Advanced (Stage IIIB-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer Clinical Trial
— MITO25Official title:
A Randomized, Molecular Driven Phase II Trial of Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib, Selected According to HRD Status, in Patients With Advanced (Stage III B-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer Preceded by a Phase I Dose Escalation Study on Rucaparib-Bevacizumab Combination
This trial is a randomized, open-label Phase I-2 multi-center study designed to evaluate the effect of Carboplatin-Paclitaxel-Bevacizumab (in combination and maintenance) vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib (Rucaparib only in maintenance) vs Carboplatin-Paclitaxel-Rucaparib (Rucaparib only in maintenance) on progression-free survival in patients with advanced high grade ovarian cancer treated according to HRD status . The trial will test the hypothesis that Carboplatin-Paclitaxel-Bevacizumab-Rucaparib and the Carboplatin-Paclitaxel-Rucaparib arms will improve the progression-free survival in comparison to standard Carboplatin-Paclitaxel-Bevacizumab in HRD negative (HR proficient) patients and that Carboplatin-Paclitaxel-Bevacizumab-Rucaparib will improve PFS with respect to Carboplatin-Paclitaxel-Rucaparib in HRD positive patients. The randomized phase of the study will be preceded by a single arm Phase I study which will be conducted only in the National Cancer Institute of Milan, aiming at evaluating the MTD of the combination Rucaparib-Bevacizumab. Once the MTD has been reached, the randomized study will start.
| Status | Recruiting |
| Enrollment | 290 |
| Est. completion date | March 1, 2025 |
| Est. primary completion date | March 1, 2025 |
| Accepts healthy volunteers | No |
| Gender | Female |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria: 1. Women aged >=18 years at the time of study inclusion; 2. Patients with newly diagnosed, histologically confirmed, high grade serous, high grade endometrioid, FIGO stage IIIB-C-IV epithelial ovarian cancer, primary peritoneal cancer and / or Fallopian-tube cancer. Patients with mixed histology (carcinosarcoma) are eligible providing that high grade tumor represent more than 50% of the total histology. Stage III patients should have had one attempt at optimal debulking surgery (upfront or interval debulking). Stage IV patients must have had either a biopsy and/or upfront or interval debulking surgery; 3. Archival tumor tissue available. At progression fresh biopsy is optional for patients willing to submit ; 4. ECOG Performance Status of 0-1; 5. Measurable and not measurable disease; 6. Adequate renal and hepatic function, defined as: - Total serum bilirubin = 1.5 institutional ULN unless patient has Gilbert's syndrome in which case total serum bilirubin must be <2 ULN for the institution AST and/or ALT = 2.5 x ULN for the institution. (or = 5 x ULN if liver metastases are present); - Alkaline phosphatase < 1.5 x ULN for the institution (if > 1.5 x ULN, then alkaline phosphatase liver fraction must be < 1.5 ULN) - Serum creatinine = 1.5 x ULN for the institution (or calculated creatinine clearance = 45 mL/min/1.73 m2); 7. Adequate bone marrow function, defined as: - Total leukocytes 2.5 x 109/L; - ANC 1.5 x 109/L; - Platelet count 100 x 109/L; 8. Able to understand and give written informed consent; 9. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment. Exclusion Criteria: 1. Women who are pregnant or lactating; 2. Presence of brain or other central nervous system metastases, not adequately controlled by treatment; 3. Prior Anticancer treatment; 4. Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 3 weeks prior to randomization; 5. Another primary malignancy except for: 1. Curatively treated non-melanoma skin cancer; 2. Breast cancer treated curatively =5 years ago, or other solid tumor treated curatively =5 years ago, without evidence of recurrence; 3. Synchronous endometrioid endometrial cancer (except for Stage 1A G1/G2); 6. Known active HIV, hepatitis B or C infection; 7. Concurrent treatment with immunosuppressive or investigational agents; 8. History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or subarachnoid haemorrhage within _6 months prior to the first study treatment); 9. Clinically significant (i.e. active) cardiovascular disease, including: - Myocardial infarction or unstable angina within _6 months prior to the first study treatment; - New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF); - Serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia); - Peripheral vascular disease > grade 3 (i.e.symptomatic and interfering with activities of daily living requiring repair or revision); 10. Serious active infection requiring i.v. antibiotics at enrolment; 11. Known hypersensitivity to any of the study drugs or excipients (including cremophor and hamster Ovary cell products); 12. Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer, etc.), physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment related complications; 13. Prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with absorption of study drug; 14. Received administration of strong CYP1A2 or CYP3A4 inhibitors =7 days prior to first dose of Rucaparib or have on-going requirements for these medications. |
| Country | Name | City | State |
|---|---|---|---|
| Italy | Ospedale Mater Salutis | Legnago | |
| Italy | ASST Grande Ospedale Metropolitano Niguarda | Milan | |
| Italy | Istituto Nazionale Tumori IRCCS Fondazione G. Pascale | Naples | |
| Italy | Azienda Ospedaliera di Perugia | Perugia | |
| Italy | Nuovo Ospedale degli Infermi | Ponderano | |
| Italy | Fondazione Policlinico Universitario A.Gemelli IRCCS | Rome | |
| Italy | Istituto di Candiolo - Fondazione del Piemonte per l'Oncologia - IRCCS | Turin |
| Lead Sponsor | Collaborator |
|---|---|
| Fondazione Policlinico Universitario Agostino Gemelli IRCCS | Foundation Medicine, Istituto Di Ricerche Farmacologiche Mario Negri |
Italy,
Abkevich V, Timms KM, Hennessy BT, Potter J, Carey MS, Meyer LA, Smith-McCune K, Broaddus R, Lu KH, Chen J, Tran TV, Williams D, Iliev D, Jammulapati S, FitzGerald LM, Krivak T, DeLoia JA, Gutin A, Mills GB, Lanchbury JS. Patterns of genomic loss of heter — View Citation
Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, Dobrovic A, Birrer MJ, Webb PM, Stewart C, Friedlander M, Fox S, Bowtell D, Mitchell G. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian — View Citation
Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA; Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006 Jan 5;354(1):34-43. — View Citation
Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott C, Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt A. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 m — View Citation
Beucher A, Birraux J, Tchouandong L, Barton O, Shibata A, Conrad S, Goodarzi AA, Krempler A, Jeggo PA, Löbrich M. ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2. EMBO J. 2009 Nov 4;28(21):3413-27. doi: — View Citation
Bindra RS, Gibson SL, Meng A, Westermark U, Jasin M, Pierce AJ, Bristow RG, Classon MK, Glazer PM. Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res. 2005 Dec 15;65(24):11597-604. — View Citation
Bindra RS, Schaffer PJ, Meng A, Woo J, Måseide K, Roth ME, Lizardi P, Hedley DW, Bristow RG, Glazer PM. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol. 2004 Oct;24(19):8504-18. — View Citation
Birkbak NJ, Wang ZC, Kim JY, Eklund AC, Li Q, Tian R, Bowman-Colin C, Li Y, Greene-Colozzi A, Iglehart JD, Tung N, Ryan PD, Garber JE, Silver DP, Szallasi Z, Richardson AL. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA- — View Citation
Borgström P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res. 19 — View Citation
Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005 Apr 14;434(7035):913-7. Erratum in: Nature. 200 — View Citation
Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX; Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 20 — View Citation
Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011 Jun 29;474(7353):609-15. doi: 10.1038/nature10166. Erratum in: Nature. 2012 Oct 11;490(7419):298. — View Citation
Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, Douglas J, Burger RA, Armstrong D, Wenham R, McGuire W. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 200 — View Citation
Chan JK, Cheung MK, Husain A, Teng NN, West D, Whittemore AS, Berek JS, Osann K. Patterns and progress in ovarian cancer over 14 years. Obstet Gynecol. 2006 Sep;108(3 Pt 1):521-8. — View Citation
Chanoux RA, Yin B, Urtishak KA, Asare A, Bassing CH, Brown EJ. ATR and H2AX cooperate in maintaining genome stability under replication stress. J Biol Chem. 2009 Feb 27;284(9):5994-6003. doi: 10.1074/jbc.M806739200. Epub 2008 Dec 2. — View Citation
De Bono JS, Mina LA, Gonzalez M, Curtin NJ, Wang E, Henshaw JW, et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. J Clin Oncol. 2013;31(suppl):2580.
