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2. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial

Author

Clamp, Andrew R, James, Elizabeth C, McNeish, Iain A, Dean, Andrew, Kim, Jae-Won, O'Donnell, Dearbhaile M, Gallardo-Rincon, Dolores, Blagden, Sarah, Brenton, James, Perren, Tim J, Sundar, Sudha, Lord, Rosemary, Dark, Graham, Hall, Marcia, Banerjee, Susana, Glasspool, Rosalind M, Hanna, C Louise, Williams, Sarah, Scatchard, Kate M, Nam, Helena, Essapen, Sharadah, Parkinson, Christine, McAvan, Lucy, Swart, Ann Marie, Popoola, Babasola, Schiavone, Francesca, Badrock, Jonathan, Fananapazir, Fuad, Cook, Adrian D, Parmar, Mahesh, Kaplan, Richard, and Ledermann, Jonathan A

Published
2022
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3. A phase 2 study of anastrozole in patients with oestrogen receptor and/progesterone receptor positive recurrent/metastatic granulosa cell tumours/sex-cord stromal tumours of the ovary: The PARAGON/ANZGOG 0903 trial

Author

Banerjee, Susana N., Tang, Monica, O'Connell, Rachel L., Sjoquist, Katrin, Clamp, Andrew R., Millan, David, Nottley, Steven, Lord, Rosemary, Mullassery, Vinod Menon, Hall, Marcia, Gourley, Charlie, Bonaventura, Tony, Goh, Jeffrey C., Sykes, Peter, Grant, Peter T., McNally, Orla, Alexander, Laura, Kelly, Caroline, Carty, Karen, Divers, Laura, Bradshaw, N., Edmondson, Richard J., and Friedlander, Michael

Published
2021
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4. Objective responses to first-line neoadjuvant carboplatin–paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial

Author

Morgan, Robert D, McNeish, Iain A, Cook, Adrian D, James, Elizabeth C, Lord, Rosemary, Dark, Graham, Glasspool, Rosalind M, Krell, Jonathan, Parkinson, Christine, Poole, Christopher J, Hall, Marcia, Gallardo-Rincón, Dolores, Lockley, Michelle, Essapen, Sharadah, Summers, Jeff, Anand, Anjana, Zachariah, Abel, Williams, Sarah, Jones, Rachel, Scatchard, Kate, Walther, Axel, Kim, Jae-Weon, Sundar, Sudha, Jayson, Gordon C, Ledermann, Jonathan A, and Clamp, Andrew R

Published
2021
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6. Weekly platinum-based chemotherapy versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled trial

Author

Blagden, Sarah P, Cook, Adrian D, Poole, Christopher, Howells, Lesley, McNeish, Ian A, Dean, Andrew, Kim, Jae-Weon, O'Donnell, Dearbhaile M, Hook, Jane, James, Elizabeth C, White, Ian R, Perren, Timothy, Lord, Rosemary, Dark, Graham, Earl, Helena M, Hall, Marcia, Kaplan, Richard, Ledermann, Jonathan A, and Clamp, Andrew R

Published
2020
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7. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial

Author

Clamp, Andrew R, James, Elizabeth C, McNeish, Iain A, Dean, Andrew, Kim, Jae-Weon, O'Donnell, Dearbhaile M, Hook, Jane, Coyle, Christopher, Blagden, Sarah, Brenton, James D, Naik, Raj, Perren, Tim, Sundar, Sudha, Cook, Adrian D, Gopalakrishnan, Gosala S, Gabra, Hani, Lord, Rosemary, Dark, Graham, Earl, Helena M, Hall, Marcia, Banerjee, Susana, Glasspool, Rosalind M, Jones, Rachel, Williams, Sarah, Swart, Ann Marie, Stenning, Sally, Parmar, Mahesh, Kaplan, Richard, and Ledermann, Jonathan A

Published
2019
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8. Phase 2 study of anastrozole in recurrent estrogen (ER)/progesterone (PR) positive endometrial cancer: The PARAGON trial – ANZGOG 0903

Author

Mileshkin, Linda, Edmondson, Richard, O'Connell, Rachel L., Sjoquist, Katrin M., Andrews, John, Jyothirmayi, Rema, Beale, Philip, Bonaventura, Tony, Goh, Jeffrey, Hall, Marcia, Clamp, Andrew, Green, John, Lord, Rosemary, Amant, Frédéric, Alexander, Laura, Carty, Karen, Paul, James, Scurry, James, Millan, David, Nottley, Steven, and Friedlander, Michael

Published
2019
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9. An international, phase III randomized trial in patients with mucinous epithelial ovarian cancer (mEOC/GOG 0241) with long-term follow-up: and experience of conducting a clinical trial in a rare gynecological tumor

Author

Gore, Martin, Hackshaw, Allan, Brady, William E., Penson, Richard T., Zaino, Richard, McCluggage, W. Glenn, Ganesan, Raji, Wilkinson, Nafisa, Perren, Timothy, Montes, Ana, Summers, Jeffrey, Lord, Rosemary, Dark, Graham, Rustin, Gordon, Mackean, Melanie, Reed, Nicholas, Kehoe, Sean, Frumovitz, Michael, Christensen, Helen, Feeney, Amanda, Ledermann, Jonathan, and Gershenson, David M.

