untitled h1
11.3 required documentation (for multi-site

Before the study can be initiated at any sub-site, the following documentation must be provided to the UTSW Research Manager.  
- A copy of the official IRB approval letter for the protocol and informed consent - IRB membership list or Federal-wide Assurance letter - CVs and medical licensure for the principal investigator and any associate investigators who will be involved in the study
- Form FDA 1572 appropriately filled out and signed with appropriate documentation
(NOTE: This is required if UT Southwestern holds the IND. Otherwise, the affiliate Investigator's signature on the protocol is sufficient to ensure compliance)
- A copy of the IRB-approved consent form - Protocol Signature Page - Acknowledgement for bemcentinib Investigator's Brochure (IB) - CAP and CLIA Laboratory certification numbers and institution lab normal values - Signed site-specific monitoring plan - Executed clinical research contract
untitled h1
11.4 registration procedures

All subjects must be registered with the multi-site IIT team at UTSW before enrollment to study. Prior to registration, eligibility criteria must be confirmed with the multi-site IIT team at UTSW. To register a subject, email SCCC-IIT@UTSouthwestern.edu and Kelly Kyle at Kelly.Kyle@UTSouthwestern.edu Monday through Friday, 9:00AM-5:00PM.  
Each site will be given a number beginning with 01. New subjects at each site will receive a number upon study consent such that the first subject consented is numbered 001, the second subject consented receives the number 002, etc. In practice, the first subject at the first site will be numbered 01-001, the first subject at the second site will be 02-001, This number will not change upon confirmation of eligibility and enrollment or screen failure.  
Each newly consented subject should be numbered using the schema provided above. Upon registration, the registrar will assign the additional registration/randomization code according to the numbering schema outlined above, which should then be entered as the patient study id in Velos upon updating the status to enrolled.
untitled h1
11.5 data management and monitoring/auditing

REDCap is the UTSW SCCC institutional choice for the electronic data capture of case report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic case report forms in accordance with Simmons Comprehensive Cancer Center requirements, as appropriate for the project In order to facilitate remote source to case report form verification, the Simmons Comprehensive Cancer Center study team will require other institutions participating in this trial as sub-sites to enter data into the selected EDC system and upload selected deidentified source materials when instructed.  
Trial monitoring will be conducted according to the study specific monitoring plan. For guidance on creating a monitoring plan, refer to the UTSW SCCC IIT Management Manual.  
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for all UTSW SCCC clinical trials. As part of that responsibility, the DSMC reviews all serious adverse events and UPIRSOs in real time as they are reported and reviews adverse events on a quarterly basis. The quality assurance activity for the Clinical Research Office provides for periodic auditing of clinical research documents to ensure data integrity and regulatory compliance. A copy of the DSMC plan is available upon request. The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of ongoing clinical trials, for which it serves as the DSMC of record. The Quality Assurance Coordinator (QAC) works as part of the DSMC to conduct regular audits based on the level of risk. Audit findings are reviewed at the next available DSMC meeting. In this way, frequency of DSMC monitoring is dependent upon the level of risk. Risk level is determined by the DSMC Chairman and a number of factors such as the phase of the study; the type of investigational agent, device or intervention being studied; and monitoring required to ensure the safety of study subjects based on the associated risks of the study. Protocolspecific DSMC plans must be consistent with these principles.  
11.6 **Adherence to the Protocol**
Except for an emergency situation, in which proper care for the protection, safety, and wellbeing of the study subject requires alternative treatment, the study shall be conducted exactly as described in the approved protocol.  
11.6.1 **Exceptions** (also called single-subject exceptions or single-subject waivers):
include any departure from IRB-approved research that is *not due to an* emergency and is:
- intentional on part of the investigator; or
- in the investigator's control; or
- not intended as a systemic change (e.g., single-subject exceptions to eligibility
[inclusion/exclusion] criteria)
➢ **Reporting requirement***: Exceptions are non-emergency deviations that require *prospective* IRB approval before being implemented. Call the IRB if your request is urgent. If IRB approval is not obtained beforehand, this constitutes a major deviation. For eligibility waivers, studies which utilize the SCCC-DSMC as the DSMC of record must also obtain approval from the DSMC prior to submitting to IRB for approval.  
11.6.2 **Emergency Deviations:** include any departure from IRB-approved research that is necessary to:
- avoid immediate apparent harm, or - protect the life or physical well-being of subjects or others
➢ **Reporting requirement***: Emergency deviations must be promptly
reported to the IRB within 5 working days of occurrence.  
11.6.3 **Serious Noncompliance** (formerly called major deviations or **violations**):
include any departure from IRB-approved research that:
- Increase risk of harm to subjects; and/or adversely affects the rights, safety, or welfare of subjects (any of which may also be an unanticipated problem); and/or
- adversely affects the integrity of the data and research (i.e., substantially compromises the integrity, reliability, or validity of the research)
➢ **Reporting requirement***: Serious Noncompliance must be promptly reported to the IRB within 5 working days of discovery.  
11.6.4 **Continuing Noncompliance:** includes a pattern of repeated noncompliance (in or more protocols simultaneously, or over a period of time) which continues **after**
initial discovery, including inadequate efforts to take or implement corrective or preventive action within a reasonable time frame.  
➢ **Reporting requirement***: Continuing Noncompliance must be promptly reported to the IRB within 5 working days of discovery.
untitled h1
11.6.5 noncompliance (that is neither

