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13.3 accountability procedures

Drug accountability records will be maintained for all clinical supplies. All empty and partially used vials and clinical trial supplies will be destroyed locally according to the institution's standard operating procedures for drug destruction. The pharmacy will maintain detailed documentation of the number and identification of vials which are destroyed, and copies of these documents will be provided to the sponsor. Disposition of all unused boxes of study drug will be carried out according to instructions provided by the sponsor at the end of the study after drug accountability is performed by the study monitor.
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14.0 references

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34. Gill SI, Vides V, Frey NV, et al. Prospective Clinical Trial of Anti-CD19 CAR T Cells in Combination with Ibrutinib for the Treatment of Chronic Lymphocytic Leukemia Shows a High Response Rate. Blood 2018;132:298-. 35. Gauthier J, Hirayama AV, Hay KA, et al. Comparison of Efficacy and Toxicity of CD19-Specific Chimeric Antigen Receptor T-Cells Alone or in Combination with Ibrutinib for Relapsed and/or Refractory CLL. Blood 2018;132:299-.  
36. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014;123:3390-7. 37. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370:997-1007.  
38. Mato AR, Hill BT, Lamanna N, et al. Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in Chronic Lymphocytic Leukemia: Results from a Multi-Center Study of 683 Patients. Ann Oncol 2017. 39. Godet S, Protin C, Dupuis J, et al. Outcome of chronic lymphocytic leukemia patients who switched from either ibrutinib or idelalisib to alternate kinase inhibitor: A retrospective study of the French innovative leukemia organization (FILO). Am J Hematol 2018;93:E52-E4.  
40. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013;19:202-8. 41. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 2016;374:311-22. 42. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 2018;378:1107-20.  
43. Kater AP, Seymour JF, Hillmen P, et al. Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. J Clin Oncol 2019;37:269-77. 44. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol 2018;19:65-75. 45. Knight ZA, Gonzalez B, Feldman ME, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 2006;125:733-47.  
46. Vanhaesebroeck B, Vogt PK, Rommel C. PI3K: from the bench to the clinic and back. Curr Top Microbiol Immunol 2010;347:1-19. 47. Clayton E, Bardi G, Bell SE, et al. A crucial role for the p110delta subunit of phosphatidylinositol 3kinase in B cell development and activation. The Journal of experimental medicine 2002;196:753-63.  
48. Fung-Leung WP. Phosphoinositide 3-kinase delta (PI3Kdelta) in leukocyte signaling and function. Cell Signal 2011;23:603-8. 49. Cheung SM, Kornelson JC, Al-Alwan M, Marshall AJ. Regulation of phosphoinositide 3-kinase signaling by oxidants: hydrogen peroxide selectively enhances immunoreceptor-induced recruitment of phosphatidylinositol (3,4) bisphosphate-binding PH domain proteins. Cell Signal 2007;19:902-12.  
50. Bilancio A, Okkenhaug K, Camps M, et al. Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells. Blood 2006;107:642-50. 51. Dil N, Marshall AJ. Role of phosphoinositide 3-kinase p110 delta in TLR4- and TLR9-mediated B cell cytokine production and differentiation. Mol Immunol 2009;46:1970-8. 52. Durand CA, Hartvigsen K, Fogelstrand L, et al. Phosphoinositide 3-kinase p110 delta regulates natural antibody production, marginal zone and B-1 B cell function, and autoantibody responses. J Immunol 2009;183:5673-84. 53. Srinivasan L, Sasaki Y, Calado DP, et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 2009;139:573-86. 54. Zhang TT, Okkenhaug K, Nashed BF, et al. Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production. J Allergy Clin Immunol 2008;122:811-9 e2.  
55. Okkenhaug K, Bilancio A, Farjot G, et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 2002;297:1031-4. 56. Rommel C, Camps M, Ji H. PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 2007;7:191-201.  
57. Garcon F, Patton DT, Emery JL, et al. CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer. Blood 2008;111:1464-71. 58. Haylock-Jacobs S, Comerford I, Bunting M, et al. PI3Kdelta drives the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation. J
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59. Jarmin SJ, David R, Ma L, et al. T cell receptor-induced phosphoinositide-3-kinase p110delta activity is required for T cell localization to antigenic tissue in mice. J Clin Invest 2008;118:1154-64. 60. Liu D, Uzonna JE. The p110 delta isoform of phosphatidylinositol 3-kinase controls the quality of secondary anti-Leishmania immunity by regulating expansion and effector function of memory T cell subsets.  
