We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Clinical Trial ProtocolOpen AccessOpen Access license

FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer

    Kathleen N Moore

    *Author for correspondence: Tel.: +1 405 271 8707;

    E-mail Address: kathleen-moore@ouhsc.edu

    Department of Obstetrics & Gynecology, Stephenson Oklahoma Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

    ,
    Ignace Vergote

    Gynaecological Oncology, Leuven Cancer Institute, Leuven 3000, Belgium

    ,
    Ana Oaknin

    Medical Oncology Department, Vall D'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain

    ,
    Nicoletta Colombo

    Gynecologic Oncology, The European Institute of Oncology, Milan 20141, Italy

    ,
    Susana Banerjee

    Gynaecology Unit, Royal Marsden Hospital, London, SW3 6JJ, UK

    ,
    Amit Oza

    Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto M5G 2M9, Canada

    ,
    Patricia Pautier

    Department of Adult Medicine, Gustave Roussy Cancer Campus, Villejuif 94800, France

    ,
    Karim Malek

    Clinical Development, ImmunoGen, Inc., Waltham, MA 02451, USA

    &
    Michael J Birrer

    Division of Hematology–Oncology, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL 35294, USA

    Published Online:https://doi.org/10.2217/fon-2017-0646

    Mirvetuximab soravtansine, an antibody–drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136(5), e359–e386 (2015).
    • 2 Reid BM, Permuth JB, Sellers TA. Epidemiology of ovarian cancer: a review. Cancer Biol. Med. 14(1), 9–32 (2017).
    • 3 Lacey JV, Sherman ME. Ovarian neoplasia. In: Robboy's Pathology of the Female Reproductive Tract. Robboy SL, Mutter GL, Prat J (Eds). Churchill Livingstone, Elsevier, Oxford, UK, 601 (2009).
    • 4 Desai A, Xu J, Aysola K et al. Epithelial ovarian cancer: an overview. World J. Transl. Med. 3(1), 1–8 (2014).
    • 5 Davis A, Tinker AV, Friedlander M. ‘Platinum resistant’ ovarian cancer: what is it, who to treat and how to measure benefit? Gynecol. Oncol. 133(3), 624–631 (2014).
    • 6 Markman M, Bookman MA. Second-line treatment of ovarian cancer. Oncologist 5(1), 26–35 (2000).
    • 7 Luvero D, Milani A, Ledermann JA. Treatment options in recurrent ovarian cancer: latest evidence and clinical potential. Ther. Adv. Med. Oncol. 6(5), 229–239 (2014).
    • 8 Pujade-Lauraine E, Hilpert F, Weber B et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized Phase III trial. J. Clin. Oncol. 32(13), 1302–1308 (2014). •• Pivotal Phase III trial results that resulted in approval of bevacizumab for the treatment of ovarian cancer.
    • 9 Poveda AM, Selle F, Hilpert F et al. Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian cancer: analysis by chemotherapy cohort of the randomized Phase III AURELIA trial. J. Clin. Oncol. 33(32), 3836–3838 (2015).
    • 10 Pistollato F, Calderon Iglesias R, Ruiz R et al. The use of natural compounds for the targeting and chemoprevention of ovarian cancer. Cancer Lett. 411, 191–200 (2017).
    • 11 Liu J, Matulonis UA. New strategies in ovarian cancer: translating the molecular complexity of ovarian cancer into treatment advances. Clin. Cancer Res. 20(20), 5150–5156 (2014).
    • 12 Della Pepa C, Tonini G, Pisano C et al. Ovarian cancer standard of care: are there real alternatives? Chin. J. Cancer 34(1), 17–27 (2015).
    • 13 Colombo N, Conte PF, Pignata S, Raspagliesi F, Scambia G. Bevacizumab in ovarian cancer: focus on clinical data and future perspectives. Crit. Rev. Oncol. Hematol. 97, 335–348 (2016).
    • 14 Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br. J. Cancer 115(10), 1157–1173 (2016).
