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IV ovarian cancer: Preliminary results
Gynecologic Oncology 137 (2015) 2–91
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Abstracts Presented for the 2015 Society of Gynecologic Oncology 46th Annual Meeting on Women's Cancer® March 28–31, 2015 Hilton Chicago, Chicago, IL Opening Scientific Session Saturday, March 28, 2015 Moderators: Uziel Beller, MD, Shaare Zedek Medical Center, Jerusalem, Israel Joel I. Sorosky, MD, Abington Memorial Hospital, Abington, PA, USA Farr R. Nezhat, MD, FACOG, FACS, St. Luke's-Roosevelt Hospital, New York, NY, USA 1 — Scientific Plenary Randomized phase II trial of maintenance autologous tumor cell vaccine (FANG™) following clinical complete response (cCR) in stage III/IV ovarian cancer: Preliminary results J. Oha, M. Barvea,b, E.A. Grosenc, B.A. Finea, T.P. Heffernand, C.M. Matthewsa, C.A. Stringera, E.C. Koona, H.M. Goodmane, E.L. Flemingf, L.R. DeMarsf, M.S. Bergmanc, N. Senzerb,g, J. Nemunaitisa,b,g,h. aTexas Oncology, P.A., Dallas, TX, USA, bMary Crowley Cancer Research Centers, Dallas, TX, USA, cCancer Care Northwest, Spokane, WA, USA, dNorth Texas Gynecologic Oncology, Dallas, TX, USA, eFlorida Cancer Specialists, West Palm Beach, FL, USA, fDartmouth Hitchcock Medical Center, Lebanon, NH, USA, gGradalis, Inc., Dallas, TX, USA, hMedical City Dallas Hospital, Dallas, TX, USA Objectives: Phase I evaluation of FANG vaccine (granulocyte macrophage colony-stimulating factor [GMCSF]/bi-shRNAi furin vector transfected autologous tumor cells) demonstrated safety; confirmed both GMCSF transgene expression and knockdown of furin and consequent transforming growth factor-b1 and b2 expression; showed T-cell activation per gamma interferon (IFN)enzyme-linked immunospot assay (ELISPOT); and resulted in a longer-than-expected survival duration correlated with ELISPOT “turn on.” These findings justified phase II testing (Senzer et al. Mol Ther. 2012; Senzer et al. Vaccines and Vaccination. 2013). The majority of women with stage III/IV ovarian cancer who achieve cCR with standard of care (SOC) (the combination of debulking surgery and chemotherapy) relapse within 2 years. The objective of this trial was to determine regression-free survival difference in a 2:1 randomized phase II trial. Methods: This 2:1 randomized phase II open-label trial of FANG used tumor harvested at the time of surgical debulking. Stage III/IV ovarian cancer patients achieving cCR following primary surgical debulking and chemotherapy were entered to undergo vaccine construction. Given the high recurrence rate and subsequent 0090-8258/$ – see front matter
progression seen with frontline SOC treatment, we initiated a randomized phase II study of maintenance FANG vaccination following initial debulking/chemotherapy. Patients received 1.0 × 107 cells/intradermal injection once a month for up to 12 doses or were followed as per SOC, i.e., without maintenance therapy. Key endpoints included safety, immune response (RFS). Results: Twenty-one evaluable (ELISPOT-negative following confirmed cCR) patients were randomized, 14 of whom had received at least 1 FANG injection and 7 of whom had been randomized to No FANG treatment. This trial design allowed for control group crossover at time of progression. No toxic effects were observed. A higher rate of IFN ELISPOT response was elicited in this prior chemotherapynaive population in comparison to that achieved in phase I trial (92% vs. 50%). Mean and median RFS of the FANG and No FANG patients are shown in Fig. 1. Conclusions: Based on safety, the high rate of T-cell activation in this population in correlation, and the marked delay in time to regression, randomization was discontinued and phase III testing involving 382 evaluable patients is being pursued.
