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vital signs

Small increases in mean systolic and diastolic blood pressure (SBP and DBP) were observed across most dose cohorts in Part A within the first week of treatment, although no significant dose-response relationship could be identified. In Part B a small mean increase in DBP was  
observed after 1 week of BID dosing, reaching a maximum increase after 3 weeks BID dosing and being resolved by Week 12. There were no clinically significant trends observed for pulse rate or percentage of oxygen saturation in blood (SpO2) at any dose in study. Mandatory assessment of LV dysfunction and ejection fraction (LVEF) was performed at baseline, after 8 weeks on study, and ad hoc on the occurrence of cardiorespiratory AEs. Data indicate a trend towards a mean decrease in LVEF at Week 8 across all dose cohorts, with no obvious dose-response relationship.  
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Review of the electrocardiogram (ECG) parameters demonstrated no consistent trend of significant prolongation of the corrected QT interval (QTc) across the dose cohorts in Part A, the maximum increase in mean QTc was noted in the 75-mg BID cohort with a 12.9 msec increase (standard deviation 13.2 msec, range –1 to +27 msec) 2 hours post-dose on day 8, n=5. Laboratory parameters There were a few minor differences in the clinical laboratory profile (primarily in renal and hematological parameters) between the AZD6244 free-base and hydrogen sulfate formulations; however, the information for hydrogen sulfate is based on a limited data set.  
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The AZD6244 capsule formulation contains vitamin E as an excipient. High doses of vitamin E have been reported to potentiate the anticoagulant activity of coumarins, such as warfarin. Therefore, patients who take such anticoagulants and receive the capsule formulation of AZD6244 will be advised to have an increased frequency of anticoagulation assessments, such as international normalized ratio (INR) measurements, upon starting AZD6244 therapy. In addition, the concomitant intake of excessive doses of vitamin E should be avoided in patients receiving the capsule formulation. Based on preclinical reproductive toxicology studies, AZD6244 hydrogen sulfate (capsule formulation) should not be administered to pregnant or breast-feeding women, and conception while on treatment must be avoided. Potential Drug Interactions I
In vitro metabolic studies of AZD6244 using hepatocytes from humans and animals found that the biologically active N-desmethyl derivative was detected in mouse and human hepatocytes, was detected minimally in monkeys; and was not detected in rats (Investigator's Brochure, 2009). CYP1A2 was the enzyme primarily responsible for the formation of the N-desmethyl derivative; CYP2C19 and CYP3A4 were also minimally involved in the transformation. Neither AZD6244 nor its active metabolite were found to be inhibitors of CYP isoforms 1A2, 2C8, 2C19, 2D6, or 3A4. However, AZD6244 was found to be a weak inhibitor of CYP2C9 (IC50 = 44.7 uM) and the N-desmethyl derivative was a weak inhibitor of CYP1A2 (IC50 = 18.9 uM). Thus, at the systemic AZD6244 concentrations observed following 100 mg AZD6244 free-base formulation in man, no significant cytochrome P450 interactions would be expected. Since the formation of N-desmethyl AZD6244 from AZD6244 may occur through the CYP 1A2 pathway and smoking induces this pathway, the smoking status of the subjects should to be recorded in all studies (i.e., smoker or non-smoker) to investigate whether smoking status influences systemic drug exposures of N-desmethyl AZD6244.  
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18.1.1.3 erlotinib

OSI-774 (erlotinib, Tarceva®) is an orally active, potent, selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase (160). OSI-774 inhibits the human EGFR tyrosine kinase with a 50% inhibitory concentration (IC50) of 2 nM (0.786 ng/mL) in an in vitro enzyme assay and reduces EGFR autophosphorylation in intact tumor cells with an IC50 of 20 nM (7.86 ng/mL). OSI-774 inhibits EGF-dependent proliferation of cells at submicromolar concentrations and blocks cell-cycle progression in the G1 phase.  
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OSI-774 appears to bind specifically to EGFR. In a study of OSI-774 binding specificity, affinity of OSI-774 for 67 cellular receptors was examined (160). OSI-774 was shown to bind with low affinity to peripheral benzodiazepine (IC50=2.5 µM [980 ng/ml]), adenosine A1 (IC50=6.8 µM [2700 ng/ml]), and µ-opiate (IC50=7.0 µM [2800 ng/ml]) receptors. Binding affinities were 1250-fold higher than the IC50 concentration needed to inhibit purified EGFR tyrosine kinase (2 nM [0.79 ng/ml]). When tested at concentrations up to 1 µM (390 ng/ml), no significant inhibition of ligand binding to 64 other neurotransmitter receptors, regulatory binding sites, calcium channels, opioid receptors, or neurotransmitter uptake sites were observed. Nonclinical Studies O
In mice, daily oral administration of OSI-774 for 20 days inhibited subcutaneous (SC) growth of the HN5 human head and neck carcinoma in a dose-dependent manner as compared to vehicletreated mice, with an estimated effective dose for 50% inhibition (ED50) of 9.2 mg/kg/day (160).  
Treatment with 11 mg/kg/day of OSI-774 immediately halted growth or slightly decreased the size of HN5 tumors >1 cm in diameter. The tumor stasis profile appeared to extend beyond the treatment period such that the tumor size for OSI-774-treated animals did not exceed pretreatment levels until at least 33 days post-treatment. Similar results were observed in A431 squamous cell carcinoma xenografts at a dose of 11 mg/kg/day OSI-774 over 20 days.  