- Does not meet the definition of serious noncompliance or continuing noncompliance
➢ **Reporting requirement***: Noncompliance that is neither serious nor continuing should be tracked and summarized the next IRB continuing review, or the notice of study closure- whichever comes first..  
*Reporting Requirements reflect UTSW HRPP/IRB guidelines; participating sites should follow the reporting guidelines for their IRB of record
untitled h1
11.7 amendments to the protocol

Should amendments to the protocol be required, the amendments will be originated and documented by the Principal Investigator. A summary of changes document outlining proposed changes as well as rationale for changes, when appropriate, is highly recommended. When an amendment to the protocol substantially alters the study design or the potential risk to the patient, a revised consent form might be required.  
The written amendment, and if required the amended consent form, must be sent to the IRB for approval prior to implementation.  
11.8 **Record Retention**
Study documentation includes all Case Report Forms, data correction forms or queries, source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms). Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study.  
Government agency regulations and directives require that the study investigator retain all study documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking regulatory approval and marketing, these documents shall be retained for at least two years after the last approval of marketing application in an International Conference on Harmonization (ICH) region. In all other cases, study documents should be kept on file until three years after the completion and final study report of this investigational study.
untitled h1
11.9 obligations of investigators

The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator is responsible for personally overseeing the treatment of all study patients. The Principal Investigator must assure that all study site personnel, including sub-investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study completion. The Principal Investigator at each institution or site will be responsible for assuring that all the required data will be collected and entered onto the Case Report Forms. Periodically, monitoring visits may be conducted, and the Principal Investigator will provide access to his/her original records to permit verification of proper entry of data. At the completion of the study, all case report forms will be reviewed by the Principal Investigator and will require his/her final signature to verify the accuracy of the data.
untitled h1
12.0 references

