Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients

D Lorusso, G Scambia, G Amadio, A di Legge, A Pietragalla, R De Vincenzo, V Masciullo, M Di Stefano, G Mangili, G Citterio, M Mantori, A Lambiase, C Bordignon, D Lorusso, G Scambia, G Amadio, A di Legge, A Pietragalla, R De Vincenzo, V Masciullo, M Di Stefano, G Mangili, G Citterio, M Mantori, A Lambiase, C Bordignon

Abstract

Background: The NGR-hTNF (asparagine-glycine-arginine-human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels.

Methods: Patients progressing after ≥ 1 platinum/taxane-based regimen received NGR-hTNF 0.8 μg m(-2) and doxorubicin 60 mg m(-2) every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients.

Results: A total of 37 patients with platinum-free interval lower than 6 months (PFI<6; n=25), or between 6 and 12 months (PFI=6-12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2-2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23%; 95% CI 12-39%) had partial response (2 with PFI<6; 6 with PFI=6-12) and 15 (43%) had stable disease (10 with PFI<6; 5 with PFI=6-12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI<6, and 7.8 months for patients with PFI=6-12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001).

Conclusion: Tolerability and activity of this combination warrant further randomised testing in patients with PFI<6. The role of PBLC as a blood-based biomarker deserves further investigation.

Figures

Figure 1
Figure 1
Individual patient radiological responses (n=31). (A) Maximal change from baseline of target lesions. (B) Change from baseline over treatment of the total sum of longest diameters of target lesions. Tumour measurements were not repeated in six patients because of development of new lesions (n=4) and clinical deterioration before reassessment (n=2). Each bar or full line represent an individual patient. Upper, intermediate, and lower dotted lines indicate progression, partial, or complete response, respectively, according to the RECIST criteria.
Figure 2
Figure 2
Kaplan–Meier estimates of (A) progression-free survival and (B) overall survival for the whole study population (n=37). Vertical ticks denote censored observations.
Figure 3
Figure 3
Kaplan–Meier estimates of (A) progression-free survival and (B) overall survival for the whole study population (n=37) according to the baseline peripheral blood lymphocyte count. Vertical ticks denote censored observations.