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OSI-774 (10 mg/kg/day) has been studied in combination with cisplatin, doxorubicin, 5fluorouracil, paclitaxel, vinorelbine tartrate, and gemcitabine (160). No antagonism of therapeutic efficacy was observed, and additive effects were observed with cisplatin (10 mg/kg intravenous [IV] daily × 1), doxorubicin (15 mg/kg IV daily × 1), paclitaxel (10 mg/kg intraperitoneal [IP] daily × 5), and gemcitabine (100 mg/kg IP three times daily × 4). Nonclinical toxicology studies in rats and dogs have included acute and long-term general toxicology, genetic toxicology, reproductive toxicology, and local tissue tolerance of erlotinib. Clinical signs of toxicity in rats and/or dogs following a single dose of OSI-774 were dose dependent and included transient emesis, ataxia, papillary dilation, increased heart rate, decreased blood pressure, decreased activity, irregular respiration, convulsions, rapid chewing, salivation, and death. Following chronic administration in rats and dogs, the following toxicities were observed in at least one species: effects on the cornea (atrophy and ulceration); effects on the skin (follicular degeneration and inflammation, redness, and alopecia); atrophy of the ovary, lacrimal glands, and salivary glands; necrosis of the liver; papillary necrosis and tubular dilatation of the kidney; inflammation in the mandibular lymph nodes; hematopoiesis; delayed gastric emptying; and diarrhea. Increases in alanine aminotransferase, aspartate aminotransferase, and bilirubin were observed.  
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OSI-774 causes maternal toxicity with associated embryo-fetal lethality and abortion in rabbits at doses 3 times those in humans (AUC at 150 mg daily dose). However, when administered during organogenesis at plasma concentrations approximately equal to humans, no increase in embryo-fetal lethality or abortion in rats or rabbits was observed. Female rats treated with doses 0.3 to 0.7 times the human dose prior to mating and during the first week of gestation had an increase in early resorptions. No teratogenic effects were observed in rats or rabbits. Pharmacokinetics V
The total clearance of OSI-774 decreased with increasing dose, resulting in supraproportional increases in exposure (AUC) over the dose range of 1-2 mg/kg IV in rats and 0.5-7 mg/kg IV in dogs (160). In vitro, OSI-774 is slowly oxidized by liver microsomes. The majority of the absorbed dose is extensively metabolized in rats and dogs, and only a small amount is excreted as unchanged drug in urine, bile, and feces. The oral bioavailability of an aqueous suspension is 77% in rats and ~88% in dogs. Plasma protein binding of OSI-774 ranges from 92% to 95% in man, monkey, rat, and mouse, and is 85% in the dog. Corrected for protein binding of 95%, at the average plasma concentration responsible for 50% inhibition of tumor growth (oral dose of 9.2 mg/kg/day in the murine/human tumor xenograft model), the unbound concentration of drug in the plasma is estimated to be 86 nM (34 ng/mL). The estimated unbound concentration of OSI-774 in plasma is consistent (4-fold higher) with the IC50 for the in vitro cellular phosphotyrosine reduction assay and is 43-fold higher than the IC50 for the in vitro (isolated enzyme) tyrosine kinase assay. Finally, OSI-774 plasma protein binding depends on the levels of α-1-acid glycoprotein (AAG). Thus, AAG might be a significant determinant of pharmacokinetic and possibly pharmacokinetic–pharmacodynamic relationships in patients.  
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Pharmacokinetic Data OSI-774 pharmacokinetics were examined in patients with advanced solid tumors who were treated daily for 21 days. Plasma samples were collected on Days 1, 3, and 21 for analysis. The following table lists the pharmacokinetic data for these patients:  
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| Dose   | N         | AUC0-24   | R*      | Cavg   | Cmax   |       |      |       |       |        |      |      |
|--------|-----------|-----------|---------|--------|--------|-------|------|-------|-------|--------|------|------|
| (mg)   | (ng•h/ml) | (ng/ml)   | (ng/ml) |        |        |       |      |       |       |        |      |      |
| D      |           |           |         |        |        |       |      |       |       |        |      |      |
| Day 1  | Day 3     | Day       | Day 3   | Day    | Day 1  | Day 3 | Day  | Day 1 | Day 3 | Day 21 |      |      |
| 21     | 21        | 21        |         |        |        |       |      |       |       |        |      |      |
| 25     | 3         | 1580      | 2180    | 1.38   | 66     | 91    | 208  | 310   |       |        |      |      |
| (40)   | (49)      | (11)      | (38)    | (40)   |        |       |      |       |       |        |      |      |
| 50     | 6a        | 5650      | 5790    | 14900  | 1.59   | 1.83  | 235  | 241   | 621   | 508    | 716  | 682  |
| (54)   | (57)      | (69)      | (31)    | (30)   | (34)   | (55)  | (59) |       |       |        |      |      |
| 100    | 8b        | 9210      | 9080    | 32200  | 1.75   | 3.21  | 384  | 378   | 1340  | 765    | 1140 | 1740 |  
| (92)   | (49)   | (148)   | (35)   | (56)   | (69)   | (49)   | (85)   |      |      |      |      |      |
|--------|--------|---------|--------|--------|--------|--------|--------|------|------|------|------|------|
| 150    | 7c     | 1420    | 2060   | 45800  | 1.74   | 2.57   | 670    | 859  | 1910 | 1040 | 2040 | 1730 |
| 0 (71) | 0 (22) | (99)    | (6.7   | (47)   | (70)   | (21)   | (82)   |      |      |      |      |      |
| 200    | 7      | 3600    | 74200  | 2.01   | 1360   | 3200   | 1420   | 2910 |      |      |      |      |
| 0 (34) | (29)   | (42)    | (47)   | (29)   |        |        |        |      |      |      |      |      |  
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Abbreviations: AUC0-24, Area under the time-concentration curve from 0 to 24 hours; Cavg, daily average plasma concentration; Cmax, maximum serum/plasma concentration; CV, coefficient of variance; R, accumulation ratio *Accumulation ratio = AUCDay 3 or 21/AUCDay 1 aOnly 3 patients day 3, 3 subjects day 21 bOnly 2 patients day 3, 3 subjects day 21 cOnly 6 patients day 21 O
After oral ingestion, the OSI-774 Cmax values (Tmax) were achieved at a median of 3 hours
(range, 2 to 12 hours). Both Cmax and AUC0-24 values were roughly proportional to the OSI774 dose in the range of 25 to 200 mg/d (R2 = 0.33 and 0.46, respectively, on Day 1). Intersubject variability was moderate at the 150-mg/d dose level, as indicated by coefficient of variation values of 64% for Day 1 AUC0-24 and Cmax.