Published
2019
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10. #159 ICON8B: GCIG phase III randomised trial comparing weekly dose-dense chemotherapy + bevacizumab to three-weekly chemotherapy+ bevacizumab in first-line high-risk stage III-IV epithelial ovarian cancer treatment: primary progression-free survival analysis

Author

Clamp, Andrew, primary, Mcneish, Iain, additional, Lord, Rosemary, additional, Hall, Marcia, additional, Essapen, Sharadah, additional, Cook, Audrey, additional, Agarwal, Roshan, additional, Walther, Axel, additional, Blagden, Sarah, additional, O’Donnell, Dearbhaile, additional, Brenton, James D, additional, Sundar, Sudha, additional, Sessa, Cristiana, additional, Cook, Adrian, additional, Radice, Domenico, additional, Schiavone, Francesca, additional, Gentry-Maharaj, Aleksandra, additional, Kaplan, Richard, additional, Parmar, Mahesh Kb, additional, and Ledermann, Jonathan, additional

Published
2023
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13. Data from Ad hoc Analysis of the Phase III ENGOT-OV16/NOVA Study: Niraparib Efficacy in Germline BRCA Wild-type Recurrent Ovarian Cancer with Homologous Recombination Repair Defects

Author

Mirza, Mansoor Raza, primary, Lindahl, Gabriel, primary, Mahner, Sven, primary, Redondo, Andrés, primary, Fabbro, Michel, primary, Rimel, Bobbie J., primary, Herrstedt, Jørn, primary, Oza, Amit M., primary, Canzler, Ulrich, primary, Berek, Jonathan S., primary, González-Martín, Antonio, primary, Follana, Phillipe, primary, Lord, Rosemary, primary, Azodi, Masoud, primary, Estenson, Kasey, primary, Wang, Zebin, primary, Li, Yong, primary, Gupta, Divya, primary, Matulonis, Ursula, primary, and Feng, Bin, primary

Published
2023
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14. Supplementary Data S1 from Ad hoc Analysis of the Phase III ENGOT-OV16/NOVA Study: Niraparib Efficacy in Germline BRCA Wild-type Recurrent Ovarian Cancer with Homologous Recombination Repair Defects

Author

Mirza, Mansoor Raza, primary, Lindahl, Gabriel, primary, Mahner, Sven, primary, Redondo, Andrés, primary, Fabbro, Michel, primary, Rimel, Bobbie J., primary, Herrstedt, Jørn, primary, Oza, Amit M., primary, Canzler, Ulrich, primary, Berek, Jonathan S., primary, González-Martín, Antonio, primary, Follana, Phillipe, primary, Lord, Rosemary, primary, Azodi, Masoud, primary, Estenson, Kasey, primary, Wang, Zebin, primary, Li, Yong, primary, Gupta, Divya, primary, Matulonis, Ursula, primary, and Feng, Bin, primary

Published
2023
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15. Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial

Author

Symonds, R Paul, Gourley, Charlie, Davidson, Susan, Carty, Karen, McCartney, Elaine, Rai, Debbie, Banerjee, Susana, Jackson, David, Lord, Rosemary, McCormack, Mary, Hudson, Emma, Reed, Nicholas, Flubacher, Maxine, Jankowska, Petra, Powell, Melanie, Dive, Caroline, West, Catharine M L, and Paul, James

Published
2015
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16. Ad hoc Analysis of the Phase III ENGOT-OV16/NOVA Study: Niraparib Efficacy in Germline BRCA Wild-type Recurrent Ovarian Cancer with Homologous Recombination Repair Defects

Author

Mirza, Mansoor Raza, primary, Lindahl, Gabriel, additional, Mahner, Sven, additional, Redondo, Andrés, additional, Fabbro, Michel, additional, Rimel, Bobbie J., additional, Herrstedt, Jørn, additional, Oza, Amit M., additional, Canzler, Ulrich, additional, Berek, Jonathan S., additional, González-Martín, Antonio, additional, Follana, Phillipe, additional, Lord, Rosemary, additional, Azodi, Masoud, additional, Estenson, Kasey, additional, Wang, Zebin, additional, Li, Yong, additional, Gupta, Divya, additional, Matulonis, Ursula, additional, and Feng, Bin, additional

