligible. Patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessment 1 month prior to and after initiation of treatment to calculate tumor doubling time and after every even numbered cycle. The primary endpoints were progression-free survival at 4 months, concomitant with a demonstrated 30% increase in tumor doubling time relative to the pretreatment growth rate.

Results: 12 patients (7 female) were enrolled. The study was terminated prematurely due to withdrawal of financial support by the sponsor. 8 subjects were eligible for the primary analysis, whereas 4 patients were in a predefined exploratory "slow-growing" cohort. In the "fast-growing" cohort, 3 of the 8 patients (37.5%) eligible for first-stage analysis were deemed "success" by the preplanned criteria, adequate to proceed to second-stage accrual. In addition, 1 of the 4 patients in the "slow-growing" cohort experienced a partial remission. Grade 1-2 diarrhea was the most common adverse event, and grade 3 events were infrequent.

Conclusion: This study illustrates a novel method of demonstrating positive drug activity in osteosarcoma by increasing tumor doubling time, and this is further supported by a partial response in a patient with "slow-growing" disease. This trial is registered with NCT01759303.

Conflict of interest statement

The authors declare they have no conflicts of interest.

Copyright © 2022 Paul Frankel et al.

Figures

Figure 1
Figure 1
Consort diagram.
Figure 2
Figure 2
Growth rates in patients with clinical benefit with pazopanib.
Figure 3
Figure 3
Growth rates in patients with absence of clinical benefit from pazopanib.

References

    1. Casali P. G., Bielack S., Abecassis N., et al. Bone sarcomas: ESMO-PaedCan-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology . 2018;29(4):iv79–iv95.
    1. Raymond A. K., Jaffe N. Osteosarcoma multidisciplinary approach to the management from the pathologist’s perspective. Cancer Treatment and Research . 2009;152:63–84. doi: 10.1007/978-1-4419-0284-9_4.
    1. . Osteosarcoma—childhood and adolescence: statistics. 2021. .
    1. Misaghi A., Goldin A., Awad M., Kulidjian A. A. Osteosarcoma: a comprehensive review. SICOT-J . 2018;4:p. 12. doi: 10.1051/sicotj/2017028.
    1. Marina N. M., Smeland S., Bielack S. S., et al. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. The Lancet Oncology . 2016;17(10):1396–1408. doi: 10.1016/s1470-2045(16)30214-5.
    1. Malawer M. M., Link M. P., Donaldson S. S. Cancer: Principles and Practice of Oncology . 6th. Vol. 1. Philadelphia, PA, USA: Lippincott Williams & Wilkins; 2001. Sarcomas of bone; pp. 1891–1935.
    1. Ferrari S., Briccoli A., Mercuri M., et al. Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival. Journal of Clinical Oncology . 2003;21(4):710–715. doi: 10.1200/jco.2003.03.141.
    1. Treasure T., Fiorentino F., Scarci M., Møller H., Utley M. Pulmonary metastasectomy for sarcoma: a systematic review of reported outcomes in the context of Thames cancer registry data. BMJ Open . 2012;2(5) doi: 10.1136/bmjopen-2012-001736.e001736
    1. Kager L., Zoubek A., Pötschger U., et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant cooperative osteosarcoma study group protocols. Journal of Clinical Oncology . 2003;21(10):2011–2018. doi: 10.1200/jco.2003.08.132.
    1. Abdeen A., Chou A. J., Healey J. H., et al. Correlation between clinical outcome and growth factor pathway expression in osteogenic sarcoma. Cancer . 2009;115(22):5243–5250. doi: 10.1002/cncr.24562.
    1. Kaya M., Wada T., Akatsuka T., et al. Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research . 2000;6(2):572–577.
    1. Schutz F. A. B., Choueiri T. K., Sternberg C. N. Pazopanib: clinical development of a potent anti-angiogenic drug. Critical Reviews in Oncology . 2011;77(3):163–171. doi: 10.1016/j.critrevonc.2010.02.012.
    1. van der Graaf W. T., Blay J.-Y., Chawla S. P., et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet . 2012;379(9829):1879–1886. doi: 10.1016/s0140-6736(12)60651-5.
    1. Hurwitz H. I., Dowlati A., Saini S., et al. Phase I trial of pazopanib in patients with advanced cancer. Clinical Cancer Research . 2009;15(12):4220–4227. doi: 10.1158/1078-0432.ccr-08-2740.
    1. Glade Bender J. L., Lee A., Adamson P. C., et al. Phase I study of pazopanib in children with relapsed or refractory solid tumors (ADVL0815): a Children’s Oncology Group phase i consortium trial. Journal of Clinical Oncology . 2011;29(15):p. 9501. doi: 10.1200/jco.2011.29.15_suppl.9501.
    1. Grignani G., Palmerini E., Dileo P., et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Annals of Oncology . 2012;23(2):508–516. doi: 10.1093/annonc/mdr151.
    1. Fox E., Patel S., Wathen J. K., et al. Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of Sarcoma Alliance for Research through Collaboration study 003. The Oncologist . 2012;17(3):321–e329. doi: 10.1634/theoncologist.2010-0265.
    1. Palmerini E., Jones R. L., Marchesi E., et al. Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone. BMC Cancer . 2016;16(1):p. 280. doi: 10.1186/s12885-016-2312-3.
    1. Suttle A. B., Ball H. A., Molimard M., et al. Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma. British Journal of Cancer . 2014;111(10):1909–1916. doi: 10.1038/bjc.2014.503.
    1. Verheijen R. B., Swart L. E., Beijnen J. H., Schellens J. H. M., Huitema A. D. R., Steeghs N. Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients: opportunities for dose optimization. Cancer Chemotherapy and Pharmacology . 2017;80(6):1171–1178. doi: 10.1007/s00280-017-3463-x.
    1. Gaspar N., Campbell-Hewson Q., Bielack S. S., et al. A multicenter, open-label, randomized, phase 2 study to compare the efficacy and safety of lenvatinib in combination with ifosfamide and etoposide versus ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma (OLIE; ITCC-082) Annals of Oncology . 2020;31(S6) doi: 10.1016/j.annonc.2020.08.1893.

Source: PubMed

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