J Immunol 2010;184:3098-105. 61. Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B. The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol 2006;177:5122-8. 62. Reif K, Okkenhaug K, Sasaki T, Penninger JM, Vanhaesebroeck B, Cyster JG. Cutting edge:
Differential roles for phosphoinositide 3-kinases, p110 gamma and p110 delta, in lymphocyte chemotaxis and homing. Journal of Immunology 2004;173:2236-40. 63. Soond DR, Bjorgo E, Moltu K, et al. PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans. Blood 2010;115:2203-13. 64. Webb LM, Vigorito E, Wymann MP, Hirsch E, Turner M. Cutting edge: T cell development requires the combined activities of the p110gamma and p110delta catalytic isoforms of phosphatidylinositol 3-kinase. J
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65. Schmid MC, Avraamides CJ, Dippold HC, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell 2011;19:715-27. 66. Konrad S, Ali SR, Wiege K, et al. Phosphoinositide 3-kinases gamma and delta, linkers of coordinate C5a receptor-Fcgamma receptor activation and immune complex-induced inflammation. The Journal of biological chemistry 2008;283:33296-303.  
67. Marwick JA, Caramori G, Stevenson CS, et al. Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med 2009;179:542-8. 68. Randis TM, Puri KD, Zhou H, Diacovo TG. Role of PI3Kdelta and PI3Kgamma in inflammatory arthritis and tissue localization of neutrophils. Eur J Immunol 2008;38:1215-24.  
69. Ali K, Bilancio A, Thomas M, et al. Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature 2004;431:1007-11. 70. Kim MS, Radinger M, Gilfillan AM. The multiple roles of phosphoinositide 3-kinase in mast cell biology. Trends Immunol 2008;29:493-501.  
71. Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD. Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. Faseb J
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73. Kim N, Saudemont A, Webb L, et al. The p110delta catalytic isoform of PI3K is a key player in NKcell development and cytokine secretion. Blood 2007;110:3202-8.  
74. Saudemont A, Garcon F, Yadi H, et al. p110gamma and p110delta isoforms of phosphoinositide 3kinase differentially regulate natural killer cell migration in health and disease. Proc Natl Acad Sci U S A 2009;106:5795-800. 75. Tassi I, Cella M, Gilfillan S, et al. p110gamma and p110delta phosphoinositide 3-kinase signaling pathways synergize to control development and functions of murine NK cells. Immunity 2007;27:214-27.  
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77. Chen SS, Ham S, Rai KR, McGovern K, Kutok JL, Chiorazzi N. Dual Inhibition of PI3K-Delta and Gamma By Duvelisib (IPI-145) Impairs CLL B- and T-Cell Migration, Survival and Proliferation in a Murine Xenograft Model Using Primary Chronic Lymphocytic Leukemia Cells. Blood 2015;126. 78. Dong S, Guinn D, Dubovsky JA, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood 2014;124:3583-6.  
79. Chen SS, Kutok JL, Ferrer G, et al. Dual Inhibition of PI3K-delta and PI3K-gamma By Duvelisib Eliminates CLL B Cells, and Overcomes Ibrutinib Resistance in a Patient-Derived Xenograft Model. Blood 2018;132.  
80. Niemann CU, Herman SE, Maric I, et al. Disruption of in vivo chronic lymphocytic leukemia tumormicroenvironment interactions by ibrutinib - findings from an investigator-initiated phase II study. Clinical cancer research : an official journal of the American Association for Cancer Research 2016;22:1572-82. 81. Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 2011;117:6287-96. 82. Davids MS, Kim HT, Nicotra A, et al. Umbralisib in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: a multicentre phase 1-1b study.  
The Lancet Haematology 2019;6:e38-e47. 83. Smith TJ, Bohlke K, Armitage JO. Recommendations for the Use of White Blood Cell Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Oncol Pract 2015;11:511-3. 84. Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820-2.  
85. Geller NL. Advances in clinical trial biostatistics. New York: Marcel Dekker; 2004.  
86. Chomarat P, Banchereau J. Interleukin-4 and interleukin-13: their similarities and discrepancies. Int Rev Immunol 1998;17:1-52.  