Published
2022
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17. Ad hoc Analysis of the Phase III ENGOT-OV16/NOVA Study: Niraparib Efficacy in Germline BRCA Wild-type Recurrent Ovarian Cancer with Homologous Recombination Repair Defects

Author

Mirza, Mansoor Raza, Lindahl, Gabriel, Mahner, Sven, Redondo, Andres, Fabbro, Michel, Rimel, Bobbie J., Herrstedt, Jorn, Oza, Amit M., Canzler, Ulrich, Berek, Jonathan S., Gonzalez-Martin, Antonio, Follana, Phillipe, Lord, Rosemary, Azodi, Masoud, Estenson, Kasey, Wang, Zebin, Li, Yong, Gupta, Divya, Matulonis, Ursula, Feng, Bin, Mirza, Mansoor Raza, Lindahl, Gabriel, Mahner, Sven, Redondo, Andres, Fabbro, Michel, Rimel, Bobbie J., Herrstedt, Jorn, Oza, Amit M., Canzler, Ulrich, Berek, Jonathan S., Gonzalez-Martin, Antonio, Follana, Phillipe, Lord, Rosemary, Azodi, Masoud, Estenson, Kasey, Wang, Zebin, Li, Yong, Gupta, Divya, Matulonis, Ursula, and Feng, Bin

Abstract

In this analysis, we examined the relationship between progression-free survival (PFS) and mutation status of 18 homologous recombination repair (HRR) genes in patients in the non-germline BRCA-mutated (non-gBRCAm) cohort of the ENGOT-OV16/NOVA trial (NCT01847274), which evaluated niraparib maintenance therapy for patients with recurrent ovarian cancer. This post hoc exploratory biomarker analysis was performed using tumor samples collected from 331 patients enrolled in the phase III ENGOT-OV16/NOVA trial's non-gBRCAm cohort. Niraparib demonstrated PFS benefit in patients with either somatic BRCA-mutated (sBRCAm; HR, 0.27; 95% confidence interval, CI, 0.08–0.88) or BRCA wild-type (BRCAwt; HR, 0.47; 95% CI, 0.34–0.64) tumors. Patients with BRCAwt tumors with other non-BRCA HRR mutations also derived benefit from niraparib (HR, 0.31; 95% CI, 0.13–0.77), as did patients with BRCAwt/HRRwt (HRR wild-type) tumors (HR, 0.49; 95% CI, 0.35–0.70). When patients with BRCAwt/HRRwt tumors were further categorized by genomic instability score (GIS), clinical benefit was observed in patients with homologous recombination–deficient (GIS ≥ 42; HR, 0.33; 95% CI, 0.18–0.61) and in patients with homologous recombination–proficient (HRp; GIS < 42; HR, 0.60; 95% CI, 0.36–0.99) disease. Although patients with sBRCAm, other non-BRCA HRR mutations, or GIS ≥ 42 benefited the most from niraparib treatment, PFS benefit was also seen in HRp (GIS < 42) patients without HRR mutations. These results support the use of niraparib in patients with recurrent ovarian cancer regardless of BRCA/HRR mutation status or myChoice CDx GIS. Significance: We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA-mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non-BRCA HRR mutations generally benefited from second-line maintenance treatment with niraparib compa

Published
2022
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18. Ad hoc Analysis of the Phase III ENGOT-OV16/NOVA Study:Niraparib Efficacy in Germline BRCA Wild-type Recurrent Ovarian Cancer with Homologous Recombination Repair Defects

Author

Mirza, Mansoor Raza, Lindahl, Gabriel, Mahner, Sven, Redondo, Andrés, Fabbro, Michel, Rimel, Bobbie J, Herrstedt, Jørn, Oza, Amit M, Canzler, Ulrich, Berek, Jonathan S, González-Martín, Antonio, Follana, Phillipe, Lord, Rosemary, Azodi, Masoud, Estenson, Kasey, Wang, Zebin, Li, Yong, Gupta, Divya, Matulonis, Ursula, Feng, Bin, Mirza, Mansoor Raza, Lindahl, Gabriel, Mahner, Sven, Redondo, Andrés, Fabbro, Michel, Rimel, Bobbie J, Herrstedt, Jørn, Oza, Amit M, Canzler, Ulrich, Berek, Jonathan S, González-Martín, Antonio, Follana, Phillipe, Lord, Rosemary, Azodi, Masoud, Estenson, Kasey, Wang, Zebin, Li, Yong, Gupta, Divya, Matulonis, Ursula, and Feng, Bin