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drug interactions

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In *in vitro* human liver microsomes studies OSI-774 was slowly oxidized. OSI-774 appeared to be a substrate for CYP3A4, suggesting that OSI-774 could reduce the clearance of coadministered drugs whose metabolism is dependent on these P450 cytochrome isoenzymes.  
- Erlotinib is both protein bound (92% to 95%) and metabolized by CYP3A4. Therefore, a potential for drug-drug interactions exists when erlotinib is co-administered with drugs that are highly protein-bound or CYP3A4 inhibitors or inducers.  
- There is a potential interaction between erlotinib and warfarin. Patients have experienced elevated international normalized ratios (INRs) and bleeding with this combination of drugs. Patients on warfarin and erlotinib should have more frequent INR/prothrombin time (PT) determinations (e.g., weekly for the first month and weekly for a minimum of 2 weeks following Discontinuation of erlotinib).  
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- Proton pump inhibitor: Erlotinib's solubility decreases as the pH increases.  
Coadministration of omeprazole with erlotinib will decrease the AUC and Cmax by 46% and 61%, respectively.  
- H2-antagonist: Avoid concomitant use of erlotinib with gastric acid-reducing agents if possible. When ranitidine 300 mg is given with erlotinib, erlotinib AUC and Cmax decrease by 33% and 54%, respectively. Increasing the dose of erlotinib will not compensate the loss of exposure. However, if an H2-antagonist receptor is needed, take
erlotinib at least 2 hours before or 10 hours following the H2-antagonist administration. Dosing such, erlotinib loss of exposure is minimized to AUC of 15% and Cmax of 17%.  
- Smoking: Advise smokers to stop smoking while taking OSI-774. Smoking induces CYP1A2 enzymes and alters OSI-774 exposure by 64%.  
- Food-drug interaction: Avoid grapefruit /grapefruit juice (potent CYP3A4) while taking  
  
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Adverse Events Associated with OSI-774
A comprehensive list of AEs possibly related to OSI-779 is provided in the CAEPR. Additional information can also be found in the Investigator's Brochure and the Package Insert. A few common or serious AEs are described below. Rash or dermatosis: (Grades 1-3) has been reported in many subjects (~50%) during the first several days of treatment, although severity diminishes after 4 weeks of therapy. The use of topical agents (i.e., diphenhydramine, corticosteroids) and oral antibiotics (tetracycline) has been instituted in some patients with variable results. In patients with severe rash, treatment has been discontinued or the study drug dose reduced. The etiology of the rash is still unknown, but may be related to the mechanism of action of OSI-774.  
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Nausea and diarrhea: (Grades 1-2) have been observed in approximate half of all subjects treated with OSI-774. Both adverse events are transient and usually do not require a reduction in dosage. Diarrhea is well controlled in most patients by either the use of loperamide or dose reduction. All ongoing clinical trials recommend the institution of therapy with loperamide. As of June 2001, no significant drug interactions have been observed between OSI-774 and loperamide.  
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Hepatic toxicities: Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of OSI-779, particularly in patients with baseline hepatic impairment. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is recommended. In the setting of worsening liver function tests, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. OSI-779 dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values.  
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Renal insufficiencies: Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia, or concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (e.g., pre-existing renal disease, medical conditions or medications that may lead to renal disease, or other predisposing conditions including advanced age), OSI-779 therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration.  
Gastrointestinal perforation: Patients receiving OSI-779 are at increased risk of developing gastrointestinal perforation, which was observed uncommonly. Some cases had a fatal outcome.  
Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxanebased chemotherapy, or who have prior history of peptic ulceration or diverticular disease, are at increased risk. OSI-779 should be permanently discontinued in patients who develop gastrointestinal perforation.  
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Bullous and exfoliative skin disorders: Bullous, blistering, and exfoliative skin conditions have been reported, including very rare cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis (which in some cases were fatal). OSI-779 treatment should be interrupted or discontinued if the patient develops severe bullous, blistering, or exfoliating conditions. Ocular disorders: Very rare cases of corneal perforation or ulceration have been reported during use of OSI-779. Other ocular disorders, including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with OSI-779 treatment and are known risk factors for corneal perforation/ulceration. OSI-779 therapy should be interrupted or discontinued if patients present with acute/worsening ocular disorders such as eye pain.  
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Fertility and teratology: These studies have not been conducted with OSI-774, and safety for women of childbearing capacity cannot be implied from the existing data. OSI-774 has not been tested for carcinogenic activity in a lifetime rodent bioassay.
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16.1.1.4 lapatinib

Lapatinib is a small molecule member of the quinazoline class of kinase inhibitors and is a dual reversible inhibitor of both EGFR and HER2 receptors. Lapatinib has a median inhibitory concentration for the EGFR receptor at a dose of 12 nmol/l and HER2 receptor at a dose of 9 nmol/l. Lapatinib prevents phosphorylation and subsequent signal transduction of both the Ras/Raf mitogen activated protein kinase and the phosphoinositol-3-kinase/Akt pathways, leading to an increase in apoptosis and decreased cellular proliferation. Lapatinib at nanomolar concentration blocks cell-cycle proliferation at the G1 phase. It has a high specificity for both the EGFR TKD and HER2 TKD and has no other inhibition of other cell receptors and nonreceptor tyrosine kinases. Results from pharmacokinetic studies showed that lapatinib is highly protein bound in humans (> 99%). Oxidation is the primary route of metabolism via the hepatic cytochromes CYP3A4, CYP3A5 and CYP2C19.  