du Bois A, Quinn M, Thigpen T, Vermorken J, Avall-Lundqvist E, Bookman M, Bowtell D, Brady M, Casado A, Cervantes A, Eisenhauer E, Friedlaender M, Fujiwara K, Grenman S, Guastalla JP, Harper P, Hogberg T, Kaye S, Kitchener H, Kristensen G, Mannel R, Meier — View Citation
Engel J, Eckel R, Schubert-Fritschle G, Kerr J, Kuhn W, Diebold J, Kimmig R, Rehbock J, Hölzel D. Moderate progress for ovarian cancer in the last 20 years: prolongation of survival, but no improvement in the cure rate. Eur J Cancer. 2002 Dec;38(18):2435- — View Citation
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005 Apr 14 — View Citation
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J — View Citation
Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcino — View Citation
Gottipati P, Vischioni B, Schultz N, Solomons J, Bryant HE, Djureinovic T, Issaeva N, Sleeth K, Sharma RA, Helleday T. Poly(ADP-ribose) polymerase is hyperactivated in homologous recombination-defective cells. Cancer Res. 2010 Jul 1;70(13):5389-98. doi: 1 — View Citation
Gourley, C. McCavigan, A Perren, T et al Molecular subgroup of high-grade serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab. Abstract 5502 ASC0 2014
Harries M, Gore M. Part I: chemotherapy for epithelial ovarian cancer-treatment at first diagnosis. Lancet Oncol. 2002 Sep;3(9):529-36. Review. — View Citation
Hennessy BT, Timms KM, Carey MS, Gutin A, Meyer LA, Flake DD 2nd, Abkevich V, Potter J, Pruss D, Glenn P, Li Y, Li J, Gonzalez-Angulo AM, McCune KS, Markman M, Broaddus RR, Lanchbury JS, Lu KH, Mills GB. Somatic mutations in BRCA1 and BRCA2 could expand t — View Citation
Iain A. McNeish, Amit M. Oza, Robert L. Coleman, et al. Results of ARIEL2: A Phase II trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis. J Clin Oncol 33, 2015 (suppl; abstr 5508)
International Collaborative Ovarian Neoplasm Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lan — View Citation
Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001 Sep;7(9):987-9. Review. — View Citation
Kanai T, Konno H, Tanaka T, Baba M, Matsumoto K, Nakamura S, Yukita A, Asano M, Suzuki H, Baba S. Anti-tumor and anti-metastatic effects of human-vascular-endothelial-growth-factor-neutralizing antibody on human colon and gastric carcinoma xenotransplante — View Citation
Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, Amnon A, Bell-McGuinn KM, Chen LM, Friedlander M, Safra T, Vergote I, Wickens M, Lowe ES, Carmichael J, Kaufman B. Phase II, open-label, randomized, multicenter study comparing the efficacy a — View Citation
Kurumizaka H, Ikawa S, Nakada M, Eda K, Kagawa W, Takata M, Takeda S, Yokoyama S, Shibata T. Homologous-pairing activity of the human DNA-repair proteins Xrcc3.Rad51C. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5538-43. Epub 2001 May 1. — View Citation
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N — View Citation
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott CL, Meier W, Shapira-Frommer R, Safra T, Matei D, Fielding A, Spencer S, Dougherty B, Orr M, Hodgson D, Barrett JC, Matulonis U. Olaparib maintenance therapy in patients with plat — View Citation
Lim JJ, Yang K, Taylor-Harding B, Wiedemeyer WR, Buckanovich RJ. VEGFR3 inhibition chemosensitizes ovarian cancer stemlike cells through down-regulation of BRCA1 and BRCA2. Neoplasia. 2014 Apr;16(4):343-53.e1-2. doi: 10.1016/j.neo.2014.04.003. — View Citation
Lisby M, Rothstein R, Mortensen UH. Rad52 forms DNA repair and recombination centers during S phase. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8276-82. — View Citation
Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, Rimel B, Buss MK, Nattam S, Hurteau J, Luo W, Quy P, Whalen C, Obermayer L, Lee H, Winer EP, Kohn EC, Ivy SP, Matulonis UA. Combination cediranib and olaparib versus olaparib alone for women — View Citation
Liu JF, Tolaney SM, Birrer M, Fleming GF, Buss MK, Dahlberg SE, Lee H, Whalen C, Tyburski K, Winer E, Ivy P, Matulonis UA. A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (A — View Citation
McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, Giavara S, O'Connor MJ, Tutt AN, Zdzienicka MZ, Smith GC, Ashworth A. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibiti — View Citation
McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996 Jan 4;334(1 — View Citation