Abstract

In this analysis, we examined the relationship between progression-free survival (PFS) and mutation status of 18 homologous recombination repair (HRR) genes in patients in the non-germline BRCA-mutated (non-gBRCAm) cohort of the ENGOT-OV16/NOVA trial (NCT01847274), which evaluated niraparib maintenance therapy for patients with recurrent ovarian cancer. This post hoc exploratory biomarker analysis was performed using tumor samples collected from 331 patients enrolled in the phase III ENGOT-OV16/NOVA trial's non-gBRCAm cohort. Niraparib demonstrated PFS benefit in patients with either somatic BRCA-mutated (sBRCAm; HR, 0.27; 95% confidence interval, CI, 0.08–0.88) or BRCA wild-type (BRCAwt; HR, 0.47; 95% CI, 0.34–0.64) tumors. Patients with BRCAwt tumors with other non-BRCA HRR mutations also derived benefit from niraparib (HR, 0.31; 95% CI, 0.13–0.77), as did patients with BRCAwt/HRRwt (HRR wild-type) tumors (HR, 0.49; 95% CI, 0.35–0.70). When patients with BRCAwt/HRRwt tumors were further categorized by genomic instability score (GIS), clinical benefit was observed in patients with homologous recombination–deficient (GIS ≥ 42; HR, 0.33; 95% CI, 0.18–0.61) and in patients with homologous recombination–proficient (HRp; GIS < 42; HR, 0.60; 95% CI, 0.36–0.99) disease. Although patients with sBRCAm, other non-BRCA HRR mutations, or GIS ≥ 42 benefited the most from niraparib treatment, PFS benefit was also seen in HRp (GIS < 42) patients without HRR mutations. These results support the use of niraparib in patients with recurrent ovarian cancer regardless of BRCA/HRR mutation status or myChoice CDx GIS. Significance: We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA-mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non-BRCA HRR mutations generally benefited from second-line maintenance treatment with ni, UNLABELLED: In this analysis, we examined the relationship between progression-free survival (PFS) and mutation status of 18 homologous recombination repair (HRR) genes in patients in the non-germline BRCA-mutated (non-gBRCAm) cohort of the ENGOT-OV16/NOVA trial (NCT01847274), which evaluated niraparib maintenance therapy for patients with recurrent ovarian cancer. This post hoc exploratory biomarker analysis was performed using tumor samples collected from 331 patients enrolled in the phase III ENGOT-OV16/NOVA trial's non-gBRCAm cohort. Niraparib demonstrated PFS benefit in patients with either somatic BRCA-mutated (sBRCAm; HR, 0.27; 95% confidence interval, CI, 0.08-0.88) or BRCA wild-type (BRCAwt; HR, 0.47; 95% CI, 0.34-0.64) tumors. Patients with BRCAwt tumors with other non-BRCA HRR mutations also derived benefit from niraparib (HR, 0.31; 95% CI, 0.13-0.77), as did patients with BRCAwt/HRRwt (HRR wild-type) tumors (HR, 0.49; 95% CI, 0.35-0.70). When patients with BRCAwt/HRRwt tumors were further categorized by genomic instability score (GIS), clinical benefit was observed in patients with homologous recombination-deficient (GIS ≥ 42; HR, 0.33; 95% CI, 0.18-0.61) and in patients with homologous recombination-proficient (HRp; GIS < 42; HR, 0.60; 95% CI, 0.36-0.99) disease. Although patients with sBRCAm, other non-BRCA HRR mutations, or GIS ≥ 42 benefited the most from niraparib treatment, PFS benefit was also seen in HRp (GIS < 42) patients without HRR mutations. These results support the use of niraparib in patients with recurrent ovarian cancer regardless of BRCA/HRR mutation status or myChoice CDx GIS.SIGNIFICANCE: We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA-mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non-BRCA HRR mutations generally benefited from second-line maintenance treatment

Published
2022

20. Extended panel testing in ovarian cancer reveals BRIP1as the third most important predisposition gene

Author

Morgan, Robert D., Burghel, George J., Flaum, Nicola, Schlecht, Helene, Clamp, Andrew R., Hasan, Jurjees, Mitchell, Claire, Salih, Zena, Moon, Sarah, Hogg, Martin, Lord, Rosemary, Forde, Claire, Lalloo, Fiona, Woodward, Emma R., Crosbie, Emma J., Taylor, Stephen S., Jayson, Gordon C., and Evans, D. Gareth R.

Abstract

The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain.

Published
2024
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21. PARAGON: A phase 2 study of anastrozole (An) in patients with estrogen receptor(ER) and / progesterone receptor (PR) positive recurrent/metastatic granulosa cell tumors/sex-cord stromal tumors (GCT) of the ovary.

