Evaluation of utility of pharmacokinetic studies

in phase I trials of two oncology drugs

Kehua Wu1, Larry House1, Jacqueline Ramírez1, Michael J. Seminerio1,2, Mark J.

Ratain1,2,3

1Departments of Medicine, 2Committee on Clinical Pharmacology and

Pharmacogenomics, 3Comprehensive Cancer Center, The University of Chicago,

Chicago, IL

Running Title: Utility of pharmacokinetic drug-drug interaction studies

Corresponding Author: Mark J. Ratain, The University of Chicago, 5841 South

Maryland Avenue, MC 2115, Chicago, IL 60637, USA. Phone: 773-702-4400;

Fax: 773-702-3969; E-mail: [email protected]

Supplementary Tables

1 Table S1. Data collection form

Items Instruction or coding

Year published Indicate year of publication Indicate PubMed PMID PMID

Drug Indicate the name of the drugs

0 No clear rationale 1 Specific rationale If there is a rationale, specify the rationale as following: a Inhibition or induction of drug metabolizing enzyme or transporter Preclinical rationale as stated b Both drugs are substrates for the same enzyme or transporter in the paper c Alteration of liver or renal function d Alteration of drug absorption (for example, the drug changes the stomach’s emptying time or the pH of the GI tract) e Clinical data f Other (bind to same protein,etc.)

Actual rationale Same codes as above. 0 Randomized crossover (A followed by A+B, and A+B followed by A) 1 Parallel design (A in one cohort and A+B in another cohort) Study design 2 One-sequence crossover (A always followed by A+B, or vice versa) 3 Historical controls (A+B) 4 Other

Total # of patients used for PK analysis Indicate the number of patients for pharmacokinetic DDI evaluation

Total # of samples collected for PK analysis Indicate the number of samples for pharmacokinetic DDI evaluation

0 Traditional analysis Data analysis 1 Population analysis

0 Negative interaction Authors' interpretation 1 Positive interaction 2 Undetermined interaction

0 Industry Study sponsor 1 National health agency

2 Other: foundation, multiple resources, etc.

0 No specific statistical method 1 T-test Statistical method 2 Non-parametric analysis 3 Analysis of variance 4 Others

2

Table S2. Collected data

Total # of Author stated Objectively Total # of Study samples Data Authors' Study Statistical Year PMID Drug A Drug B preclinical existing patients used design collected in analysis interpretation sponsor method rationale rationale for PK analysis the study

2007 17908982 imatinib mesylate 0 0 2 33 495 0 0 1 3 2007 18000498 pertuzumab 0 0 2 36 468 0 0 1 0 2007 17519066 docetaxel 0 1(b) 2 36 1296 0 0 0 3 2007 17146732 LY293111 0 0 2 23 690 0 0 1 3 2007 17704424 lapatinib 0 0 1 19 931 0 0 2 3 2007 18187952 docetaxel 1(b) 1(a) 3 10 100 0 0 1 0 2007 17149608 gemcitabine erlotinib 0 0 2 20 360 0 0 0 3 2007 17699864 sorafenib erlotinib 0 1(b) 2 17 306 0 0 1 2 2007 17317832 calcitriol gefitinib 0 0 2 31 1426 0 0 1 0 2007 17908977 flavopiridol docetaxel 0 0 2 21 294 0 0 1 0 2007 17195945 irinotecan capecitabine 1(a) 1(a) 2 12 264 0 0 0 1 2007 17947485 0 0 3 17 374 0 0 1 0 2007 17362316 0 0 2 10 160 0 0 1 1 2007 17577220 everolimus gefitinib 0 1(a) 2 9 270 0 0 0 0 2007 18048823 tanespimycin trastuzumab 0 0 2 23 - 0 0 2 0 2007 16642371 sulindac 0 0 2 17 136 0 0 0 3 2007 18269776 epirubicin 0 0 3 34 67 0 0 0 0 2007 17255280 lonafarnib paclitaxel 1(b) 1(b) 2 24 800 0 0 1 3 2007 17255275 pemetrexed irinotecan 0 0 3 51 1122 0 0 0 3 2007 17345085 irinotecan gemcitabine 0 0 2 24 576 0 0 1 0 2007 17473200 sorafenib gefitinib 1(b) 1(b) 2 19 304 0 1 1 3