Abstracts / Gynecologic Oncology 137 (2015) 2–91 RFS since treatment start Treatment status
Total N
No. recurrences
Mean (days)
Median (days)
No FANGa FANGa
7 14
5 7
149 509
94 399
Data as of 03-25-2014. 2 patients unevaluable for efficacy at baseline and 2 control patients who were ELISPOT +. a
3
carboplatin, this therapy enriched for the SCSC, and tumors grew robustly after cessation of treatment. Under the conditions tested, neither Birinapant nor P53AI alone was able to eliminate tumors completely. Conclusions: Our results demonstrate that complete eradication of serous cancers requires therapeutic targeting of the SCSC. This goal can be achieved simply by adding an additional therapy tailored to the patient's tumor that can sensitize the SCSC to carboplatin.
doi:10.1016/j.ygyno.2015.01.003
doi:10.1016/j.ygyno.2015.01.004
2 — Scientific Plenary Restoration of apoptosis in serous cancer stem cells sensitizes them to platinum therapy resulting in tumor eradication D.M. Janzena, E. Tiourina, J.A. Salehia, J. Lub, A. Soragnib, D.S. Eisenbergb, M. Pellegrinib, S. Memarzadeha. aUCLA David Geffen School of Medicine, Los Angeles, CA, USA, bUniversity of California, Los Angeles, Los Angeles, CA, USA
3 — Scientific Plenary A phase III randomized controlled clinical trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinumsensitive, recurrent ovarian, peritoneal primary and fallopian tube cancer (Gynecologic Oncology Group 0213) R.L. Colemana, M.F. Bradyb, T.J. Herzogc, P. Sabbatinid, D.K. Armstronge, J.L. Walkerf, B.G. Kimg, K. Fujiwarah, K.S. Tewarii, D.M. O'Malleyj. aThe University of Texas MD Anderson Cancer Center, Houston, TX, USA, b University of Buffalo, Buffalo, NY, USA, cUniversity of Cincinnati, Cincinnati, OH, USA, dMemorial Sloan Kettering Cancer Center, New York, NY, USA, e Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA, fThe University of Oklahoma, Oklahoma City, OK, USA, gSungkyunkwan University School of Medicine, Seoul, South Korea, hSaitama Medical University International Medical Center, Hidaka-Shi, Japan, iUC Irvine Medical Center, Orange, CA, USA, jThe Ohio State University, James Cancer Hospital, Columbus, OH, USA
Objectives: Relapse of disease in serous cancer patients despite normal examination findings and serum CA-125 values suggests that there is a platinum-resistant CA-125-negative tumor population. Using primary human serous carcinomas, we recently discovered that the CA-125negative tumor cell population contains serous cancer stem cells (SCSC) that efficiently initiate tumors and undergo multi-lineage differentiation in vivo. Importantly, the CA-125-negative SCSC were carboplatinresistant due to antiapoptotic signaling. Pathways involved in evasion of apoptosis in the SCSC included high expression of inhibitor of apoptosis proteins (IAPs) and inactivation of TP53. In this investigation, we evaluated whether therapy-resistant SCSC could be sensitized to carboplatin by restoration of apoptosis. Methods: Two strategies were used to enhance apoptosis in serous tumors: 1) degradation of IAPs using the United States Food and Drug Administration-approved drug Birinapant and 2) restoration of TP53 function using a novel structure-based peptide (P53AI) that prevents TP53 aggregation. Mice harboring xenografts derived from either a primary human cancer cell line or control cell lines with known drug sensitivities were treated with the combination of carboplatin (50 mg/kg intraperitoneally [IP] qw ×3–4) and either Birinapant (30 mg/kg ip biw ×9) or P53AI (15 mg/kg ip qd ×28). For comparison, the efficacy of each drug was examined as a single agent. Results: The combinatorial therapeutic approaches using either Birinapant or P53AI in conjunction with carboplatin were the only treatments capable of eliminating all serous tumors cells, including the SCSC (Fig. 1). Combination therapies were also the only treatments that provided durable response, evidenced by no relapse of tumor after cessation of treatment (Fig. 1). While tumors shrank in response to