| Permanent  D/C of  Duvelisib  After C6D28 Progression  of Disease  *30 days  after last  dose  C1D28 C2D28 C3D28 C4D28 C5D28 C6D28 After C6D28 Unscheduled  Visit   | Window +/- days +/- 4 wks +/- 7D +/- 7D +/- 7D +/- 7D +/- 7D +/- 7D +/- 15D + 7D   | day /month  Clinical                       | Consent X X X X X X X X X X  X X X X X X X X X X  X X X X X X X X X X  X X X X X X X X X X   | X X4 X4 X X X X X X X  X X X X X X X X X X  X X X X X X X X X X  X X X X X X X X X X  X X X X X X X X X X   | X X X X X X X X X X  X X X X X X X X X X  X X X X X X X X X X        | Pregnancy test X3  Lymphocyte phenotyping (T, B, NK) X X X X5 X X  ,*+9PXWDWLRQDQDO\VLVEORRGRU%0" X1  3HULSKHUDOEORRGIORZF\WRPHWU\IRU&// X X X7 X   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|--------------------------------------------|----------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------|---|
| X X X X  X X X X X X X X                                                                                                                                            |                                                                                    |                                            |                                                                                              |                                                                                                             |                                                                      |   |
| Screen and  Baseline Visit                                                                                                                                          | X1                                                                                 |                                            |                                                                                              |                                                                                                             |                                                                      |   |
| X                                                                                                                                                                   | X                                                                                  | X                                          | X                                                                                            | X                                                                                                           | X  Thyroid function panel (thyroid stimulating hormone, free T4, T3) |   |
| APPENDIX A: SCHEDULE OF EVENTS                                                                                                                                      | EVALUATION AND ASSESSMENTS                                                         | Iron studies (ferritin, transferrin, iron) |                                                                                              |                                                                                                             |                                                                      |   |
| Concomitatnt Medication Review                                                                                                                                      | Acute Care & Mineral Panel                                                         | Tot. protein, Uric Acid, LDH               |                                                                                              |                                                                                                             |                                                                      |   |
| PROTOCOL TIMEPOINT                                                                                                                                                  | CBC with Differential                                                              | Reticulocyte Count                         |                                                                                              |                                                                                                             |                                                                      |   |
| Physical Exam                                                                                                                                                       | SPEP with IFE                                                                      | ȕ0LFURJOREXOLQ                                            |                                                                                              |                                                                                                             |                                                                      |   |
| Hepatic Panel                                                                                                                                                       | SFL with qIG                                                                       | )RODWH9LW%                                            |                                                                                              |                                                                                                             |                                                                      |   |
| Labs                                                                                                                                                                | HLA Typing                                                                         | +DSWRJORELQ                                |                                                                                              |                                                                                                             |                                                                      |   |
| ECOG PS                                                                                                                                                             | PT, PTT                                                                            |                                            |                                                                                              |                                                                                                             |                                                                      |   |
| History                                                                                                                                                             | CRP                                                                                | DAT                                        |                                                                                              |                                                                                                             |                                                                      |   |  
| Viral Studies  Viral Studies (HIV, Hepatitis B & C, HTLV-I/II) X  HBV DNA Quantitative PCR X2 X2 X2 X2 X2 X2 X2 X2 X2 X2   | CMV and EBV                               |                                    |                |                                            |      |      |               |
|----------------------------------------------------------------------------------------------------------------------------|-------------------------------------------|------------------------------------|----------------|--------------------------------------------|------|------|---------------|
| X O                                                                                                                        | X O                                       | X X                                | PET Scan O     | Bone Marrow Asiprate and Biopsy O O O X7 O | O O1 | O O1 | X X X X X O X |
| X X X X6 X                                                                                                                 | X X X X7 X                                |                                    |                |                                            |      |      |               |
| X X X X X X X  X X X                                                                                                       | X                                         |                                    |                |                                            |      |      |               |
| &//),6+LQFOXGHVSUREHVIRUT-T-, 17p-, t(11:14))                                                                                                                            | Unstimulated and CpG-stimulated karyotype | Bone marrow flow cytometry for CLL | 5HVHDUFKEORRGXSWRP/                |                                            |      |      |               |
| STUDY MEDICATION                                                                                                           | Duvelisib                                 | Research Samples                   | Lymphapheresis | /\PSKQRGHELRSV\                                            |      |      |               |
| EVALUATIONS                                                                                                                | CT Neck, CAP                              |                                    |                |                                            |      |      |               |
| Ibrutinib                                                                                                                  | EKG                                       |                                    |                |                                            |      |      |               |  
O = Optional 2 PD\EHREWDLQHGEHIRUHVWDUWLQJGXYHOLVLEDQGRULQVXEMHFWVZLWKSHUVLVWHQWO\PSKRF\WRVLVDQGRUDWSURJUHVVLRQRIGLVHDVHRUVXVSLFLRQRISURJUHVVLYHGLVease ; DWDQ\WLPHEHIRUHVWDUWLQJGXYHOLVLE; )RUVXEMHFWVZLWKDSRVLWLYH+%F$EKHSDWLWLV%'1$3&5ZLOOEHSHUIRUPHGX3 :&%3RQHQHJDWLYHSUHJQDQF\WHVWVZLWKLQZHHNEHIRUHVWDUWLQJGXYHOLVLE; HYHU\ZHHNVIRU&\FOHV-WHVWVFRQGXFWHGDWRXWVLGHLQVWLWXWLRQVDUHDFFHSWHG; WREHSHUIRUPHGHYHU\PRQWKV; WREHSHUIRUPHGHYHU\PRQWKVIRUVW\HDURQGXEHOLVLEWKHQDQQXDOO\; ZKHQVXEMHFWPHHWVDOORWKHUFULWHULDIRUFRPSOHWHUHPLVVLRQDVGHWDLOHGLQ6HFWLRQ* 7HVWVZLOOEHSHUIRUPHGGD\VGD\VDIWHUODVWGRVHRIGXYHOLVLELVDGPLQLVWHUHGRUEHIRUHWKHQH[WWUHDWPHQWVWDUWV, whichever occurs first.