1. American Cancer Society sp. 2013;www.cancer.org.  
2. Matrisian L, Aizenberg R, Rosenzweig A. Pancreatic Cancer Action Network Special Report: The alarming rise of pancreatic cancer deaths in the United States: Why we need to stem the tide today. http://wwwpancanorg/section_research/reports/pdf/incidence_report_2012pdf 2012.  
3. Gessner C, Liebers U, Kuhn H, et al. BAX and p16INK4A are independent positive prognostic markers for advanced tumour stage of nonsmall cell lung cancer. The European respiratory journal 2002;19:134-40.  
4. Gu CD, Osaki T, Oyama T, et al. Detection of micrometastatic tumor cells in pN0 lymph nodes of patients with completely resected nonsmall cell lung cancer: impact on recurrence and Survival. Annals of surgery 2002;235:133-9.  
5. Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res 2008;100:35-83.  
6. Verma A, Warner SL, Vankayalapati H, Bearss DJ, Sharma S. Targeting Axl and Mer kinases in cancer. Mol Cancer Ther 2011;10:1763-73.  
7. Li Y, Ye X, Tan C, et al. Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene 2009;28:3442-55.  
8. Rankin EB, Fuh KC, Taylor TE, et al. AXL is an essential factor and therapeutic target for metastatic ovarian cancer. Cancer Res 2010;70:7570-9.  
9. Vajkoczy P, Knyazev P, Kunkel A, et al. Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proc Natl Acad Sci U S A 2006;103:5799-804.  
10. Chen PX, Li QY, Yang Z. Axl and prostasin are biomarkers for prognosis of ovarian adenocarcinoma.  
Ann Diagn Pathol 2013;17:425-9.  
11. Zhang Z, Lee JC, Lin L, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 2012;44:852-60.  
12. Song X, Wang H, Logsdon CD, et al. Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma. Cancer 2011;117:734-43.  
13. Kirane A, Ludwig KF, Sorrelle N, et al. Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis. Cancer Res 2015;75:3699-705.  
14. Ludwig KF, Du W, Sorrelle NB, et al. Small-Molecule Inhibition of Axl Targets Tumor Immune Suppression and Enhances Chemotherapy in Pancreatic Cancer. Cancer Res 2018;78:246-55.  
15. Paolino M, Choidas A, Wallner S, et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 2014;507:508-12.  
16. Ye X, Li Y, Stawicki S, et al. An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene 2010;29:5254-64.  
17. Akalu YT, Rothlin CV, Ghosh S. TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev 2017;276:165-77.  
18. Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signalling and potential therapeutic targeting in human cancer. Adv Cancer Res 2008 100:35–83.  
19. Linger RM, Keating AK, Earp HS, Graham DK. Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors. Expert Opin Ther Targets 2010 14(10):1073-1090.  
20. Song X, Wang H, Logsdon CD, et al. Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma. Cancer 2011 117(4):734-43.  
21. Paccez JD, Vasques GJ, Correa RG, et al. The receptor tyrosine kinase Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target. Oncogene 2013 32:689–698.  
22. Ishikawa M, Sonobe M, Nakayama E, et al. Higher Expression of Receptor Tyrosine Kinase Axl and Differential Expression of its Ligand, Gas6, Predict Poor Survival in Lung Adenocarcinoma Patients. Ann Surg Oncol 2013 Dec;20 Suppl 3:S467-476.  
23. Zhang Z, Lee JC, Lin L, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 2012 44:852-60.  
24. Gjerdrum C, Tiron C, Hoiby T, et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci USA 2010 107(3):1124-1129.  
25. Yuen H-F, McCrudden CM, Huang Y-H, et al. TAZ Expression as a Prognostic Indicator in Colorectal Cancer. PLOS ONE 2013 8(1):e54211.  
26. Ben-Batalla I, Schultze A, Wroblewski M, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine cross-talk of leukemia cells with bone marrow stroma. Blood.  
2013 Oct 3;122(14):2443-2452.  
27. Byers LA, Diao L, Wang J, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin. Cancer Res. 2013 19:279-90.  
28. Holland SJ, Pan A, Franci C, et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010 70(4):1544-1554.  
29. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009 9: 265–273.  
30. Nieto MA. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 2011 27:347-376.  
31. Thomson S, Petti F, Sujka-Kwok I, et al. A systems view of epithelial-mesenchymal transition signaling states. Clin Exp Metastasis 2011 28(2):137-55.  
32. Blick T, Hugo H, Widodo E, et al. Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44hi/CD24lo/- stem cell phenotype in human breast cancer. J Mammary Gland Biol Neoplasia. 2010 15(2):235-252.  
33. Vuoriluoto K, H Haugen H, Kiviluoto S, et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 2011 30(12):1436-1448.  
34. Lou Y, Diao l, Byers LA et al. Association of epithelial-mesenchymal transition status with PD1/PDL1 expression and a distinct immunophenotype in non-small cell lung cancer: Implications for immunotherapy biomarkers. J Clin Oncol 32:5s, 2014 (suppl; abstr 3018).  
35. Chen L, Gibbons DL, Goswami S, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 2014 28
(5):5241. doi: 10.1038/ncomms6241.  
36. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703.  
STU062018-024, Beg, FormA-ResearchProtocol-V6-10.02.2020, Mod_10, 08-09-21 (2)
53 37. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.  
38. Jameson GS BE, Babiker HM, Poplin E, et al. A phase Ib/II pilot trial with nab-paclitaxel plus gemcitabine plus cisplatin in patients (pts) with stage IV pancreatic cancer. Journal of Clinical Oncology 2017;35, no. 4_suppl 341-.  
39. Desai N, et al. Increased endothelial transcytosis of nanoparticle albumin-bound paclitaxel (ABI-007)
by gp60-receptors: a pathway inhibited by taxol. . Proceedings of San Antonio Breast Cancer Symposium2004.  
40. Commisso C, Davidson SM, Soydaner-Azeloglu RG, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 2013;497:633-7.  
41. Frese KK, Neesse A, Cook N, et al. nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer discovery 2012;2:260-9.  
42. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clinical cancer research : an official journal of the American Association for Cancer Research 2006;12:1317-24.  
43. ten Tije A, Verweij J, Loos W et al. Pharmacological effects of formulation vehicles - Implications for cancer chemotherapy. Clin Pharmacokinet 2003; 42(7):665-685.  
44. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours:
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.  
45. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 1989;10:1-10.
untitled h1
13.0 appendices appendix 1