Min A, Im SA, Yoon YK, Song SH, Nam HJ, Hur HS, Kim HP, Lee KH, Han SW, Oh DY, Kim TY, O'Connor MJ, Kim WH, Bang YJ. RAD51C-deficient cancer cells are highly sensitive to the PARP inhibitor olaparib. Mol Cancer Ther. 2013 Jun;12(6):865-77. doi: 10.1158/15 — View Citation
Muggia FM, Braly PS, Brady MF, Sutton G, Niemann TH, Lentz SL, Alvarez RD, Kucera PR, Small JM. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecol — View Citation
Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012 Nov 1;72(21):5588-99. doi: 10.1158/0008-5472.CAN-12-2753. — View Citation
Niedzwiedz W, Mosedale G, Johnson M, Ong CY, Pace P, Patel KJ. The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair. Mol Cell. 2004 Aug 27;15(4):607-20. — View Citation
Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stähle A, Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, — View Citation
Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, Stuart G, Kaye S, Vergote I, Blom R, Grimshaw R, Atkinson RJ, Swenerton KD, Trope C, Nardi M, Kaern J, Tumolo S, Timmers P, Roy JA, Lhoas F, Lindvall B, Bacon M, Birt A, Andersen JE, Zee — View Citation
Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997 Oct 15;57(20):4593-9 — View Citation
Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, Sorio R, Vergote I, Witteveen P, Bamias A, Pereira D, Wimberger P, Oaknin A, Mirza MR, Follana P, Bollag D, Ray-Coquard I. Bevacizumab combined with chemotherapy for platinum-resistan — View Citation
Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, Hylands L, Riisnaes R, Forster M, Omlin A, Kreischer N, Thway K, Gevensleben H, Sun L, Loughney J, Chatterjee M, Toniatti C, Carpenter CL, Iannone R, Kaye SB, de Bono JS, Wenham RM. The pol — View Citation
Shinohara A, Ogawa H, Ogawa T. Rad51 protein involved in repair and recombination in S. cerevisiae is a RecA-like protein. Cell. 1992 May 1;69(3):457-70. Erratum in: Cell 1992 Oct 2;71(1):following 180. — View Citation
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29. doi: 10.3322/caac.20138. Epub 2012 Jan 4. — View Citation
Sigurdsson S, Van Komen S, Petukhova G, Sung P. Homologous DNA pairing by human recombination factors Rad51 and Rad54. J Biol Chem. 2002 Nov 8;277(45):42790-4. Epub 2002 Aug 29. — View Citation
Sørensen CS, Hansen LT, Dziegielewski J, Syljuåsen RG, Lundin C, Bartek J, Helleday T. The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol. 2005 Feb;7(2):195-201. Epub 2005 Jan 23. — View Citation
Spannuth WA, Sood AK, Coleman RL. Angiogenesis as a strategic target for ovarian cancer therapy. Nat Clin Pract Oncol. 2008 Apr;5(4):194-204. doi: 10.1038/ncponc1051. Epub 2008 Feb 12. Review. — View Citation
Sweeney CJ, Miller KD, Sissons SE, Nozaki S, Heilman DK, Shen J, Sledge GW Jr. The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but an — View Citation
Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, Ardern-Jones A, Norman A, Kaye SB, Gore ME. "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cance — View Citation
Tentori L, Lacal PM, Muzi A, Dorio AS, Leonetti C, Scarsella M, Ruffini F, Xu W, Min W, Stoppacciaro A, Colarossi C, Wang ZQ, Zhang J, Graziani G. Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis. Eur J Cancer. 20 — View Citation
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutat — View Citation
Wang ZC, Birkbak NJ, Culhane AC, Drapkin R, Fatima A, Tian R, Schwede M, Alsop K, Daniels KE, Piao H, Liu J, Etemadmoghadam D, Miron A, Salvesen HB, Mitchell G, DeFazio A, Quackenbush J, Berkowitz RS, Iglehart JD, Bowtell DD; Australian Ovarian Cancer Stu — View Citation
Yang YG, Herceg Z, Nakanishi K, Demuth I, Piccoli C, Michelon J, Hildebrand G, Jasin M, Digweed M, Wang ZQ. The Fanconi anemia group A protein modulates homologous repair of DNA double-strand breaks in mammalian cells. Carcinogenesis. 2005 Oct;26(10):1731 — View Citation
Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Pro — View Citation
Zhang J, Willers H, Feng Z, Ghosh JC, Kim S, Weaver DT, Chung JH, Powell SN, Xia F. Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Mol Cell Biol. 2004 Jan;24(2):708-18. — View Citation
* Note: There are 61 references in all — Click here to view all references
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Phase I Primary Objective: MTD | To identify the Maximum Tolerated Dose (MTD) of the combination Rucaparib-Bevacizumab in stage IIIB-C-IV ovarian cancer patients | 4 months | |