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appendix b cyp3a inhibitors inducers

The following list provides medications or foods known to induce or inhibit CYP3A activity. Note that this is not a comprehensive list of all medications or foods which may modulate CYP3A activity. Additional information can be found at: https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/uc m093664.htm Note: Subjects receiving duvelisib are prohibited from concomitant use of medications or foods that are known to be strong inhibitors or inducers of CYP3A.  
| Table 7. Classification of In Vivo Inhibitors of CYP3A  Strong Inhibitors1  Moderate inhibitors2                                                                                                                                                   | Weak inhibitors3                                                                                                                                                          |                                                                                                                                                                                                                                                                    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Boceprevir,  clarithromycin, conivaptan,  grapefruit juice4 , indinavir,  itraconazole, ketoconazole,  lopinavir/ritonavir,  mibefradil5 nefazodone, nelfinavir,  posaconazole, ritonavir,  saquinavir,  telaprevir,  telithromycin,  voriconazole | Amprenavir, aprepitant,  atazanavir, ciprofloxacin,  darunavir/ritonavir, diltiazem,  erythromycin, fluconazole,  fosamprenavir, grapefruit juice4 ,  imatinib, verapamil | Alprazolam, amiodarone,  amlodipine, atorvastatin,  bicalutamide, cilostazol,  cimetidine,  cyclosporine, fluoxetine,  fluvoxamine, ginkgo6 ,  goldenseal6 ,  isoniazid, nilotinib,  oral contraceptives, ranitidine,  ranolazine,  tipranavir/ritonavir, zileuton |
| 1.                                                                                                                                                                                                                                                 | A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for                                                                |                                                                                                                                                                                                                                                                    |  
1. A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for WKDW&<3E\-fold or > 80% decrease in CL.  
2. A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for that CYP by less than 5-fold but equal to or more than 2-fold or 50-80% decrease in CL.  
3. A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for that CYP by less than 2-fold but equal to or more than 5-fold or 20-50% decrease in CL.  
4. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparationdependent. Studies have shown that it can be classified as a "strong CYP3A inhibitor" when a certain preparation was used (e.g., high dose, double strength) or as a "moderate CYP3A inhibitor" when another preparation was used (e.g., low dose, single strength).  
5. Withdrawn from the United States market because of safety reasons. 6. Herbal product.
untitled h1
medications known to induce cyp3a

| Table 8. Classification of In Vivo Inducers of CYP3A  6WURQJ,QGXFHUV• Moderate Inducers                                                                      | Weak Inducers                                                 |                         |
|----------------------------------------------------------------------|---------------------------------------------------------------|-------------------------|
| decrease in AUC                                                      | 50-GHFUHDVHLQ$8&                                                               | 20-GHFUHDVHLQ$8&                         |
| Avasimibe1 , arbamazepine,  phenytoin, rifampin, St. John's  Wort2,3 | Bosentan, efavirenz, etravirine,                              | Amprenavir, aprepitant, |
| modafinil, nafcillin                                                 | armodafinil, Echinacea3 pioglitazone, prednisone,  rufinamide |                         |
| Abbreviations: AUC: area under the curve; CYP3A: cytochrome P450 3A. |                                                               |                         |  
Bosentan, efavirenz, etravirine, modafinil, nafcillin  
Amprenavir, aprepitant,  
armodafinil, Echinacea3  
pioglitazone, prednisone,  
rufinamide  
Abbreviations: AUC: area under the curve; CYP3A: cytochrome P450 3A.  
1. Not a marketed drug.  
2. The effect of St. John's Wort varies widely and is preparation-dependent. 3. Herbal product.  
Known sensitive CYP3A substrates and CYP3A substrates with a narrow therapeutic range are listed in Table . Drugs or foods that are substrates of CYP3A should only be used if medically necessary and therapeutic alternatives do not exist. Additional information can be found at x https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteraction slabeling/ucm093664.htm x http://www.pharmacytimes.com/issue/pharmacy/2008/2008-09/2008-09-8687  
| Table 9. Cytochrome P450 3A (CYP3A) Substrates  Sensitive CYP3A Substrates  budesonide  buspirone  eplerenone  eletriptan  felodipine  fluticasone  lovastatin  midazolam  saquinavir  sildenafil  simvastatin  triazolam  vardenafil  CYP3A Substrates with a Narrow Therapeutic Range  alfentanil  astemizole  cisapride  cyclosporine  diergotamine  ergotamine  fentanyl  pimozide  quinidine  sirolimus  tacrolimus  terfenadine   |
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