Author

Banerjee, Susana N., primary, Tang, Monica, additional, O'Connell, Rachel, additional, Clamp, Andrew R., additional, Lord, Rosemary, additional, Mullassery, Vinod Menon, additional, Hall, Marcia, additional, Gourley, Charlie, additional, Bonaventura, Tony, additional, Goh, Jeffrey C., additional, Sykes, Peter, additional, Grant, Peter T., additional, McNally, Orla, additional, Edmondson, Richard J, additional, and Friedlander, Michael, additional

Published
2018
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23. METRO-BIBF: Phase II, randomised, placebo controlled, multicentre, trial of low dose (metronomic) cyclophosphamide (MCy) with or without nintedanib in relapsed ovarian cancer (ROC).

Author

Hall, Marcia, primary, Debhi, Hakim-Moulay, additional, Nicum, Shibani, additional, Lord, Rosemary, additional, Banerjee, Susana N., additional, Clamp, Andrew R., additional, Lilleywhite, Rachel, additional, Glasspool, Rosalind Margaret, additional, Feeney, Amanda, additional, Hackshaw, Allan, additional, and Ledermann, Jonathan A., additional

Published
2018
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25. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer

Author

Mirza, Mansoor R, Monk, Bradley J, Herrstedt, Jørn, Oza, Amit M, Mahner, Sven, Redondo, Andrés, Fabbro, Michel, Ledermann, Jonathan A, Lorusso, Domenica, Vergote, Ignace, Ben-Baruch, Noa E, Marth, Christian, Madry, Radoslaw, Christensen, René D, Berek, Jonathan S, Dørum, Anne, Tinker, Anna V, du Bois, Andreas, González-Martín, Antonio, Follana, Philippe, Benigno, Benedict, Rosenberg, Per, Gilbert, Lucy, Rimel, Bobbie J, Buscema, Joseph, Balser, John P, Agarwal, Shefali, Matulonis, Ursula A, Lund, Bente, Malander, Susanne, Woie, Kathrine, Hellman, Kristina, Nøttrup, Trine Juhler, Havsteen, Hanne, Sehouli, Jalid, Harter, Philipp, Canzler, Ulrich, Lück, Hans-Joachim, Wölber, Linn, Marmé, Frederik, Meier, Werner, Heubner, Martin, Hilpert, Felix, Emons, Günter, Burges, Alexander, Bover Barcelo, Isabel Maria, Gil Martín, Marta, Palacio Vázquez, Isabel, Casado Herráez, Antonio, Maria del Campo, José, Lesoin, Anne, Berton-Rigaud, Dominique, N'Guyen, Thierry, Hardy-Bessard, Anne-Claire, Banerjee, Susana, Lord, Rosemary, Waters, Justin, Montes, Ana, Chan, Stephen, Williams, Sarah J, Barlow, Claire, Mullard, Anna, Colombo, Nicoletta, Scambia, Giovanni, Tognon, Germana, Scollo, Paolo, Kridelka, Frédéric, Leroy, Chantal, Debruyne, Philip, Huizing, Manon, Rosengarten, Ora, Levy, Talia, Frommer, Ronnie Shapira, Fishman, Ami, Edelman, David, Safra, Tamar, Amit, Amnon, Pikiel, Joanna, Suzin, Jacek, Mackowiak-Matejczyk, Beata, Reinthaller, Alexander, Petru, Edgar, Csoszi, Tibor, Bessette, Paul, Provencher, Diane, Lau, Susie, Ellard, Susan, Ghatage, Prafull, Moore, Kathleen, Wenham, Robert, Pineda, Mario, Azodi, Masoud, Mantia-Smaldone, Gina, Cloven, Noelle, Bailey, Cheryl, Lee, Christine, Secord, Angeles, Patel, Manish, Method, Michael, Callahan, Michael, Veena, John, Chan, John, Zarwan, Corrine, DiSilvestro, Paul, Teneriello, Michael, Gupta, Divya, Geller, Melissa, Burris, Howard, Slomovitz, Brian, Hendrickson, Andrea Wahner, McCormick, Colleen, Hanjani, Parviz, Blank, Stephanie, Haluska, Paul, Matei, Daniela, Vasilev, Stephen, Neidhart, Jeffrey, Boente, Matthew, Tchabo, Nana, Miller, David, and Targeted Gynaecologic Oncology (TARGON)