| Primary | Phase II Primary Objective: PFS | To compare progression-free survival (PFS) of patients with advanced ovarian, primary peritoneal and Fallopian tube cancer when treated with Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs carboplatin-Paclitaxel-Rucaparib according to Homologous Recombination Deficient (HRD) status. | from the date of randomization to the date of documented progression disease, recurrence or death (whichever occurs first), assessed up to 64 months | |
| Secondary | Phase I Secondary Objectives: toxicity of the Rucaparib-Bevacizumab combination in terms of haematologic and non haematologic events | Toxicity will be evaluated according to U.S. NCI Common Toxicity Criteria version 4.03 | 4 months | |
| Secondary | Phase I Secondary Objectives: maximum plasma concentration (Cmax at Steady State) of Rucaparib | The evaluation of the effect of bevacizumab on rucaparib Cmax at SS will be performed by comparing (in each individual patient) the Cmax during cycle 1, on days 1 and 21, with the Cmax obtained on day -7 in which only Rucaparib will be administered. For these parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on days -7,1,21 | |
| Secondary | Phase I Secondary Objectives: minimal plasma concentration (Cmin at Steady State) of Rucaparib | The evaluation of the effect of bevacizumab on rucaparib Cmin at SS will be performed by comparing (in each individual patient) the Cmin during cycle 1, on days 1 and 21, with the Cmax obtained on day -7 in which only Rucaparib will be administered. For these parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on days -7,1,21 | |
| Secondary | Phase I Secondary Objectives: Area Under Curve (AUC) | The evaluation of the effect of bevacizumab on rucaparib AUC will be performed by comparing (in each individual patient) during cycle 1, on days 1 and 21, rucaparib AUC with AUC obtained on day -7 in which only Rucaparib will be administered. For this parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on days -7,1,21 | |
| Secondary | Phase I Secondary Objectives: Cmax | The evaluation of the effect of bevacizumab on rucaparib Cmax will be performed by measuring the maximum seric concentration of drug. For this parameter, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on day1 | |
| Secondary | Phase I Secondary Objectives: Tmax | The evaluation of the effect of bevacizumab on rucaparib will be performed by measuring the amount of time that the drug is present at the maximum concentration in serum. For this parameter, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on day1 | |
| Secondary | Phase I Secondary Objectives: AUC (0-24h) | The evaluation of the effect of bevacizumab on rucaparib will be performed by measuring the AUC during 24 h. For this parameter, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean. | will be evaluated during cycle 1, on day1 | |
| Secondary | Phase II Secondary Objectives: OS | Overall survival | from the date of randomization to the date of death, assessed up to 64 months | |
| Secondary | Phase II Secondary Objectives: PFS2 | Progression-free survival 2 | from randomisation to second objective disease progression or death, assessed up to 64 months | |
| Secondary | Phase II Secondary Objectives: TFST | Time to first subsequent therapy | from randomisation to the initiation of first subsequent therapy or death of patients, assessed up to 64 months | |
| Secondary | Phase II Secondary Objectives: TSST | Time to second subsequent therapy | from randomisation to the initiation of second subsequent therapy or death, assessed up to 64 months | |
| Secondary | Phase II Secondary Objectives: ORR | Overall response rate | 64 months | |
| Secondary | Phase II Secondary Objectives: Safety and tolerability | Safety and tolerability will be evaluated by U.S. National Cancer Institute Common Toxicity Criteria Adverse Event (NCI CTCAE) version 4.03 and the number of dose reductions | 64 months | |
| Secondary | Phase II Secondary Objectives: PRO for PHYSICAL WELL-BEING | Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A). | 64 months | |
| Secondary | Phase II Secondary Objectives: PRO for SOCIAL/FAMILY WELL-BEING | Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A). | 64 months | |
| Secondary | Phase II Secondary Objectives: PRO for EMOTIONAL WELL-BEING | Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A). | 64 months | |
| Secondary | Phase II Secondary Objectives: PRO for FUNCTIONAL WELL-BEING | Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A). | 64 months |