3 2007 17628744 irofulven capecitabine 0 0 2 24 432 0 0 0 0 2007 17679729 valproic acid 0 0 2 13 247 0 0 2 1 2007 17569044 vinorelbine docetaxel 1(b) 1(a) 2 19 266 1 0 1 1 2007 17623836 lonafarnib imatinib mesylate 0 1(a) 2 23 322 0 0 2 0 2007 17285128 indisulam carboplatin 0 0 3 16 368 1 0 2 0 2007 17095207 irinotecan sorafenib 1(b) 1(a) 2 24 552 0 1 0 4 2007 17051371 gemcitabine 0 0 2 23 299 0 0 1 0 2007 17285317 carboplatin paclitaxel 0 0 2 14 308 0 0 2 1 2007 16832665 irinotecan 0 1(b) 2/3 8 104 0 0 1 0 2008 18519774 oxaliplatin paclitaxel 0 0 3 23 414 1 1 2 5 2008 18319713 ispinesib docetaxel 0 1(b) 3 24 115 1 0 1 0 2008 18927308 0 0 3 41 820 0 0 1 0 2008 18043132 enzastaurin capecitabine 0 0 2 13 468 0 0 1 4/2 2008 18217204 CEP-701 gemcitabine 0 0 2 12 - 0 0 0 0 2008 18281547 erlotinib docetaxel 0 1(b) 3 21 336 0 0 1 0 2008 18320191 PI-88 docetaxel 0 0 2 16 576 0 0 1 0 2008 18628463 lapatinib letrozole 1(a) 1(a) 0 20 560 0 0 1 3 2008 18758179 epirubicin docetaxel 0 0 3 3 30 0 0 1 0 2008 18794549 erlotinib 0 0 2 18 756 0 0 1 2 2008 17429623 irinotecan UCN-01 0 0 2 16 608 0 1 1 1 2008 18692224 lapatinib carboplatin 0 1(a) 2 10 30 0 0 1 0 2008 18565892 lapatinib docetaxel 1(a) 1(a) 0 17 476 0 0 0 3 2008 18379785 trabectedin gemcitabine 0 0 3 15 585 0 2 0 1 2008 19047120 lapatinib 1(a) 1(a) 2 11 528 0 1 2 3 2008 19088046 carboplatin 0 0 2 43 1247 0 0 1 0 2008 19047122 AG014699 temozolomide 0 0 3 31 1116 0 0 0 0 2008 18971935 motesanib gemcitabine 0 0 2 26 936 0 0 1 0 2008 18359865 imatinib temozolomide 0 0 1 20 360 0 0 1 0 2008 18414469 indisulam capecitabine 1(a) 1(a) 3 33 858 1 1 0 0

4 2008 18490651 lapatinib trastuzumab 0 0 0 27 756 0 0 0 3 2008 18497430 trabectedin doxorubicin 0 0 3 25 300 0 0 0 0 2008 18451238 pertuzumab capecitabine 0 0 2 18 324 0 0 0 0 2008 18039566 everolimus letrozole 0 1(a) 2 13 156 0 0 1 0 2008 18245546 OGX-011 docetaxel 0 0 - 40 960 0 0 1 1 2008 18327587 doxorubicin 0 1(a) 3 32 288 0 0 2 0 2008 18765554 EKB-569 capecitabine 0 0 2 11 198 0 0 1 1 2008 18600301 cisplatin 9-nitrocamptothecin 1(a) 0 2 27 540 0 0 1 1 2008 18597837 paclitaxel poliglumex carboplatin 0 0 2 11 231 0 0 0 0 2008 17694310 gefitinib temozolomide 0 0 2 26 260 0 2 1 1 2008 18519777 17-AAG paclitaxel 0 0 2 25 350 0 0 1 0 2008 18927314 irinotecan 17-AAG 0 0 2 14 - 0 0 1 2 2009 19417029 tariquidar vinorelbine 0 0 2 8 160 0 0 1 0 2009 19738417 CAI paclitaxel 1(b) 1(b) 3 24 - 0 1 1 5 2009 19637344 ADH-1 0 0 3 12 84 0 0 0 0 2009 19331202 vinorelbine cisplatin 1( c) 0 2 11 198 0 0 1 3 2009 19723647 nilotinib imatinib 0 1(a) 1 44 1276 0 1 0 0 2009 19118069 pemetrexed cisplatin 0 0 3 21 630 0 0 0 0 2009 19687340 irinotecan gefitinib 1(a) 1(a) 2 25 275 0 1 2 2 2009 19568235 NGR-hTNF doxorubicin 0 0 2 15 450 0 2 1 0 2009 19487488 enzastaurin pemetrexed 0 0 3 86 2176 0 0 0 4 2009 18956139 pemetrexed paclitaxel 0 0 3 92 870 0 0 0 0 2009 19903778 sorafenib tipifarnib 0 1(b) 3 24 144 0 0 1 0 2009 19090012 irinotecan carboplatin 0 0 3 22 308 0 0 0 0 sodium 2009 19789320 5-azacytidine 0 0 3 12 300 0 0 1 0 phenylbutyrate 2009 19449006 troxacitabine cisplatin 0 0 3 31 558 0 0 1 0 2009 19430790 temozolomide O6-benzylguanine 0 0 3 21 273 0 0 1 0 2010 19633045 ABT-751 docetaxel 0 0 2/3 18 288 0 0 0 2