Objectives: Platinum-based doublets have become a standard of care for women with platinum-sensitive recurrent ovarian cancer. The roles of secondary surgery and addition of bevacizumab have yet to be defined as neither intervention has demonstrated an improvement in overall survival (OS) in a phase III trial. GOG0213 sought to examine both. Methods: GOG0213 is a bifactorial, randomized, phase III trial with two primary objectives: (1) to examine the role of bevacizumab (15 mg/kg) in combination with paclitaxel (175 mg/m2) + carboplatin (AUC5) followed by bevacizumab maintenance and (2) to examine the role of secondary cytoreduction before initiation of chemotherapy. The primary endpoint for both objectives is overall survival (OS). Secondary endpoints include: safety/toxicity, allergy (HSR), progression-free survival (PFS), and intervention-dependent quality of life (QoL). Three strata were prospectively defined: participation on Objective 2, Platinum-free interval (6–12, N12 months) and prior bevacizumab treatment. Chemotherapy randomization for Objective 1 terminated on 8/29/11 and matured for OS (n = 214 events in the control arm) on 11/5/2014. Enrollment for Objective 2 is ongoing. Results: Six hundred seventy four patients (n = 567, Objective 1; n = 107, Objectives 1 and 2) were randomized to CT (n = 374) or CTB (n = 374) and evaluable for OS. Equal representation in each treatment arm was observed for each stratum (Objective 2 (y/n): 53/54; PFI: 6– 12/12+:181/493; Prior bevacizumab (y/n): 67/606). Median age: 60 and predominant histology was serous: 81%. Relative to CT, CTB improved the stratified estimated treatment hazard ratio (HR) of death by 18.6% [HROS: 0.827 (95% CI: 0.683–1.005), p=0.056) corresponding to a median OS of 42.2 vs 37.3 mos. PFS was similarly improved by CTB (HRPFS: 0.614, 95% CI: 0.522–0.722, pb0.0001), corresponding to a median PFS of 13.8 mos vs. 10.4 mos). CTB was associated with more toxicity relative to CT (Table). HSR (all grades, CT vs CTB) occurred in 25.1% and 26.7% (p = 0.66), respectively. QoL measures are being analyzed. Conclusions: GOG0213 met its primary endpoint of improving OS when women with platinum-sensitive recurrent ovarian cancer were treated with CTB. This represents the first phase III trial to reach this endpoint. CTB was associated with more toxicity but no new safety signals were observed.
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Abstracts Presented for the 2015 Society of Gynecologic Oncology 46th Annual Meeting on Women's Cancer® March 28–31, 2015 Hilton Chicago, Chicago, IL Opening Scientific Session Saturday, March 28, 2015 Moderators: Uziel Beller, MD, Shaare Zedek Medical Center, Jerusalem, Israel Joel I. Sorosky, MD, Abington Memorial Hospital, Abington, PA, USA Farr R. Nezhat, MD, FACOG, FACS, St. Luke's-Roosevelt Hospital, New York, NY, USA 1 — Scientific Plenary Randomized phase II trial of maintenance autologous tumor cell vaccine (FANG™) following clinical complete response (cCR) in stage III/IV ovarian cancer: Preliminary results J. Oha, M. Barvea,b, E.A. Grosenc, B.A. Finea, T.P. Heffernand, C.M. Matthewsa, C.A. Stringera, E.C. Koona, H.M. Goodmane, E.L. Flemingf, L.R. DeMarsf, M.S. Bergmanc, N. Senzerb,g, J. Nemunaitisa,b,g,h. aTexas Oncology, P.A., Dallas, TX, USA, bMary Crowley Cancer Research Centers, Dallas, TX, USA, cCancer Care Northwest, Spokane, WA, USA, dNorth Texas Gynecologic Oncology, Dallas, TX, USA, eFlorida Cancer Specialists, West Palm Beach, FL, USA, fDartmouth Hitchcock Medical Center, Lebanon, NH, USA, gGradalis, Inc., Dallas, TX, USA, hMedical City Dallas Hospital, Dallas, TX, USA Objectives: Phase I evaluation of FANG vaccine (granulocyte macrophage colony-stimulating factor [GMCSF]/bi-shRNAi furin vector transfected autologous tumor cells) demonstrated safety; confirmed both GMCSF transgene expression and knockdown of furin and consequent transforming growth factor-b1 and b2 expression; showed T-cell activation per gamma interferon (IFN)enzyme-linked immunospot assay (ELISPOT); and resulted in a longer-than-expected survival duration correlated with ELISPOT “turn on.” These findings justified phase II testing (Senzer et al. Mol Ther. 2012; Senzer et al. Vaccines and Vaccination. 