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Lapatinib has been approved by the FDA to be used in combination with capecitabine for treatment of patients with metastatic breast cancer whose tumors overexpress HER2. A Phase III trial in women whose tumors overexpressed HER2 and who had failed trastuzumab randomized patients to receive either lapatinib at 1250 mg once daily (continuously) plus capecitabine 2000 mg/m2/day on days 1 - 14 every 21 days, or to receive capecitabine alone at a dose of 2500 mg/m2/day on days 1 - 14 every 21 days. The primary end point of this study was time to progression (TTP). Based on the results of a prespecified interim analysis, further enrollment was discontinued after 399 patients demonstrated an increase in TTP from 19.7 weeks to 36.9 weeks. The combination increased toxicity with notable side effects of diarrhea (65%), hand-foot  
syndrome (53%), nausea (44%), rash (29%) and fatigue (24%). QT prolongation is another potential toxicity of lapatinib. Lapatinib has been evaluated as a single agent in several Phase II studies. It has been studied in inflammatory breast cancer overexpressing HER2. This trial demonstrated a 35% objective response rate (ORR). It has been further investigated as a monotherapy in a Phase II trial involving heavily pretreated metastatic breast cancer patients. In this study no objective responses were seen in patients with HER2 negative tumors. A 4.3% response rate in HER2positive patients was demonstrated. A third Phase II study involved single-agent lapatinib in HER2-positive breast cancer patients with brain metastases. In the 39 subjects enrolled in this trial, only one had a CNS response.  
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HER2 overexpression has been reported in 4 - 20% of NSCLC and is associated with a poor prognosis. A Phase II trial tested lapatinib as monotherapy in the first- or second-line setting in metastatic NSCLC. This trial was discontinued after enrollment of 131 patients, after only one PR was seen. The use of lapatinib is now being tested in other solid tumors, including gastric, ovarian and colorectal carcinomas. Predictors of HER2-TKI sensitivity and resistance O
Clinical data have so far demonstrated that tumors must overexpress HER2 to be sensitive to either lapatinib or trastuzumab. Lapatinib sensitivity increases with increased expression of both HER2 and EGFR. In hormone-positive breast cancer, increased HER2 expression has been shown to downregulate estrogen receptor (ER) expression. Signaling through HER2 seems to bypass the estrogen requirement for breast cancer cell growth and may drive initially ER-positive cells into an ER-negative, or endocrine therapy-resistant state. Overexpression of both EGFR and HER2 has been associated with tamoxifen resistance. Estrogen and tamoxifen have been shown to increase phosphorylation of HER2. ER and HER2 have a bidirectional crosstalk; therefore lapatinib may have the ability to restore tamoxifen sensitivity. A Phase I study combining letrozole and lapatinib determined the optimal Phase II dosage of letrozole at 2.5 mg/day and lapatinib at 1500 mg/day, which is being tested at present.  
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Trastuzumab resistance has been seen in tumors with upregulated insulin-like growth factor receptor-1 (IGF-1R), in tumors that lack phosphatase and tensin homolog (PTEN) expression, and in tumors with activating mutations in PI3K. An overexpression of IGF-1R leads to increased phosphorylation of HER2, resulting in increased signaling. Both PTEN-deficient tumors as well as tumors with activating PI3K mutations have an increase in the PI3K signaling pathway. Additional resistant mechanisms to trastuzumab include increased membraneassociated glycoprotein mucin-4 (MUC4), which interacts directly with HER2. MUC4 provides steric hindrance to trastuzumab binding.  
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There are limited data defining the exact cause of lapatinib resistance. HER2 receptor tyrosine kinase mutations have rarely been reported in breast cancer. Proposed mechanisms of resistance have included an upregulation of estrogen receptor pathways and overexpression of both HER3 and HER4. Other proposed mechanisms of resistance have included upregulation of IGF-1R and lack of inhibition of surviving.  
A b brevi ate d Title: M olec ul ar Pr ofili n g N S C L C  
Versi o n D ate : 0 1/ 0 7/ 2 0 2 0
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1 8. 1. 2. 1

S u nit i ni b malate (s u niti ni b; S U 1 1 2 4 8; S U 0 1 1 2 4 8; S ute nt ®) is a n oral, m ulti-tar gete d, s mall m olec ule i n hi bit or of t he rece pt or t yr osi ne ki nases ( R T Ks) i n v ol ve d i n t u m or pr olifer ati o n a n d a n gi o ge nesis, i ncl u di n g v asc ular e n d ot helial gr o wt h fact or r ece pt or- 1 ( V E G F R - 1), -2, a n d - 3, platelet - deri ve d gr o wt h f act or r ece pt or ( P D G F R) - a n d - , ste m cell f act or rece pt or ( KI T), t he t yr osi ne ki nas e ( T K) rece pt or e nc o de d b y t he ret pr ot o o nc o ge n e ( R E T; rearra n ge d d uri n g tra nsfecti o n), f ms-li ke t yr osi ne ki nase 3 ( Flt 3), basic fi br o blast gr o wt h fact or ( b F G F) a n d c ol o n ysti m ulati n g fact or ( C S F)- 1 R ( O' Farrell et al., 2 0 0 3 a; C h o w a n d Ec k har dt, 2 0 0 7; Fai vre et al.,  
2 0 0 7; Ga n et al., 2 0 0 9; Mas h ka ni et al., 2 0 1 0). S u niti ni b selecti vel y a n d p ote ntl y i n hi bits t he class III a n d class V s plit - d o mai n R T Ks ( Me n del et al., 2 0 0 3).  
S u nit i ni b s h o ws si g nifica nt a ntit u m or a n d a nti-a n gi o ge nic acti vit y i n a n u m ber of h u ma n t u m or x e n o graft a n d a n gi o g e n esis m o dels i n mice as well as i n p hase 1 a n d 2 st u dies i n patie nts wit h a variet y of t u m or t y pes ( G a n et al., 2 0 0 9; Me na et al., 2 0 1 0). As of J u ne 2 0 0 8, a t otal of 8 9 3 2 s u bjects wit h s oli d mali g na nt t u m ors ha ve recei ve d s u niti ni b, i ncl u di n g patie nts wit h re nal cell carci n o ma ( R C C) a n d t h ose wit h gastr oi ntesti nal str o mal t u m ors ( GI S T) (I n vesti gat or's Br oc h ure, 2 0 0 9). I n p has e 2 st u dies i n c yt o ki ne-refract or y m etastatic R C C, s u niti ni b pr o d uce d o bjecti ve res p o nses i n 4 0 % of patie nts wit h a me dia n ti me t o-t u m or- pr o gr essi o n ( T T P) of 8. 7 m o nt hs ( M otzer et al., 2 0 0 6). I n p hase 3 st u dies of patie nts wit h i mati ni b- resista nt GI S T,  
s u niti ni b was hi g hl y s u p eri or t o place b o ( p < 0. 0 0 0 1) wit h res pect t o me dia n T T P ( 2 7. 3 wee ks vs.  