Subjects
0301 basic medicine, Oncology, Medizin, Genes, BRCA1, Platinum Compounds, POLY(ADP-RIBOSE) POLYMERASE, Kaplan-Meier Estimate, 030226 pharmacology & pharmacy, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, Maintenance therapy, Bone Marrow, Medicine, Merck Sharp & Dohme, Homologous Recombination, Indazoles/adverse effects, Ovarian Neoplasms, Aged, 80 and over, Platinum compounds, OLAPARIB, Ovarian Neoplasms/drug therapy, Obstetrics and Gynecology, Bone Marrow/drug effects, General Medicine, Middle Aged, SOLID TUMORS, BRCA MUTATION CARRIERS, 030220 oncology & carcinogenesis, TRIAL, Female, Platinum sensitive, Adult, Piperidines/adverse effects, medicine.medical_specialty, Indazoles, Adolescent, Antineoplastic Agents, Disease-Free Survival, Olaparib, Maintenance Chemotherapy, Young Adult, 03 medical and health sciences, Platinum Compounds/therapeutic use, Double-Blind Method, Internal medicine, Humans, Rucaparib, Germ-Line Mutation, Aged, Neoplasm Staging, Cancer och onkologi, business.industry, Antineoplastic Agents/adverse effects, NEGATIVE BREAST-CANCER, 030104 developmental biology, chemistry, Recurrent Ovarian Cancer, Cancer and Oncology, Johnson Johnson, business
Abstract

BACKGROUND Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODS In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2: 1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. RESULTS Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P amp;lt; 0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. CONCLUSIONS Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274.) Funding Agencies|Tesaro; Amgen; Genentech; Roche; AstraZeneca; Myriad Genetics; Merck; Gradalis; Cerulean; Vermillion; ImmunoGen; Pfizer; Bayer; Nu-Cana BioMed; INSYS Therapeutics; GlaxoSmithKline; Verastem; Mateon Therapeutics; Pharmaceutical Product Development; Clovis Oncology; Janssen/Johnson Johnson; Eli Lilly; Merck Sharp Dohme

Published
2016
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26. TRIOC: A randomised parallel group double-blind phase II study to assess the activity of MVA-5T4 vaccine versus placebo in patients with relapsed asymptomatic epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Author

Michael, Agnieszka, primary, Lord, Rosemary, additional, Hall, Geoff, additional, Hanna, Louise, additional, Anand, Anjana, additional, Walther, Axel, additional, Nicum, Shibani, additional, Clamp, Andrew R., additional, Kristeleit, Rebecca Sophie, additional, Hackshaw, Alan, additional, Parmar, Gita, additional, Ngai, Yen, additional, Farrelly, Laura, additional, Essapen, Sharadah, additional, McNeish, Iain A., additional, Harrop, Richard, additional, and Ledermann, Jonathan A., additional

Published
2016
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27. Multicentre trial of carboplatin/paclitaxel versus oxaliplatin/capecitabine, each with/without bevacizumab, as first line chemotherapy for patients with mucinous epithelial ovarian cancer (mEOC).

Author

Gore, Martin Eric, primary, Hackshaw, Allan, additional, Brady, William E, additional, Penson, Richard T., additional, Zaino, Richard J, additional, McCluggage, W. Glenn, additional, Ganesan, Raji, additional, Wilkinson, Nafisa, additional, Perren, Timothy, additional, Montes, Ana, additional, Summers, Jeffrey, additional, Lord, Rosemary, additional, Dark, Graham G., additional, Rustin, Gordon J. S., additional, Mackean, Melanie J., additional, Reed, Nicholas, additional, Kehoe, Sean, additional, Christensen, Helen, additional, Ledermann, Jonathan A., additional, and Gershenson, David Marc, additional

Published
2015
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29. Randomized phase II trial of NGR-hTNF with an anthracycline in platinum-refractory or -resistant ovarian cancer (OC).

Author

Lorusso, Domenica, primary, Scambia, Giovanni, additional, Colombo, Nicoletta, additional, Reed, Nicholas, additional, Pisano, Carmen, additional, Lord, Rosemary, additional, Mangili, Giorgia, additional, Mosconi, Annamaria, additional, Raspagliesi, Francesco, additional, Palazzo, Antonella, additional, Ditto, Antonino, additional, Salutari, Vanda, additional, Conte, Carmine, additional, Amadio, Giulia, additional, Lambiase, Antonio, additional, and Bordignon, Claudio, additional

Published
2014
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34. Chemotherapy induced peripheral neuropathy : clinical aspects and molecular genetics