2013). The majority of women with stage III/IV ovarian cancer who achieve cCR with standard of care (SOC) (the combination of debulking surgery and chemotherapy) relapse within 2 years. The objective of this trial was to determine regression-free survival difference in a 2:1 randomized phase II trial. Methods: This 2:1 randomized phase II open-label trial of FANG used tumor harvested at the time of surgical debulking. Stage III/IV ovarian cancer patients achieving cCR following primary surgical debulking and chemotherapy were entered to undergo vaccine construction. Given the high recurrence rate and subsequent 0090-8258/$ – see front matter
progression seen with frontline SOC treatment, we initiated a randomized phase II study of maintenance FANG vaccination following initial debulking/chemotherapy. Patients received 1.0 × 107 cells/intradermal injection once a month for up to 12 doses or were followed as per SOC, i.e., without maintenance therapy. Key endpoints included safety, immune response (RFS). Results: Twenty-one evaluable (ELISPOT-negative following confirmed cCR) patients were randomized, 14 of whom had received at least 1 FANG injection and 7 of whom had been randomized to No FANG treatment. This trial design allowed for control group crossover at time of progression. No toxic effects were observed. A higher rate of IFN ELISPOT response was elicited in this prior chemotherapynaive population in comparison to that achieved in phase I trial (92% vs. 50%). Mean and median RFS of the FANG and No FANG patients are shown in Fig. 1. Conclusions: Based on safety, the high rate of T-cell activation in this population in correlation, and the marked delay in time to regression, randomization was discontinued and phase III testing involving 382 evaluable patients is being pursued.
Abstracts / Gynecologic Oncology 137 (2015) 2–91 RFS since treatment start Treatment status
Total N
No. recurrences
Mean (days)
Median (days)
No FANGa FANGa
7 14
5 7
149 509
94 399
Data as of 03-25-2014. 2 patients unevaluable for efficacy at baseline and 2 control patients who were ELISPOT +. a
3
carboplatin, this therapy enriched for the SCSC, and tumors grew robustly after cessation of treatment. Under the conditions tested, neither Birinapant nor P53AI alone was able to eliminate tumors completely. Conclusions: Our results demonstrate that complete eradication of serous cancers requires therapeutic targeting of the SCSC. This goal can be achieved simply by adding an additional therapy tailored to the patient's tumor that can sensitize the SCSC to carboplatin.
doi:10.1016/j.ygyno.2015.01.003
doi:10.1016/j.ygyno.2015.01.004
2 — Scientific Plenary Restoration of apoptosis in serous cancer stem cells sensitizes them to platinum therapy resulting in tumor eradication D.M. Janzena, E. Tiourina, J.A. Salehia, J. Lub, A. Soragnib, D.S. Eisenbergb, M. Pellegrinib, S. Memarzadeha. aUCLA David Geffen School of Medicine, Los Angeles, CA, USA, bUniversity of California, Los Angeles, Los Angeles, CA, USA
3 — Scientific Plenary A phase III randomized controlled clinical trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinumsensitive, recurrent ovarian, peritoneal primary and fallopian tube cancer (Gynecologic Oncology Group 0213) R.L. Colemana, M.F. Bradyb, T.J. Herzogc, P. Sabbatinid, D.K. Armstronge, J.L. Walkerf, B.G. Kimg, K. Fujiwarah, K.S. Tewarii, D.M. O'Malleyj. aThe University of Texas MD Anderson Cancer Center, Houston, TX, USA, b University of Buffalo, Buffalo, NY, USA, cUniversity of Cincinnati, Cincinnati, OH, USA, dMemorial Sloan Kettering Cancer Center, New York, NY, USA, e Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA, fThe University of Oklahoma, Oklahoma City, OK, USA, gSungkyunkwan University School of Medicine, Seoul, South Korea, hSaitama Medical University International Medical Center, Hidaka-Shi, Japan, iUC Irvine Medical Center, Orange, CA, USA, jThe Ohio State University, James Cancer Hospital, Columbus, OH, USA