6. 4 wee ks), pr o gressi o n- free s ur vi val ( P F S), a n d o verall s ur vi val ( O S) ( De metri et al., 2 0 0 6).  
S u niti ni b was gra nte d r e g ular a p pr o v al o n J a n uar y 2 6, 2 0 0 6 b y F o o d a n d Dr u g A d mi nistrati o n  
( F D A) f or t he treat me nt of gastr oi ntesti nal str o mal t u m or ( GI S T) after disease pr o gr essi o n o n or i nt olera nt t o i mati ni b mes ylate a n d accelerate d a p pr o val f or a d v a nce d re n al cell car ci n o ma  
( R C C) ( G o o d ma n et al., 2 0 0 7; Izze di ne et al., 2 0 0 7; R oc k et al., 2 0 0 7), w hi c h was c h a n ge d t o re g ular a p pr o val o n Fe br uar y 2, 2 0 0 7.
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mec h a nis m

T u m or V E G F e x pressi o n h as bee n ass o ciate d cli ni call y wit h disease pr o g n osis i n ma n y differe nt t y pes of m ali g n a ncies. V E G F e x pressi o n is i ncrease d b y di v erse sti m uli i ncl u di n g pr ot oo nc o ge ne acti vati o n a n d h y p o xia, wit h t he h y p o xic state fr e q ue ntl y arisi n g i n s oli d t u m ors beca us e of i na de q u ate perf usi o n. I n a d diti o n t o its a n gi o ge nic r ole, V E G F als o pr of o u n dl y i ncreas es t he per m ea bilit y of t he v asc ulat ur e t her e b y, p ote ntiall y c o ntri b uti n g t o t u m or pr o gressi o n. A lea k y t u m or e n d ot heli u m e n ha nces n utrie nt a n d cata b olite e x c ha n ge a n d re pres e nts less of a b arrier t o t u m or cell mi gr ati o n a n d i ntra vasati o n d uri n g metastasis. T w o hi g h -affi nit y rece pt ors f or V E G F wit h ass ociate d T K acti vit y h a ve bee n i d e ntifie d o n h u ma n vasc ular e n d ot heli u m; V E G F R- 1/ Flt - 1 a n d V E G F R- 2/ ki nase i nsert d o mai n c o ntai ni n g rece pt or  
( K D R). Alt h o u g h t he rel ati ve c o ntri b uti o ns of K D R a n d Flt-1 si g nali n g i n me diati n g t u m or pr o gressi o n ha ve n ot b ee n el uci date d, a n u m b er of st u dies s u g gest t hat K D R perf or ms a pre d o mi na nt r ole.  
I n a d diti o n t o V E G F r ece pt or si g nali n g, i ncr easi n g e vi de nce i m plicates P D G F R si g n ali n g i n t u m or a n gi o ge n esis. Rece nt n o ncli nical e vi de nce s u g gests t hat i n hi biti o n of P D G F R si g n ali n g  
augments the antitumor and anti-angiogenic effects of VEGFR inhibitors. In addition, PDGF signaling is implicated in the autocrine growth of tumor cells and in the recruitment and regulation of tumor fibroblasts. Upon chronic oral dosing, sunitinib is expected to inhibit PDGF- and VEGF-driven angiogenesis and as a consequence, limit solid tumor growth. Because angiogenesis is necessary for the growth and metastasis of solid tumors, and VEGF is believed to have a pivotal role in this process, sunitinib treatment may have broad-spectrum clinical utility (Chow and Eckhardt, 2007; Gan et al., 2009). Sunitinib also exerts direct antitumor activity on cells that express target RTKs associated with tumor cell proliferation, such as KIT, PDGFR, and RET. The clinical activity of sunitinib in patients with advanced GIST is an example of this antitumor effect.  
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Nonclinical Specificity and Efficacy Studies In vitro studies have demonstrated the specificity of sunitinib for inhibition of the Class 3 and Class 5 RTKs, including receptors for VEGF (VEGFR), KIT, Flt-3, and PDGFR (Investigator's Brochure, 2009). Specifically, receptor phosphorylation inhibition studies have shown that sunitinib inhibits KIT-ligand-induced phosphotyrosine levels in a dose-dependent manner with IC50 values of 0.001-0.01 mcM in vitro and reduced PDGFR-β phosphotyrosine levels in vivo (Abrams et al., 2003a). Sunitinib also selectively inhibited proliferation of human umbilical vein endothelial cells (HUVEC) stimulated with VEGF (IC50=0.04 mcM) compared to FGFstimulated proliferation (IC50=0.7 mcM) (Mendel et al., 2003).  
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In animal efficacy studies, sunitinib showed broad antitumor activity in mouse xenograft models against a variety of human tumor cell lines including colorectal cancer (HT-29, Colo205), nonsmall cell lung cancer (H460), breast cancer (MDA-MB-435), melanoma (A375), epidermoid cancer (A431), and glioma (SF763T) (Mendel et al., 2003). Sunitinib has also demonstrated antitumor activity against other breast cancer models (MMTV-v-Ha-ras transgenic mouse mammary carcinoma and dimethylbenzanthracene [DMBA]-induced rat mammary carcinomas) (Abrams et al., 2003b). In an animal model of KIT-expressing small cell lung cancer (SCLC; NCI-H526), sunitinib administration resulted in greater tumor growth inhibition than did imatinib (Abrams et al., 2003a).  