Author

Cliff, Joanne, Lord, Rosemary, and Pirmohamed, Munir

Subjects
610
Abstract

As the treatment of cancer evolves, complexity is increasing with the range of and number therapies now being offered to patients. Patients are living with or beyond cancer for longer periods of time. Cancer survivorship issues are therefore gaining greater importance, and long term toxicities from cancer therapies must be acknowledged and addressed. One such adverse effect is chemotherapy induced peripheral neuropathy (CIPN). Many widely used cytotoxic agents lead to peripheral neuropathy in a proportion of patients. For some, the neuropathy settles after completion of treatment but for a small, but not insignificant minority, the neuropathy persists. The aims of this project were to systematically explore the clinical and molecular genetic risk factors, and effect on quality of life, of this potentially debilitating toxicity. Chapter 1 comprises an introduction to the topic including a narrative review of clinical risk factors. Choice of agent, duration of infusion and cumulative dose affect the development of CIPN. Patient-related factors are less clear, but body mass index and race appear to be of particular interest as possible determinants. Chapter 2 includes systematic reviews of the impact of diabetes and alcohol intake on risk of CIPN which identified a number of studies but meta-analysis was not possible and no definitive conclusion on effect could be drawn as findings from the included studies were contradictory. Chapter 3 describes a comprehensive systematic review of pharmacogenetic studies related to the risk of developing CIPN. This identified 93 studies for inclusion with a median sample size of 118 patients. GSTP Ile105Val was the most commonly investigated SNP, with SNPs in the excision repair genes, ABC transporter genes and CYP 3A4, 3A5 and 2C8 genes also frequently investigated. Meta-analysis was carried out where possible, the majority of which showed no significant association. CYP3A4*22 did show significant association but this data was based on two cohorts within the same study. Many studies however were not eligible for inclusion in meta-analysis due to lack of sufficient data presented. Pharmacogenetic studies in this field are fraught with methodological flaws. Accurate phenotypic definition and recognising potential clinical confounding factors in research populations is key to improving the quality of research. Chapter 4 presents a candidate gene study in both a taxane- and an oxaliplatin-treated cohort of patients. 187 taxane-treated patients were included for genotype analysis. Based on the systematic review, seven single nucleotide polymorphisms (SNPs) were identified for investigation. However, no significant associations were identified for CYP2C8*3, CYP3A4*22, EPHA4, EPHA5, EPHA6, FGD4, and XKR4. For the oxaliplatin cohort of 120 patients, three SNPs, ACYP2 rs843748, FARS2 rs17140129 and TAC1 rs10486003, were investigated based on previous GWAS results. Again, no significant effects were seen in this population. A strength of this pharmacogenetic study was use of both medical assessment of CIPN and patient reported outcome to support phenotypic definition. The quality of life study is presented in chapter 5 and confirmed a statistically significant correlation between patient reported neuropathy scores and both quality of life and functional measures. In the paclitaxel cohort, the sensory score was negatively correlated with a functional score at 6 months postchemotherapy. In the oxaliplatin cohort, at the end of the treatment time point for those who received >6 cycles, there was a significant negative correlation between the sensory score and both functional and global QoL scores. More consistently over time, however, correlations with QoL and functional scores in those who scored more highly on the motor aspects of the CIPN20 module were seen. Persistent neuropathy leading to higher scores in the motor aspects of the CIPN20 showed a statistically significant difference in functional score (p=0.002) and global QoL score (p=0.026) at the 18 month time-point. Finally, chapter 6 comprises discussion of the work and concludes that future work needs to build a clinical and genetic model upon which to assess an individual's risk for development of this toxicity which can impact quality of life and function many months and years after treatment. Improving assessment and standardising outcome measurements, potentially through the development of consortia to further the pharmacogenetic research aspect of cancer drug safety is key to improving the evidence base to build risk models which may start to improve individualisation of treatment and develop a more personalised assessment of risk of harm.

Published
2018
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35. An Investigation into the Immunological Mechanisms of Immune Related Adverse Events Associated with Oncological Immune Checkpoint Inhibitors

Author

Olsson-Brown, Anna, Pirmohamed, Munir, Page, Richard, Coles, Mark, and Lord, Rosemary