Examples of CYP3A4 substrates are provided below. A further source of information on CYP3A4 substrates can be found at The University of Washington Metabolism and Transport Drug Interaction Database (see www.druginteractioninfo.org). University of Indiana CYP3A4, 5, 7 P450 Drug Interactions Abbreviated "Clinically
untitled h1
relevant" table of substrates

| Macrolide antibiotics:                                                                                                                                                              | HIV Antivirals:            | HMG CoA Reductase  Inhibitors:   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|----------------------------------|
| clarithromycin                                                                                                                                                                      | indinavir                  | atorvastatin                     |
| erythromycin (not 3A5)                                                                                                                                                              | ritonavir                  | lovastatin                       |
| NOT azithromycin                                                                                                                                                                    | saquinavir                 | NOT pravastatin                  |
| telithromycin                                                                                                                                                                       | nevirapine                 | NOT rosuvastatin simvastatin     |
| Anti-arrhythmics:                                                                                                                                                                   | Prokinetics:               |                                  |
| quinidine→3-OH                                                                                                                                                                      | cisapride                  | Others: alfentanyl               |
| Benzodiazepines:                                                                                                                                                                    | Antihistamines:            | aripiprazole                     |
| alprazolam                                                                                                                                                                          | astemizole                 | boceprevir                       |
| diazepam→3OH                                                                                                                                                                        | chlorpheniramine           | buspirone                        |
| midazolam                                                                                                                                                                           | carbamazepine              |                                  |
| triazolam                                                                                                                                                                           | Calcium Channel  Blockers: | gleevec                          |
| amlodipine                                                                                                                                                                          | haloperidol                |                                  |
| Immune Modulators:                                                                                                                                                                  | diltiazem                  | pimozide                         |
| cyclosporine                                                                                                                                                                        | felodipine                 | quinine                          |
| tacrolimus (FK506)                                                                                                                                                                  | nifedipine                 | tamoxifen                        |
| sirolimus                                                                                                                                                                           | nisoldipine                | telaprevir                       |
| nitrendipine                                                                                                                                                                        | trazodone                  |                                  |
| PDE-5 Inhibitors:                                                                                                                                                                   | verapamil                  | vincristine                      |
| sildenafil tadalafil vardenafil                                                                                                                                                     |                            |                                  |
| Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University  School of Medicine (2007). "/clinpharm/ddis/clinical-table/" Accessed 20 October 2016. |                            |                                  |
untitled h1
pharmacy times published list of