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Combination studies of sunitinib with docetaxel, 5-fluorouracil (5-FU), or doxorubicin resulted in significantly enhanced growth inhibition of human MX-1 breast cancer xenografts compared to levels of inhibition with either sunitinib or the cytotoxic agent alone (Abrams et al., 2003b). Moreover, the combination therapies each led to a significantly increased survival compared to either single agent alone (Abrams et al., 2003b). Significantly delayed tumor growth has also been demonstrated in combination studies of sunitinib and cisplatin in NCI-H526 SCLC xenografts (Abrams et al., 2003a).  
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Additional nonclinical *in vitro* and *in vivo* studies are summarized in Chow and Eckhardt, 2007. Nonclinical Toxicology Studies Single- and multiple-dose toxicology studies were conducted in mice, rats, rabbits, dogs, and monkeys (Investigator's Brochure, 2009). The acute oral maximally-tolerated dose (MTD) for mice, rats, and dogs was greater than the maximum dose of 500 mg/kg. The MTD in monkeys was greater than the 1200 mg/kg maximum dose tested, but emesis occurred at doses ≥50 mg/kg.  
A b brevi ate d Title: M olec ul ar Pr ofili n g N S C L C  
Versi o n D ate : 0 1/ 0 7/ 2 0 2 0 Treat me nt -relate d eff ects i n t he l y m p h oi d tiss ue, b o ne marr o w, a dre nal gla n ds, a n d b o ne gr o wt h plate wer e see n i n r at re p eate d - d os e st u dies wit h gastr oi ntesti nal tract, re pr o d ucti ve or ga n, ki d ne y, p a ncr eas, a n d pit uitar y eff ects re p ort e d at t he hi g hest d ose. Deat h was o bser v e d at t he hi g hest d ose le v el of 2 4 0 m g/ k g/ da y. Gastr oi ntesti nal dist ur ba nces ( diarr hea, l oss of a p petite, e mesis) as well as h e mat ol o gic dist ur ba n ces als o occ urr e d i n a n 8 wee k st u d y i n fe m ale m o n ke ys. Ot h er t o xicities see n i n m o n ke ys i ncl u de d mil d ele vati o ns i n A S T, A L T, a n d creati ni ne ki nas e ( C K), a dre nal gla n d c orte x he m orr ha ge, aci nar de gr a n ulati o n of t he sali var y gla n ds, d ecr ease d er yt hr o p oiesis i n t he b o ne marr o w, a n d l y m p h oi d atr o p h y. P ossi ble i m pair me nt of i m m u ne f u ncti o n i n t he hi g hest d ose gr o u p was ma nif este d as c yt o m e gal o vir us a n d bacterial i nfecti o ns. T here is a n i n dicati o n t hat re peate d hi g h d os es of s u niti ni b ma y l ea d t o car diac f u ncti o n/c o ntr actilit y c ha n ges as c o nfir m e d b y altere d E C G a n d M U G A or ec h ocar di o gra p hi c par a meters a n d i ncreas e d c T nI a n d/ or T i n si n gle a ni mals t hat die d or wer e e ut ha nize d earl y d ue t o a m ori b u n d c o n diti o n. T hese c ha n ges a p p ear t o be pri maril y f u n cti o nal a n d re versi ble. D ue t o t h e p o or cli nical c o n diti o n of t hese a ni mals , it a p pears t hat t he car di ac c ha n ges w ere n ot a direct res ult of s u niti ni b treat me nt, b ut rat her r es ulte d fr o m a n i m p orta nt, n o nc o m pe nsate d v ol u me l oss a n d a d diti o nal s u p pressi o n of heart f u ncti o n d ue t o c hr o n otr o pic i nc o m pete nce a n d p ossi ble m y ocar dial i n v ol ve me nt of u ncertai n eti ol o g y. Data fr o m t his st u d y i n dicate t hat f u ncti o nal car diac c ha n ges wer e i n d uce d pri maril y at t he hi g h est d ose of s u niti ni b.  
S u niti ni b was f o u n d t o be ne gati ve f or ge n ot o xicit y i n vi v o a n d i n vitr o. W o u n d- heali n g st u dies s h o we d a s u btle tra nsie nt dela y i n s ki n w o u n d heali n g i n mice treate d c o nti n u o usl y f or u p t o 5 wee ks wit h s u prat h era p e utic d oses of s u niti ni b at 8 0 m g/ k g/ da y. H o w e ver, it was deter mi ne d t hat t his alterati o n i n w o u n d heali n g h as mi ni mal bi ol o gic si g nifica n ce.  
N o ncli nic al P h ar m ac oki netics Si n g le- d ose p h ar mac o ki n etics ( P K) was e val uate d i n mice, rats, ra b bits, d o gs, a n d m o n ke ys at oral d oses of 2 0, 4 0, 8 0, a n d 1 6 0 m g/ k g, r es pecti v el y (I n vesti gat or's Br o c h ure, 2 0 0 9). At t hes e d oses, t he res pecti ve T m a x val ues i n mice were 3, 3, 0. 5, a n d 6 h o urs, w hile C ma x val ues were 4 2 0, 7 0 8, 8 7 7, a n d 2 6 7 0 m g/ m L, res pecti vel y. I n m o n ke ys, t 1/ 2 , t 1/ 2 , a n d t 1/ wer e 4, 1 4. 9, a n d 2 5 2 h o urs, res p ecti vel y. Re peat- d ose P K st u dies i n dicate d t hat i ncreas es i n e x p os ure were n ot c o nsiste ntl y pr o p orti o nal t o d ose. Stea d y state plas ma c o nce ntrati o ns were reac he d after 2 8 d a ys of d osi n g wit h little c ha n ge i n le vels t hereafter. S u niti ni b a p peare d t o rea dil y distri b ute i nt o t he C N S i n mice a n d t o a lesser e xte nt i n rats a n d m o n ke ys.  
S u nit i ni b meta b olis m is pre d o mi na ntl y me di ate d b y C Y P 3 A 4 a n d pr o d uces a n acti ve meta b olite, S U 0 1 2 6 6 2. T his meta b olite a n d s u niti ni b were t he o nl y maj or dr u g-r elate d c o m p o u n ds f o u n d i n t he s yste mic circ ulati o n i n mice, rats, m o n ke ys a n d h u ma ns. S u niti ni b a n d its maj or meta b olite are hi g hl y ( 9 0- 9 8 %) pr ot ei n b o u n d i n m o use, rat, m o n ke y, a n d h u ma n plas ma. I C 5 0 v al ues meas ure d i n vitr o are e x pecte d t o be r eac he d wit h t he c urr e ntl y r ec o m me n d e d 5 0 m g d os e.  
S u niti ni b a n d S U 0 1 2 6 6 2 are n ot p ote nt i n d ucers or i n hi bit ors of maj or C Y P 4 5 0 e nz y mes.  
T heref ore, t he y are b ot h pre dicte d t o ha v e a l o w p ote ntial t o ca use cli nicall y r ele va nt dr u g dr u g i nteracti o ns me diate d b y C Y P 4 5 0 e nz y m es a n d effl u x tra ns p orters. H o we v er, c o nc urre nt treat me nt wit h C Y P 3 A 4 i n d ucers a n d i n hi bit ors ma y aff ect s u niti ni b meta b olis m.  
Cli nic al Ex perie nce  
As of June 2008, 9204 subjects had received at least one dose of sunitinib in 77 completed or ongoing clinical studies, with 8986 subjects having received multiple doses of the agent (Investigator's Brochure, 2009). In phase 1 studies, sunitinib demonstrated single-agent activity in patients with RCC, GIST, non-GIST sarcomas, non-small cell lung cancer (NSCLC), colorectal cancer, neuroendocrine tumors (NET), melanoma, prostate cancer, and thyroid cancer. Sunitinib has also been studied in the phase 1 setting in patients with acute myeloid leukemia (AML). Pivotal trials of sunitinib in imatinib-resistant GIST (a placebo-controlled phase 3 trial), and metastatic RCC (MRCC) (single-arm, non-randomized, multicenter, open-label trial) and supporting trials in each disease were completed and submitted in support of the New Drug Application (NDA). In addition, there are several ongoing company-sponsored single agent and combination clinical trials for a variety of other indications.  
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Phase 1 Experience In an early phase 1 study designed to investigate dosing regimen and scheduling (in human subjects, the results of clinical pharmacology studies demonstrate that Cmax and AUC increased in a proportional manner after single doses of 50 to 350 mg as well as after multiple doses of 25100 mg), 41 patients with a variety of advanced solid tumors received sunitinib administered on a schedule of 2 weeks of treatment followed by 2 weeks off (2/2 schedule) or 4 weeks on with 2 weeks off (4/2 schedule) (Rosen et al., 2003). Doses evaluated on the 2/2 schedule (n=23) included 50 mg every other day (n=3), 50 mg daily (n=15), or 75 mg daily (n=5); the 18 patients enrolled in the 4/2 schedule received 25 mg daily (n=3) or 50 mg daily (n=15). The most frequent adverse events (AEs) were constitutional (fatigue/asthenia), gastrointestinal (nausea, vomiting, diarrhea) and hematologic (neutropenia, thrombocytopenia). Most of the AEs were grade 1 or 2, although at 75 mg daily, grade 3 and 4 fatigue/asthenia were dose limiting but readily reversible on discontinuation of treatment. There were 4 partial responses (PRs) assessed by RECIST and 22 patients with stable disease (SD) among the 41 patients.  
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A phase 1 dose-escalation study in 28 patients with advanced tumors evaluated sunitinib doses of 30 mg/m2 every other day, and doses of 30, 42, or 59 mg/m2 daily on the 4/2 schedule (Faivre et al., 2006). Grade 3 fatigue and hypertension were dose limiting at 59 mg/m2 as well as grade 2 bullous skin toxicity, and the MTD was defined as 42 mg/m2 daily. Based on these and other reversible AEs in the 12 patients treated at the MTD, the recommended phase 2 dose on the 4/2 schedule was determined to be 50 mg/day. Responses determined by RECIST were seen in 6 of 23 evaluable patients: 3 in RCC, 1 in NET, 1 in GIST, and 1 in adenocarcinoma of unknown primary. Tumor responses in patients treated at higher doses were often associated with reduced intratumoral vascularization and central tumor necrosis, leading to organ perforation in one patient and fistula in another. These observations suggest the possible necessity for careful tumor density monitoring to detect early evidence of necrosis.  
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Two phase 1 studies have been conducted in AML, the first with the primary endpoint of evaluation of the inhibition of FLT3 phosphorylation (O'Farrell et al., 2003b) and the second designed as a conventional dose-escalation study (Fiedler et al., 2005). O'Farrell and colleagues studied FLT3 phosphorylation in 29 AML patients who received a single dose of sunitinib at doses ranging from 50-350 mg. Over 50% of patients showed strong inhibition of Flt3 phosphorylation at doses of 200 mg and higher. As anticipated from nonclinical data, patients  
with FLT3 internal tandem duplication (ITD) mutations were more sensitive than those with wild-type Flt3 (FLT3-WT) as shown by 100% inhibition in FLT3-ITD compared to 50% in FLT3-WT. This study also gave evidence of downstream signal inhibition (STAT5 and ERK pathways), with STAT5 levels reduced primarily in FLT3-ITD patients while ERK inhibition occurred in the majority of patients independently of FLT3 inhibition. The dose-escalation study enrolled 15 patients with refractory or resistant AML who were treated with sunitinib on either the 4/2 or 4/1 schedule at a starting dose of 50 mg/day (Fiedler et al., 2005). Dose-limiting AEs (grade 4 fatigue and hypertension) occurred in both patients treated at 75 mg/day, and one of these patients (who had received prior mitoxantrone) developed cardiac failure. The 75 mg dose level was therefore terminated and 50 mg/day was considered to be the MTD. All four patients with FLT3 mutations had morphologic or partial responses compared to 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration.  