Abstract

Introduction Oncological immune checkpoint inhibitors (ICIs) are now considered standard of care for the treatment of numerous malignancies. On-target off-tissue effects can lead to immune-related adverse events (irAEs) affecting multiple organ systems with severe or life-threatening toxicity occurring in 20-60% of cases. With the increasing use of ICIs, the impact of irAEs is becoming a significant concern. Despite this, the real-world experience of irAEs and current understanding of pathological mechanisms remains poor and treatments generic and non-evidence based. Methods Local, dual- and multi-centre studies were established to assess the real world manifestation of irAEs. Deep phenotyping was subsequently conducted for specific irAEs of interest including ICI-induced colitis and thyroid dysfunction. Mechanistic evaluation of irAEs was undertaken utilising a multiomic approach. Genomic evaluation via human leucocyte antigen (HLA) typing was undertaken to determine if HLA predisposes to the development of irAEs. Transcriptomic peripheral blood mRNA analysis, proteomic analysis of cytokines and both longitudinal and paired peripheral-end organ cytometric analysis was undertaken to determine key mediators of irAEs. Results The real-world incidence of irAEs showed that the use of combination immune checkpoint inhibitors and pre-existing autoimmune disease predispose to irAEs. Advancing age was not related to increasing severity of toxicity. The incidence of irAEs in the real world population was reflective of clinical trials and appeared to be tumour agnostic. There was an apparent relationship between efficacy and toxicity with improvement in survival in patients experiencing irAEs. Deep phenotyping revealed that there are numerous pathological subtypes within each organ-specific irAE. HLA analysis highlighted the potential relevance of both HLADR4 and HLADQ8 phenotypes in ICI-induced myocarditis. No other irAEs were associated with specific HLA subtypes. Elevated baseline levels of haemoglobin and albumin were found to be associated with irAEs as were early changes in neutrophil: lymphocyte ratios. Within the setting of ICI-induced colitis, differential levels of CD45+CD3-CD16+CD56+ natural killer cells, CD45+CD3+CD4+ (including CD25+CD127- T regulatory cells) and CD45+CD3+CD8+ were seen in individuals experiencing toxicity. Activated CD8+ cells and activated memory CD8+ cells were elevated in the circulation in patients with colitis. Activated memory CD8+ cells and tissue resident memory CD8+ were elevated in colonic tissue. . The expression of the colonic-homing proteins α4β7 integrin was increased in patients with severe, corticosteroid refractory ICI-induced colitis. The cellular changes were accompanied by increased activity of Toll-like receptor proteins and decreased SMAD3 expression. The levels of TNFα, TGFβ1, TGFβ2, IFN-γ and IL-6 were increased in colitis patients, but further work is required to assess the utility of cytokine clustering. Conclusions This study has identified multiple potential predictors and mediators of irAEs including HLA subtypes, cellular subpopulations, transcription factors, cell signalling complexes and cytokines. Validation of these mediators alongside robust clinical phenotyping in larger sample sizes will promote more precise identification of the relevant mediators and enable therapeutic stratification.

37. A randomized phase II trial to examine modified vaccinia Ankara-5T4 vaccine in patients with relapsed asymptomatic ovarian cancer (TRIOC).

Author

Michael A, Wilson W, Sunshine S, Annels N, Harrop R, Blount D, Pandha H, Lord R, Ngai Y, Nicum S, Stylianou L, Gwyther S, McNeish IA, Hackshaw A, and Ledermann J

Subjects
Adult, Aged, Aged, 80 and over, Female, Humans, Middle Aged, Carcinoma, Ovarian Epithelial drug therapy, Double-Blind Method, Membrane Glycoproteins, Cancer Vaccines administration & dosage, Cancer Vaccines therapeutic use, Neoplasm Recurrence, Local prevention & control, Neoplasm Recurrence, Local therapy, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, Ovarian Neoplasms immunology, Vaccinia virus genetics, Vaccinia virus immunology
Abstract

Background: Immunotherapy directed at 5T4 tumor antigen may delay the need for further chemotherapy. An attenuated modified vaccinia Ankara virus containing the gene encoding for 5T4 (MVA-5T4) was studied in asymptomatic relapsed ovarian cancer., Objective: To assess the effectiveness and safety of MVA-5T4 as treatment for asymptomatic relapsed ovarian cancer., Methods: TRIOC was a phase II randomized (1:1), placebo-controlled, double-blind multicenter study. The primary aim was to assess the effectiveness and safety of MVA-5T4 as a treatment for asymptomatic patients with relapsed ovarian cancer. Eligible patients had International Federation of Gynecology and Obstetrics (FIGO) stage IC1-III or IVA epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, Eastern Cooperative Oncology Group (ECOG) 0-1, with relapse defined by a rise in CA-125 to twice the upper limit of normal or low-volume disease on CT scan. The primary endpoint was disease progression (including deaths from ovarian cancer) at 25 weeks. Following a brief suspension, the trial restarted as a single-arm study. The revised single-arm design required 45 evaluable patients treated with MVA-5T4 to detect a 25-week progression rate of 50%, assuming an expected 70% rate without MVA-5T4; 85% power with one-sided 5% significance., Results: A total of 94 eligible patients were recruited, median age was 65 years (range 42-82), median follow-up 34 months (range 2-46). Overall, 59 patients received MVA-5T4 and 35 patients received placebo. The median number of MVA-5T4 injections received was 7 (range 0-9), compared with a median of 6 (range 1-12) for patients receiving placebo. Median progression-free survival was the same in both arms (3.0 months). The 25-week progression rate was similar in both arms: 80.0% for patients treated with MVA-5T4 and 85.7% for those receiving placebo (risk difference -5.7%, 95% CI -21.4% to 10.0%). Median time to clinical intervention was improved with MVA-5T4: 7.6 months (range 6.7-9.5) vs 5.6 (range 4.9-7.6), CONCLUSION: MVA-5T4 vaccination in patients with asymptomatic relapse was well-tolerated but did not improve the progression rate at 25 weeks. The majority of patients who received MVA-5T4 had clinical intervention later than those assigned to placebo., Trial Registration Number: NCT01556841., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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