    • 15 Vergote IB, Marth C, Coleman RL. Role of the folate receptor in ovarian cancer treatment: evidence, mechanism, and clinical implications. Cancer Metastasis Rev. 34(1), 41–52 (2015). • Summarizes role of folate receptor in ovarian cancer, providing a rationale for targeting this receptor in the development of new therapeutic agents.
    • 16 Choi SW, Mason JB. Folate and carcinogenesis: an integrated scheme. J. Nutr. 130(2), 129–132 (2000).
    • 17 Kalli KR, Oberg AL, Keeney GL et al. Folate receptor α as a tumor target in epithelial ovarian cancer. Gynecol. Oncol. 108(3), 619–626 (2008).
    • 18 Markert S, Lassmann S, Gabriel B et al. Alpha-folate receptor expression in epithelial ovarian carcinoma and non-neoplastic ovarian tissue. Anticancer Res. 28(6A), 3567–3572 (2008).
    • 19 O'Shannessy DJ, Somers EB, Smale R, Fu YS. Expression of folate receptor-α (FRA) in gynecologic malignancies and its relationship to the tumor type. Int. J. Gynecol. Pathol. 32(3), 258–268 (2013).
    • 20 Toffoli G, Russo A, Gallo A et al. Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer. Int. J. Cancer 79(2), 121–126 (1998).
    • 21 Marchetti C, Palaia I, Giorgini M et al. Targeted drug delivery via folate receptors in recurrent ovarian cancer: a review. Onco Targets Ther. 7, 1223–1236 (2014).
    • 22 Assaraf YG, Leamon CP, Reddy JA. The folate receptor as a rational therapeutic target for personalized cancer treatment. Drug Resist. Updat. 17(4–6), 89–95 (2014).
    • 23 Ledermann JA, Canevari S, Thigpen T. Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments. Ann. Oncol. 26(10), 2034–2043 (2015).
    • 24 Vergote I, Armstrong D, Scambia G et al. A randomized, double-blind, placebo-controlled, Phase III study to assess efficacy and safety of weekly farletuzumab in combination with carboplatin and taxane in patients with ovarian cancer in first platinum-sensitive relapse. J. Clin. Oncol. 34(19), 2271–2278 (2016).
    • 25 Levin J. Merck and endocyte announce independent DSMB recommends vintafolide PROCEED Phase III trial be stopped for futility following interim analysis. FierceBiotech (2014). www.fiercebiotech.com/biotech/merck-and-endocyte-announce-independent-dsmb-recommends-vintafolide-proceed-phase-3-trial.
    • 26 Chari RV, Miller ML, Widdison WC. Antibody–drug conjugates: an emerging concept in cancer therapy. Angew. Chem. Int. Ed. Engl. 53(15), 3796–3827 (2014).
    • 27 Parslow AC, Parakh S, Lee FT, Gan HK, Scott AM. Antibody–drug conjugates for cancer therapy. Biomedicines 4(3), e254–e262 (2016).
    • 28 Thomas A, Teicher BA, Hassan R. Antibody–drug conjugates for cancer therapy. Lancet Oncol. 17(6), e254–e262 (2016).
    • 29 Lambert JM, Morris CQ. Antibody–drug conjugates (ADCs) for personalized treatment of solid tumors: a review. Adv. Ther. 34(5), 1015–1035 (2017).
    • 30 Lambert JM, Berkenblit A. Antibody–drug conjugates for cancer treatment. Annu. Rev. Med. 17(6), e254–e262 (2017). • Comprehensive review of the current status of antibody–drug conjugates undergoing advanced clinical testing.
    • 31 Gunderson CC, Moore KM. Mirvetuximab soravtansine. Folate receptor α (FR-α)-targeting antibody drug conjugate, treatment of epithelial ovarian cancer. Neoplasia 18(12), 775–784 (2016).
    • 32 Oroudjev E, Lopus M, Wilson L et al. Maytansinoid–antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol. Cancer Ther. 9(10), 2700–2713 (2010).
    • 33 Goldmacher VS, Audette CA, Guan Y et al. High-affinity accumulation of a maytansinoid in cells via weak tubulin interaction. PLoS ONE 10(2), e0117523 (2015).
    • 34 Kovtun YV, Audette CA, Ye Y et al. Antibody–drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 66(6), 3214–3221 (2006).
    • 35 Ab O, Whiteman KR, Bartle LM et al. IMGN853, a folate receptor-α (FR-α)-targeting antibody–drug conjugate, exhibits potent targeted antitumor activity against FR-α-expressing tumors. Mol. Cancer Ther. 14(7), 1605–1613 (2015). • Preclinical development and characterization of mirvetuximab soravtansine.