References

    1. Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M, Colombo N, Fowler JM, Argenta PA, De Geest K, Mutch DG, Burger RA, Swart AM, Trimble EL, Accario-Winslow C, Roth LM (2009) Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol 27: 1419–1425
    1. Calcinotto A, Grioni M, Jachetti E, Curnis F, Mondino A, Parmiani G, Corti A, Bellone M (2012) Targeting TNF-a to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy. J Immunol 188: 2687–2694
    1. Cannistra SA (2004) Cancer of the ovary. N Engl J Med 35: 2519–2529
    1. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumours. Proc Natl Acad Sci 72: 3666–3670
    1. Curnis F, Sacchi A, Borgna L, Magni F, Gasparri A, Corti A (2000) Enhancement of tumour necrosis factor alpha antitumour immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat Biotechnol 18: 1185–1190
    1. Curnis F, Sacchi A, Corti A (2002) Improving chemotherapeutic drug penetration in tumours by vascular targeting and barrier alteration. J Clin Invest 110: 475–482
    1. Dondossola E, Gasparri AM, Colombo B, Sacchi A, Curnis F, Corti A (2011) Chromogranin A restricts drug penetration and limits the ability of NGR-TNF to enhance chemotherapeutic efficacy. Cancer Res 71: 5881–5890
    1. Ferrandina G, Ludovisi M, Lorusso D, Pignata S, Breda E, Savarese A, Del Medico P, Scaltriti L, Katsaros D, Priolo D, Scambia G (2008) Phase III Trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 26: 890–896
    1. Gregorc V, Santoro A, Bennicelli E, Punt CJA, Citterio G, Timmer-Bonte JNH, Caligaris-Cappio F, Lambiase A, Bordignon C, van Herpen CML (2009) Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours. Br J Cancer 101: 219–224
    1. Gregorc V, Citterio C, Vitali G, Spreafico A, Scifo P, Borri A, Donadoni G, Rossoni G, Corti C, Caligaris-Cappio F, Del Maschio A, Esposito A, De Cobelli F, Dell’Acqua F, Troysi A, Bruzzi P, Lambiase A, Bordignon C (2010a) Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours. Eur J Cancer 46: 198–206
    1. Gregorc V, Zucali PA, Santoro A, Ceresoli GL, Citterio G, De Pas TM, Zilembo N, De Vincenzo F, Simonelli M, Rossoni G, Spreafico A, Vigano MG, Fontana F, De Braud FG, Bajetta E, Caligaris-Cappio F, Bruzzi P, Lambiase A, Bordignon C (2010b) Phase II study of asparagine-glycine-arginine-human tumor necrosis factor alpha, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma. J Clin Oncol 28: 2604–2611
    1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61: 69–90
    1. Kumaran GC, Jayson GC, Clamp AR (2009) Antiangiogenic drugs in ovarian cancer. Br J Cancer 100: 1–7
    1. Lejeune FJ, Lienard D, Matter M, Ruegg C (2006) Efficiency of recombinant human TNF in human cancer therapy. Cancer Immun 6: 6–23
    1. Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, Pujade-Lauraine E, Lisyanskaya AS, Makhson AN, Rolski J, Gorbounova VA, Ghatage P, Bidzinski M, Shen K, Yuen-Sheung Ngan H, Vergote IB, Nam JN, Park YC, Lebedinsky CA, Poveda AM (2010) Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer. J Clin Oncol 28: 3107–3114
    1. Mutch DG, Orlando M, Goss T, Teneriello MG, Gordon AN, McMeekin SD, Wang Y, Scribner DR, Marciniack M, Naumann RW, Secord AA (2007) Randomized phase III trial of gemcitabine compared to pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 25: 2811–2818
    1. Nakasone ES, Askautrud HA, Kees T, Park JH, Plaks V, Ewald AJ, Fein M, Rasch MG, Tan YX, Qiu J, Park J, Sinha P, Bissell MJ, Frengen E, Werb Z, Egeblad M (2012) Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21: 488–503
    1. Poveda A, Vergote I, Tjulandin S, Kong B, Roy M, Chan S, Filipczyk-Cisarz E, Hagberg H, Kaye SB, Colombo N, Lebedinsky C, Parekh T, Gómez J, Park YC, Alfaro V, Monk BJ (2011) Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6–12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol 22: 39–48
    1. Rangel R, Sun Y, Guzman-Rojas L, Ozawa MG, Sun J, Giordano RJ, Van Pelt CS, Tinkey PT, Behringer RR, Sidman RL, Wadih Arap W, Pasqualini R (2007) Impaired angiogenesis in aminopeptidase N-null mice. Proc Natl Acad Sci USA 104: 4588–4593
    1. Rose PG, Tian C, Bookman MA (2010) Assessment of tumour response as a surrogate endpoint of survival in recurrent/platinum-resistant ovarian carcinoma: A Gynecologic Oncology Group study. Gynec Oncol 117: 324–329
    1. Rustin GJ. (2003) Use of CA-125 to assess response to new agents in ovarian cancer trials. J Clin Oncol 21: 187–193
    1. Sacchi A, Gasparri A, Gallo-Stampino C, Toma S, Curnis F, Corti A (2006) Synergistic antitumour activity of cisplatin, paclitaxel, and gemcitabine with tumour vasculature-targeted tumour necrosis factor-alpha. Clin Cancer Res 12: 175–182
    1. Sacchi A, Gasparri A, Curnis F, Bellone M, Corti C (2004) Crucial role for interferon-gamma in the synergism between tumour vasculature-targeted tumour necrosis factor alpha (NGR-TNF) and doxorubicin. Cancer Res 64: 7150–7155
    1. Santoro A, Pressiani T, Citterio G, Rossoni G, Donadoni G, Pozzi F, Rimassa L, Personeni N, Bozzarelli S, Rossoni G, Colombi S, De Braud FG, Caligaris-Cappio F, Lambiase A, Bordignon C (2010) Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma. Br J Cancer 103: 837–844
    1. Scheurich P, Thoma B, Ucer U, Pfizenmaier K (1987) Immunoregulatory activity of recombinant human tumour necrosis factor (TNF)-α: Induction of TNF receptors on human T cells and TNF-mediated enhancement of T cell responses. J Immunol 138: 1786–1790
    1. Ten Hagen TML, Van der Veen AH, Nooijen PTGA, Van Tiel S, Seynhaeve ALB, Eggermont AMM (2000) Low-dose tumour necrosis factor-α augments antitumour activity of stealth liposomal doxorubicin in soft tissue sarcoma-bearing rats. Int J Cancer 87: 829–837
    1. van Heeckeren WJ, Bhakta S, Ortis J (2006) Promise of new vascular-disrupting agents balanced with cardiac toxicity: is it time for oncologists to get to know their cardiologists? J Clin Oncol 24: 1485–1488
    1. van Hensbergen Y, Broxtermann HJ, Rana S, van Diest PJ, Duyndam MCA, Hoekman K, Pinedo HM, Boven E (2004) Reduced growth, increased vascular area, and reduced response to cisplatin in CD13-overexpressing human ovarian cancer xenografts. Clin Cancer Res 10: 1180–1191
    1. van Laarhoven HWM, Fiedler W, Desar IME, van Asten JJA, Sandrine Marreaud S, Lacombe D, Govaerts AS, Bogaerts J, Lasch P, Timmer-Bonte JNH, Lambiase A, Bordignon C, Punt CJA, Heerschap A, van Herpen CML (2010) Phase I clinical and magnetic resonance imaging study of the vascular agent NGR-hTNF in patients with advanced cancers (European Organization for Research and Treatment of Cancer Study 16041). Clin Cancer Res 16: 1315–1323
    1. Zhang L, Conejo-Garcia JR, Katsaros D, Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoural T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348: 203–213

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj