PAveMenT: Palbociclib and Avelumab in Metastatic AR+ Triple Negative Breast Cancer

Summary

This clinical study is aiming to determine the safest doses and schedule for the combination of two drugs named palbociclib and avelumab. The study will also be investigating how effective the combination is for a subgroup of breast cancer patients whose cancer expresses the androgen receptor (AR) but not the oestrogen (hormone) or HER2 receptors. Palbociclib is a drug used in routine care for hormone-receptor (HR) positive and HER2 negative advanced breast cancer, the most common subtype of breast cancer. It is possible that the combination of palbociclib and avelumab will be a more effective cancer treatment than each drug separately, but this is unknown and this study is needed to establish the best dosage and schedule of each drug as well as how effective the combination is.

Timeline

Start

2020-08-11

Primary completion

2027-07-31

Completion

2027-07-31

Publications

• Background Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74. doi: 10.1073/pnas.191367098.
• Background Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23. doi: 10.1073/pnas.0932692100. Epub 2003 Jun 26.
• Background Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011 Jul;121(7):2750-67. doi: 10.1172/JCI45014.
• Background Lehmann BD, Jovanovic B, Chen X, Estrada MV, Johnson KN, Shyr Y, Moses HL, Sanders ME, Pietenpol JA. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One. 2016 Jun 16;11(6):e0157368. doi: 10.1371/journal.pone.0157368. eCollection 2016.
• Background Wang C, Pan B, Zhu H, Zhou Y, Mao F, Lin Y, Xu Q, Sun Q. Prognostic value of androgen receptor in triple negative breast cancer: A meta-analysis. Oncotarget. 2016 Jul 19;7(29):46482-46491. doi: 10.18632/oncotarget.10208.
• Background Tsang JY, Ni YB, Chan SK, Shao MM, Law BK, Tan PH, Tse GM. Androgen receptor expression shows distinctive significance in ER positive and negative breast cancers. Ann Surg Oncol. 2014 Jul;21(7):2218-28. doi: 10.1245/s10434-014-3629-2. Epub 2014 Mar 18.
• Background McNamara KM, Yoda T, Nurani AM, Shibahara Y, Miki Y, Wang L, Nakamura Y, Suzuki K, Yang Y, Abe E, Hirakawa H, Suzuki T, Nemoto N, Miyashita M, Tamaki K, Ishida T, Brown KA, Ohuchi N, Sasano H. Androgenic pathways in the progression of triple-negative breast carcinoma: a comparison between aggressive and non-aggressive subtypes. Breast Cancer Res Treat. 2014 Jun;145(2):281-93. doi: 10.1007/s10549-014-2942-6. Epub 2014 Apr 9.
• Background Pistelli M, Caramanti M, Biscotti T, Santinelli A, Pagliacci A, De Lisa M, Ballatore Z, Ridolfi F, Maccaroni E, Bracci R, Berardi R, Battelli N, Cascinu S. Androgen receptor expression in early triple-negative breast cancer: clinical significance and prognostic associations. Cancers (Basel). 2014 Jun 27;6(3):1351-62. doi: 10.3390/cancers6031351.
• Background Luo X, Shi YX, Li ZM, Jiang WQ. Expression and clinical significance of androgen receptor in triple negative breast cancer. Chin J Cancer. 2010 Jun;29(6):585-90. doi: 10.5732/cjc.009.10673.
• Background Asano Y, Kashiwagi S, Onoda N, Kurata K, Morisaki T, Noda S, Takashima T, Ohsawa M, Kitagawa S, Hirakawa K. Clinical verification of sensitivity to preoperative chemotherapy in cases of androgen receptor-expressing positive breast cancer. Br J Cancer. 2016 Jan 12;114(1):14-20. doi: 10.1038/bjc.2015.434.
• Background Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, Stearns V, Doane AS, Danso M, Moynahan ME, Momen LF, Gonzalez JM, Akhtar A, Giri DD, Patil S, Feigin KN, Hudis CA, Traina TA; Translational Breast Cancer Research Consortium (TBCRC 011). Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Clin Cancer Res. 2013 Oct 1;19(19):5505-12. doi: 10.1158/1078-0432.CCR-12-3327. Epub 2013 Aug 21.
• Background Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O'Shaughnessy J, Gradishar W, Schmid P, Winer E, Kelly C, Nanda R, Gucalp A, Awada A, Garcia-Estevez L, Trudeau ME, Steinberg J, Uppal H, Tudor IC, Peterson A, Cortes J. Enzalutamide for the Treatment of Androgen Receptor-Expressing Triple-Negative Breast Cancer. J Clin Oncol. 2018 Mar 20;36(9):884-890. doi: 10.1200/JCO.2016.71.3495. Epub 2018 Jan 26.
• Background Bonnefoi H, Grellety T, Tredan O, Saghatchian M, Dalenc F, Mailliez A, L'Haridon T, Cottu P, Abadie-Lacourtoisie S, You B, Mousseau M, Dauba J, Del Piano F, Desmoulins I, Coussy F, Madranges N, Grenier J, Bidard FC, Proudhon C, MacGrogan G, Orsini C, Pulido M, Goncalves A. A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann Oncol. 2016 May;27(5):812-8. doi: 10.1093/annonc/mdw067. Epub 2016 Feb 18.
• Background Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011 Jul 7;11(8):558-72. doi: 10.1038/nrc3090.
• Background Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009 Mar;9(3):153-66. doi: 10.1038/nrc2602.
• Background Aarts M, Linardopoulos S, Turner NC. Tumour selective targeting of cell cycle kinases for cancer treatment. Curr Opin Pharmacol. 2013 Aug;13(4):529-35. doi: 10.1016/j.coph.2013.03.012. Epub 2013 Apr 15.
• Background Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999 Jun 15;13(12):1501-12. doi: 10.1101/gad.13.12.1501. No abstract available.
• Background Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi: 10.1186/bcr2419.
• Background Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4;490(7418):61-70. doi: 10.1038/nature11412. Epub 2012 Sep 23.
• Background Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015 Feb;14(2):130-46. doi: 10.1038/nrd4504.
• Background Asghar US, Barr AR, Cutts R, Beaney M, Babina I, Sampath D, Giltnane J, Lacap JA, Crocker L, Young A, Pearson A, Herrera-Abreu MT, Bakal C, Turner NC. Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer. Clin Cancer Res. 2017 Sep 15;23(18):5561-5572. doi: 10.1158/1078-0432.CCR-17-0369. Epub 2017 Jun 12.
• Background Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis MJ, Ma CX, Ramm S, Krop IE, Winer EP, Roberts TM, Kim HJ, McAllister SS, Zhao JJ. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017 Aug 24;548(7668):471-475. doi: 10.1038/nature23465. Epub 2017 Aug 16.
• Background Hurvitz S MM, Fernandez Abad M, Chan D, Rostorfer R, Petru E, Barriga S, Costigan TM Michael, Caldwell CW William, Nguyen T, Press M and Slamon D, editor Biological effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with HR+, HER2- breast cancer. 2016 San Antonio Breast Cancer Symposium; 2016; San Antonio, Texas
• Background Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, Su X, Wang Y, Gonzalez-Angulo AM, Akcakanat A, Chawla A, Curran M, Hwu P, Sharma P, Litton JK, Molldrem JJ, Alatrash G. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014 Apr;2(4):361-70. doi: 10.1158/2326-6066.CIR-13-0127. Epub 2014 Jan 10.
• Background Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, Budczies J, Huober J, Klauschen F, Furlanetto J, Schmitt WD, Blohmer JU, Karn T, Pfitzner BM, Kummel S, Engels K, Schneeweiss A, Hartmann A, Noske A, Fasching PA, Jackisch C, van Mackelenbergh M, Sinn P, Schem C, Hanusch C, Untch M, Loibl S. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018 Jan;19(1):40-50. doi: 10.1016/S1470-2045(17)30904-X. Epub 2017 Dec 7.
• Background Kashiwagi S, Asano Y, Goto W, Takada K, Takahashi K, Noda S, Takashima T, Onoda N, Tomita S, Ohsawa M, Hirakawa K, Ohira M. Use of Tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. PLoS One. 2017 Feb 6;12(2):e0170634. doi: 10.1371/journal.pone.0170634. eCollection 2017.
• Background Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016 Jul 20;34(21):2460-7. doi: 10.1200/JCO.2015.64.8931. Epub 2016 May 2.
• Background Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004 Nov;3(11):1427-38.
• Background Dean JL, McClendon AK, Hickey TE, Butler LM, Tilley WD, Witkiewicz AK, Knudsen ES. Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle. 2012 Jul 15;11(14):2756-61. doi: 10.4161/cc.21195. Epub 2012 Jul 15.
• Background Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3. Epub 2014 Dec 16.
• Background Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Dieras V, Slamon DJ. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.
• Background Turner NC, Huang Bartlett C, Cristofanilli M. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Oct 22;373(17):1672-3. doi: 10.1056/NEJMc1510345. No abstract available.
• Background Heery CR, O'Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, Lamping E, Oyelakin I, Marte JL, Lepone LM, Donahue RN, Grenga I, Cuillerot JM, Neuteboom B, Heydebreck AV, Chin K, Schlom J, Gulley JL. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017 May;18(5):587-598. doi: 10.1016/S1470-2045(17)30239-5. Epub 2017 Mar 31.
• Background Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. doi: 10.1200/JCO.2016.71.6795. Epub 2017 Apr 4.
• Background Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, Britten CD, Dirix L, Lee KW, Taylor M, Schoffski P, Wang D, Ravaud A, Gelb AB, Xiong J, Rosen G, Gulley JL, Apolo AB. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018 Jan;19(1):51-64. doi: 10.1016/S1470-2045(17)30900-2. Epub 2017 Dec 5.
• Background Gulley JL, Rajan A, Spigel DR, Iannotti N, Chandler J, Wong DJL, Leach J, Edenfield WJ, Wang D, Grote HJ, Heydebreck AV, Chin K, Cuillerot JM, Kelly K. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol. 2017 May;18(5):599-610. doi: 10.1016/S1470-2045(17)30240-1. Epub 2017 Mar 31.
• Background Dirix LY, Takacs I, Jerusalem G, Nikolinakos P, Arkenau HT, Forero-Torres A, Boccia R, Lippman ME, Somer R, Smakal M, Emens LA, Hrinczenko B, Edenfield W, Gurtler J, von Heydebreck A, Grote HJ, Chin K, Hamilton EP. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat. 2018 Feb;167(3):671-686. doi: 10.1007/s10549-017-4537-5. Epub 2017 Oct 23.
• Background Kaufman HL, Russell JS, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, Shih KC, Lebbe C, Milella M, Brownell I, Lewis KD, Lorch JH, von Heydebreck A, Hennessy M, Nghiem P. Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after >/=1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer. 2018 Jan 19;6(1):7. doi: 10.1186/s40425-017-0310-x.
• Background Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, Shih KC, Lebbe C, Linette GP, Milella M, Brownell I, Lewis KD, Lorch JH, Chin K, Mahnke L, von Heydebreck A, Cuillerot JM, Nghiem P. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016 Oct;17(10):1374-1385. doi: 10.1016/S1470-2045(16)30364-3. Epub 2016 Sep 1.
• Background Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, Pearson A, Guzman M, Rodriguez O, Grueso J, Bellet M, Cortes J, Elliott R, Pancholi S, Baselga J, Dowsett M, Martin LA, Turner NC, Serra V. Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer. Cancer Res. 2016 Apr 15;76(8):2301-13. doi: 10.1158/0008-5472.CAN-15-0728. Epub 2016 Mar 28.
• Background Schaer DA, Beckmann RP, Dempsey JA, Huber L, Forest A, Amaladas N, Li Y, Wang YC, Rasmussen ER, Chin D, Capen A, Carpenito C, Staschke KA, Chung LA, Litchfield LM, Merzoug FF, Gong X, Iversen PW, Buchanan S, de Dios A, Novosiadly RD, Kalos M. The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade. Cell Rep. 2018 Mar 13;22(11):2978-2994. doi: 10.1016/j.celrep.2018.02.053.

Drugs

Indications