Objectives: Relapse of disease in serous cancer patients despite normal examination findings and serum CA-125 values suggests that there is a platinum-resistant CA-125-negative tumor population. Using primary human serous carcinomas, we recently discovered that the CA-125negative tumor cell population contains serous cancer stem cells (SCSC) that efficiently initiate tumors and undergo multi-lineage differentiation in vivo. Importantly, the CA-125-negative SCSC were carboplatinresistant due to antiapoptotic signaling. Pathways involved in evasion of apoptosis in the SCSC included high expression of inhibitor of apoptosis proteins (IAPs) and inactivation of TP53. In this investigation, we evaluated whether therapy-resistant SCSC could be sensitized to carboplatin by restoration of apoptosis. Methods: Two strategies were used to enhance apoptosis in serous tumors: 1) degradation of IAPs using the United States Food and Drug Administration-approved drug Birinapant and 2) restoration of TP53 function using a novel structure-based peptide (P53AI) that prevents TP53 aggregation. Mice harboring xenografts derived from either a primary human cancer cell line or control cell lines with known drug sensitivities were treated with the combination of carboplatin (50 mg/kg intraperitoneally [IP] qw ×3–4) and either Birinapant (30 mg/kg ip biw ×9) or P53AI (15 mg/kg ip qd ×28). For comparison, the efficacy of each drug was examined as a single agent. Results: The combinatorial therapeutic approaches using either Birinapant or P53AI in conjunction with carboplatin were the only treatments capable of eliminating all serous tumors cells, including the SCSC (Fig. 1). Combination therapies were also the only treatments that provided durable response, evidenced by no relapse of tumor after cessation of treatment (Fig. 1). While tumors shrank in response to
Objectives: Platinum-based doublets have become a standard of care for women with platinum-sensitive recurrent ovarian cancer. The roles of secondary surgery and addition of bevacizumab have yet to be defined as neither intervention has demonstrated an improvement in overall survival (OS) in a phase III trial. GOG0213 sought to examine both. Methods: GOG0213 is a bifactorial, randomized, phase III trial with two primary objectives: (1) to examine the role of bevacizumab (15 mg/kg) in combination with paclitaxel (175 mg/m2) + carboplatin (AUC5) followed by bevacizumab maintenance and (2) to examine the role of secondary cytoreduction before initiation of chemotherapy. The primary endpoint for both objectives is overall survival (OS). Secondary endpoints include: safety/toxicity, allergy (HSR), progression-free survival (PFS), and intervention-dependent quality of life (QoL). Three strata were prospectively defined: participation on Objective 2, Platinum-free interval (6–12, N12 months) and prior bevacizumab treatment. Chemotherapy randomization for Objective 1 terminated on 8/29/11 and matured for OS (n = 214 events in the control arm) on 11/5/2014. Enrollment for Objective 2 is ongoing. Results: Six hundred seventy four patients (n = 567, Objective 1; n = 107, Objectives 1 and 2) were randomized to CT (n = 374) or CTB (n = 374) and evaluable for OS. Equal representation in each treatment arm was observed for each stratum (Objective 2 (y/n): 53/54; PFI: 6– 12/12+:181/493; Prior bevacizumab (y/n): 67/606). Median age: 60 and predominant histology was serous: 81%. Relative to CT, CTB improved the stratified estimated treatment hazard ratio (HR) of death by 18.6% [HROS: 0.827 (95% CI: 0.683–1.005), p=0.056) corresponding to a median OS of 42.2 vs 37.3 mos. PFS was similarly improved by CTB (HRPFS: 0.614, 95% CI: 0.522–0.722, pb0.0001), corresponding to a median PFS of 13.8 mos vs. 10.4 mos). CTB was associated with more toxicity relative to CT (Table). HSR (all grades, CT vs CTB) occurred in 25.1% and 26.7% (p = 0.66), respectively. QoL measures are being analyzed. Conclusions: GOG0213 met its primary endpoint of improving OS when women with platinum-sensitive recurrent ovarian cancer were treated with CTB. This represents the first phase III trial to reach this endpoint. CTB was associated with more toxicity but no new safety signals were observed.