5 2009 19082825 triapine doxorubicin 0 0 3 20 440 0 0 1 0 2009 19114300 trabectedin doxorubicin 0 0 3 20 480 0 0 0 0 2009 19011858 cisplatin pemetrexed 0 0 4 13 390 0 0 0 4 2009 19770383 cetuximab irinotecan 0 0 3 35 455 0 0 0 0 naptumomab 2009 19636016 docetaxel 0 0 2 26 - 0 0 1 0 estafenatox 2009 19531625 Carboplatin topotecan 0 0 2 37 629 0 0 1 1 2009 19299235 trastuzumab erlotinib 0 0 3 16 112 0 0 0 4 2009 19127256 paclitaxel everolimus 1(b) 1(b) 2 11 242 0 0 0 0 2009 18936884 paclitaxel toremifene 1(b) 0 2 15 180 0 0 1 1 2009 19419856 trabectedin cisplatin 0 1(a) 2 22 528 0 0 0 0 2009 18682950 paclitaxel poliglumex cisplatin 0 0 3 43 473 0 0 0 0 2010 20717111 sunitinib irinotecan 0 1(a) 2 11 374 0 0 0 4 2010 20798192 topotecan pemetrexed 0 1(b) 2 26 588 0 0 0 1 2010 20091169 paclitaxel 1(b) 1(b) 2 20 10 0 1 0 1 2010 19855966 Imexon gemcitabine 0 0 4 105 1680 0 0 0 0 2010 20233177 CP-690,550 0 0 2 12 576 0 0 0 4 2010 20061136 cediranib gefitinib 0 0 2/3 24 384 0 0 0 1 2010 21045832 sirolimus sorafenib 1(b) 1(b) 2 30 750 0 0 1 1 2010 20399458 ketoconazole docetaxel 1(a) 1(a) 2 42 546 0 0 1 2 2010 20485286 sunitinib ifosamide 1(a) 1(a) 2 11 297 0 1 1 2 2010 20142592 erlotinib dasatinib 1(b) 1(a) 2 33 16 - 0 0 0 2010 20126478 vatalanib cetuximab 0 0 2 17 27 0 0 0 1 2010 20628389 docetaxel figitumumab 0 0 2 13 144 0 0 2 0 2010 20142724 sunitinib gefinitib 0 1(b) 2 11 - 0 0 0 0 2010 20855840 ridaforolimus capecitabine 0 0 2 32 544 0 0 0 1 2010 20197396 sorafenib erlotinib 0 1(b) 2 11 136 0 0 1 2 2010 20564143 everolimus docetaxel 1(b) 1(b) 2 19 24 0 2 2 0 2010 20444843 erlotonib pemetrexed 0 0 2 20 680 0 0 0 0

6 2010 20217089 panobistat docetaxel 0 1(b) 1 15 240 0 0 2 0 2011 20922800 apricoxib erlotinib 0 1(b) 2 20 - 0 0 0 0 2010 20043166 sunitinib docetaxel 0 1(b) 2 50 900 0 0 0 0 2010 20406832 AMG102 bevacizumab 0 0 3 13 182 0 0 0 0 2010 20558056 topotecan temozolomide 0 0 2 16 352 1 0 1 0 2010 19901013 ridaforolimus paclitaxel 0 1(b) 2 8 11 0 0 0 1 2010 20837944 capecitabine sunitinib 0 0 2 60 3840 0 0 0 4 2010 21147873 paclitaxel pazopanib 1(a) 1(b) 2 25 39 0 0 0 0 2010 20453691 pemetrexed enzastaurin 0 0 2 24 744 0 0 0 0 2010 20856105 carboplatin 0 0 2 14 196 0 0 1 1 2010 20525756 sorafenib tanespimycin 0 1(a) 2 23 414 0 0 1 1 2010 20479064 tremelimumab exemestane 0 0 3 6 16 0 0 0 0 2010 20406837 paclitaxel trabectedin 1(b) 1(b) 2 57 3434 0 0 1 1 2011 20461440 flavopiridol 0 0 2 31 279 0 0 0 0 2010 19894051 UCN-01 prednisone 0 0 2 24 156 0 0 0 0 2010 20199976 cisplatin 0 0 2 24 168 0 0 2 3 2010 20877350 tosedostat paclitaxel 0 0 2 22 - 0 0 2 0 2011 20821331 sorafenib 0 0 2 15 420 0 2 0 3 2011 21350820 docetaxel imatinib 1(a) 1(a) 2 12 266 0 0 1 2 2011 21436695 doxorubicin gemcitabine 0 0 2 13 104 0 0 1 1 2011 21257722 safingol cisplatin 0 0 2 39 494 0 0 1 0 2011 20694727 UCN-01 irinotecan 1(f) 1(f) 2 48 691 0 0 1 0 2011 21625179 TH-302 doxorubicin 0 0 3 16 368 0 0 0 0 2011 21387258 everolimus sorafenib 1(e) 1(b) 2 20 420 0 0 0 0 2011 21825263 lenolamide CCI-779 1(a) 1(a) 3 41 - 0 1 2 1/3 2011 20490801 erlotinib docetaxel 0 1(b) 2 56 365 1 0 1 1 2011 21177764 everolimus figitumumab 0 0 3 21 - 1 0 0 0 2011 21339064 capecitabine 0 0 3 32 768 0 0 0 0 2011 21594722 PR-104 sorafenib 0 0 2 7 56 0 0 1 1

7 2011 21209247 capecitabine sorafenib 0 0 2 29 1024 0 0 1 4 2011 21439816 SU-014813 docetaxel 0 0 2 22 618 0 0 0 4 2011 21252987 0 0 2 15 345 0 0 0 0 sorafenib or 2011 21447721 sirolimus 0 1(b) 0 14 294 1 0 1 2 sunitinib 2011 21629245 brivanib alaninate cetuximab 0 0 2 50 1092 0 0 0 4 2011 21365629 docetaxel lonafarnib 0 1(b) 2 10 140 0 0 1 2 2011 21326243 dacarbazine 0 0 2 29 464 0 0 0 0 2011 21753156 LY2334737 erlotinib 0 0 1 42 340 0 0 0 4 2011 21795476 ABT-888 topotecan 0 0 0 21 504 0 0 1 0 2011 21247755 vandetanib bevacizumab 0 0 3 4 20 - 0 1 0 2011 21321571 AVE1642 bortezomib 0 0 2 26 364 0 0 1 0 2011 21547572 tesetaxel capecitabine 0 0 2 26 780 0 0 2 3 2011 20623160 plitidepsin carboplatin 0 0 3 20 452 0 0 1 0 2011 21278245 decitabine vorinostat 0 0 3 61 812 0 2 1 1 2011 21610520 vinflunine gemcitabine 0 0 2 17 - 0 0 1 4 2011 22011284 lonafarnib gemcitabine 0 0 2 41 1066 0 0 0 0 2011 21442199 vinflunine doxorubicin 0 0 3 15 - 0 0 1 0

* (-) means not mentioned in paper

8