| Alfentanil (Alfenta)   | Docetaxel            | Ketoconazole  (Nizoral)   | Quinine    |
|------------------------|----------------------|---------------------------|------------|
| (Taxotere)             |                      |                           |            |
| Alfuzosin              | Donepezil  (Aricept) | Lapatinib (Tykerb)        | Ranolazine |
| (Uroxatral)            | (Ranexa)             |                           |            |  
| ________________________________________________________________________ Almotriptan (Axert) Doxorubicin  Levomethadyl  Repaglinide  (Adriamycin) (Orlaam) (Prandin) Alprazolam  (Xanax) Droperidol Loperamide  Rifabutin  (Imodium) (Rimactane) Amiodarone  Dutasteride  (Avodart) Lopinavir (Kaletra) Ritonavir  (Cordarone) (Norvir) Amlodipine  Ebastine  Loratadine  Saquinavir  (Norvasc) (Kestine) (Claritin) (Invirase) Aprepitant  Efavirenz  Lovastatin  Sibutramine  (Emend) (Sustiva) (Mevacor) (Meridia) Atazanavir  Eletriptan  Maraviroc  Sildenafil  (Reyataz) (Relpax) (Selzentry) (Viagra) Atorvastatin  Eplerenone  Mefloquine  Simvastatin  (Lipitor) (Inspra) (Lariam) (Zocor) Bepridil (Vascor) Ergotamine  (Ergomar) Methylprednisolone Sirolimus  (Rapamune) Bexarotene  Erlotinib  Midazolam  Solifenacin  (Targretin) (Tarceva) (Versed) (Vesicare) Bosentan  (Tracleer) Erythromycin Mifepristone  Sufentanil  (Mifeprex) (Sufenta) Bromocriptine  Estazolam  (ProSom) Modafinil (Provigil) Sunitinib  (Parlodel) (Sutent) Budesonide  Eszopiclone  (Lunesta) Nefazodone Tacrolimus  (Entocort) (Prograf) Buprenorphine  (Subutex) Ethinyl Estradiol Nevirapine  Tadalafil  (Viramune) (Cialis) Bupropion (Zyban,  Ethosuximide  Nicardipine  Tamoxifen  Wellbutrin, Voxra) (Zarontin) (Cardene) (Nolvadex) Carbamazepine  Etoposide  (Vepesid) Nifedipine (Adalat) Tamsulosin  (eg, Tegretol) (Flomax) Cevimeline  Exemestane  Nimodipine  Teniposide  (Evoxac) (Aromasin) (Nimotop) (Vumon) Cilostazol (Pletal) Felodipine  (Plendil) Nisoldipine (Sular) Testosterone Cisapride  Fentanyl  Nitrendipine  Tiagabine  (Propulsid) (Sublimaze) (Baypress) (Gabitril) Clarithromycin  Finasteride  Oxybutynin  Tinidazole  (Biaxin) (Proscar) (Ditropan) (Tindamax) Clonazepam  Flurazepam  Oxycodone  Tipranavir  (Klonopin) (Dalmane) (Percodan) (Aptivus) Clopidogrel  Fosamprenavir  (Lexiva) Paclitaxel (Taxol) Topiramate  (Plavix) (Topamax) Colchicine Galantamine  Paricalcitol  Triazolam  (Reminyl) (Zemplar) (Halcion) Cyclophosphamide  (Cytoxan) Gefitinib (Iressa) Pimozide (Orap) Vardenafil  (Levitra) Cyclosporine  Granisetron  (Kytril) Pioglitazone Verapamil  (Neoral) (Calan) Dapsone  Halofantrine  Praziquantel  Vinblastine  (Avlosulfon) (Halfan) (Biltricide) (Velbane) Darunavir  (Prezista) Ifosfamide (Ifex) Prednisolone Vincristine  (Oncovin) Dasatinib (Sprycel) Imatinib  (Gleevec) Prednisone Ziprasidone  (Geodon) Delavirdine  Indinavir  Propoxyphene  Zolpidem  (Rescriptor) (Crixivan) (Darvon) (Ambien) Dexamethasone  Irinotecan  (Camptosar) Quazepam (Doral) Zonisamide  (Decadron) (Zonegran) Dihydroergotamine Isradipine  Quetiapine  Zopiclone  (DynaCirc) (Seroquel) (Imovane)   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Diltiazem (Cardizem)   | Itraconazole  (Sporanox)   | Quinacrine   |
|------------------------|----------------------------|--------------|
| Disopyramide           | Ixabepilone  (Ixempra)     | Quinidine    |
| (Norpace)              |                            |              |  
CYP3A4 Substrates obtained from: Pharmacy Times 'Get to Know an Enzyme: CYP3A4'. John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD. Published Online: Monday, September 1, 2008
untitled h1
2c8 inhibitors

GEMFIBROZIL GLITAZONES (thiazolidinediones) MONTELUKAST QUERCETIN TRIMETHOPRIM
2C8 INDUCERS:
RIFAMPICIN
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). "https://drug-interactions.medicine.iu.edu" Accessed 29 October 2018.  
STU062018-024, Beg, FormA-ResearchProtocol-V6-10.02.2020, Mod_10, 08-09-21 (2)
58