    • 36 Ponte JF, Ab O, Lanieri L et al. Mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody–drug conjugate, potentiates the activity of standard of care therapeutics in ovarian cancer models. Neoplasia 18(12), 775–784 (2016).
    • 37 Moore KN, Borghaei H, O'Malley DM et al. Phase I dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody–drug conjugate, in patients with solid tumors. Cancer 123(16), 3080–3087 (2017).
    • 38 Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody–drug conjugates in human clinical trials. J. Ocul. Pharmacol. Ther. 31(10), 589–604 (2015).
    • 39 Martin LP, Konner JA, Moore KN et al. Characterization of folate receptor α (FR-α) expression in archival tumor and biopsy samples from relapsed epithelial ovarian cancer patients: a Phase I expansion study of the FR-α-targeting antibody–drug conjugate mirvetuximab soravtansine. Gynecol. Oncol. 147(2), 402–407 (2017).
    • 40 Moore KN, Martin LP, O'Malley DM et al. Safety and activity of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a Phase I expansion study. J. Clin. Oncol. 35(10), 1112–1118 (2017). •• Findings of a Phase I expansion cohort study indicating that mirvetuximab soravtansine is clinically active in patients with platinum-resistant epithelial ovarian cancer.
    • 41 Moore KN, Matulonis UA, O'Malley DM et al. Mirvetuximab soravtansine (IMGN853), a folate alpha (FR-α)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian caner (EOC) patients (pts): activity and safety analyses in Phase I pooled expansion cohorts. J. Clin. Oncol. 35(Suppl.), Abstract 5547 (2017).
    • 42 Marupudi NI, Han JE, Li KW, Renard VM, Tyler BM, Brem H. Paclitaxel: a review of adverse toxicities and novel delivery strategies. Expert Opin. Drug Saf. 6(5), 609–621 (2007).
    • 43 Rosenberg P, Andersson H, Boman K et al. Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum. Acta Oncol. 41(5), 418–424 (2002).
    • 44 Markman M, Hall J, Spitz D et al. Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J. Clin. Oncol. 20(9), 2365–2369 (2002).
    • 45 Gynecologic Oncology Group, Markman M, Blessing J et al. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol. Oncol. 101(3), 436–440 (2006).
    • 46 Baird RD, Tan DS, Kaye SB. Weekly paclitaxel in the treatment of recurrent ovarian cancer. Nat. Rev. Clin. Oncol. 7(10), 575–582 (2010).
    • 47 Markman M. Pegylated liposomal doxorubicin: appraisal of its current role in the management of epithelial ovarian cancer. Cancer Manag. Res. 3, 219–225 (2011).
    • 48 Markman M, Kennedy A, Webster K, Peterson G, Kulp B, Belinson J. Phase II trial of liposomal doxorubicin (40 mg/m(2)) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. Gynecol. Oncol. 78(3 Pt 1), 369–372 (2000).
    • 49 Wilailak S, Linasmita V. A study of pegylated liposomal doxorubicin in platinum-refractory epithelial ovarian cancer. Oncology 67(3–4), 183–186 (2004).
    • 50 Nakayama M, Kobayashi H, Takahara T, Nishimura Y, Fukushima K, Yoshizawa K. A comparison of overall survival with 40 and 50 mg/m2 pegylated liposomal doxorubicin treatment in patients with recurrent epithelial ovarian cancer: propensity score-matched analysis of real-world data. Gynecol. Oncol. 143(2), 246–251 (2016).
    • 51 Sehouli J, Oskay-Ozcelik G. Current role and future aspects of topotecan in relapsed ovarian cancer. Curr. Med. Res. Opin. 25(3), 639–651 (2009).
    • 52 Sehouli J, Stengel D, Harter P et al. Topotecan weekly versus conventional 5-day schedule in patients with platinum-resistant ovarian cancer: a randomized multicenter Phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J. Clin. Oncol. 29(2), 242–248 (2011).