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Preliminary results from phase 1 studies exploring the combination of sunitinib with chemotherapeutic agents like capecitabine (Sweeney et al., 2007; Chiorean et al., 2008; Royce et al., 2008), pemetrexed (Chow et al., 2008), docetaxel (Traynor et al., 2008), gemcitabine (Brell et al., 2008; Michaelson et al., 2008), FOLFOX (Leong et al., 2007), FOLFIRI (Starling et al., 2008), carboplatin/paclitaxel (Heath et al., 2008), and metronomic cyclophosphamide/methotrexate (Rugo et al., 2008) in patients with various solid tumors have been presented. The MTD of sunitinib on the 4/2 schedule with docetaxel (60 mg/m2) was 25 mg daily; with capecitabine (1000 mg/m2), it was 37.5 mg daily. The MTD of sunitinib on the 2/1 schedule with docetaxel (75 mg/m2) was 37.5 mg daily and with capecitabine (1000 mg/m2) was 50 mg daily. The MTD for sunitinib as continuous daily dosing (CDD) with capecitabine (1000 mg/m2) was 37.5 mg daily and for pemetrexed (500 mg/m2) was 37.5 mg daily. Reported DLTs included febrile neutropenia, fatigue, hand-foot syndrome, gastrointestinal hemorrhage, cerebral hemorrhage, and ischemic optic neuropathy. Phase 1 trials evaluating the combination of sunitinib with other targeted agents like temsirolimus (Patel et al., 2009; Fischer et al., 2008), bevacizumab (Feldman et al., 2008; Cooney et al., 2008) and IFN- α (Motzer et al., 2009a) have shown problems with increased toxicity in patients with RCC (Feldman et al., 2008, Fischer et al., 2008; Motzer et al., 2009a). However, the combination of bevacizumab with sunitinib in patients with miscellaneous solid tumors was well tolerated (Cooney et al., 2008).  
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phase 2 and 3 experience

Updated results have recently been published on 750 patients with MRCC treated on a phase 3 study of sunitinib at a daily dose of 50 mg on the 4/2 schedule compared to interferon (IFN)-α 9 MU subcutaneously thrice weekly (Motzer et al., 2009b). Median overall survival (OS) was greater in the sunitinib group than in the IFN-α group (26.4 vs. 21.8 months, respectively). Sunitinib treatment was associated with a higher objective response rate (RR) than IFN-α (47% vs. 12%, respectively). Eleven patients in the sunitinib group and four patients in the IFN-α group achieved a complete response per investigator assessment. Median progression-free survival (PFS) was 11 months for sunitinib compared with 5 months for IFN-α. The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). An exploratory analysis, which censored 25 patients from the IFN-α group who had crossed over to receive sunitinib on study, D  
showed a median OS time of 26.4 months for sunitinib compared with 20 months for the IFN-α group. Results from a phase 1/2 dose-finding trial of sunitinib plus gefitinib, enrolling 42 patients, have been published (Motzer et al., 2010). In phase 1, patients received sunitinib 37.5 or 50 mg on the 4/2 schedule plus gefitinib 250 mg, both once daily. The MTD was determined to be 37.5 mg. Two DLTs were observed with the 50 mg dose: grade 2 left ventricular ejection fraction decline and grade 3 fatigue. In phase 2, patients received sunitinib at the MTD plus gefitinib. Thirteen patients treated at the MTD achieved a partial response and 12 had stable disease. Median PFS was 11 months. The most commonly reported grade 3/4 adverse event was diarrhea.  
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The promising results in phase 1 trials and the involvement of KIT and PDGFR-α, two of the sunitinib target RTKs in GIST led investigators to undertake a phase 1/2 trial in patients with GIST refractory or intolerant to imatinib to determine an appropriate dose and regimen for phase 2 development of sunitinib in this disease. Patients received up to 75 mg sunitinib daily on the 2/2, 4/2, or 2/1 schedule, with 50 mg daily on the 4/2 schedule being selected for continued study. In all, 75 patients were treated on the trial. Among 41 patients treated for at least 6 months, 6 had an objective response (OR; RECIST criteria) and an additional 16 had cessation of disease progression and minor responses for >6 months. Overall, 54% of the 41 patients had evidence of clinical benefit (OR or PFS) (Desai et al., 2004). Determination of the GIST genotype in these 41 patients showed that clinical benefit had been achieved in several secondary mutational variants that conferred imatinib resistance (Demetri et al., 2004). Fifty-three of the GIST patients treated on this trial subsequently underwent serial 18FDG-PET imaging where qualitative responses were graded as good in 33/53 patients, mixed in 15/53, and poor in 5/53 (Dileo et al., 2005). Correlation with clinical response (Fisher's exact p=0.03) showed that 22 of 33 patients graded as good by 18FDG-PET imaging had clinical benefit (OR or SD ≥ 6 months) after 6 months of therapy while 4 of 15 patients graded as mixed had benefit as did 2 of 5 patients graded as poor.  
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Data from a pivotal multinational, randomized (2:1), double-blind, placebo-controlled phase 3 trial in over 300 patients with imatinib-resistant GIST has shown significant clinical effect with sunitinib compared with placebo (Demetri et al., 2006). Patients on the active treatment arm received sunitinib at a dose of 50 mg daily on the 4/2 schedule. The median TTP for the treatment arm (n=207) was 27.3 weeks compared to a median of 6.4 weeks for placebo (n=105) (p<0.0001). Therapy was reasonably well tolerated; the most common adverse events were fatigue, diarrhea, skin discoloration and nausea.  
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In addition to patients with RCC and GIST, sunitinib has been evaluated in breast cancer (Burstein et al., 2008), NSCLC (Socinski et al., 2008), transitional cell carcinoma (TCC) (Gallagher et al., 2008), NET (Kulke et al., 2008), thyroid carcinoma (Cohen et al., 2008), certain subtypes of sarcoma (Keohan et al., 2008; Vigil et al., 2008), gastro-eosophageal cancer (Moehler et al., 2009), high-grade glioma (Chaskis et al., 2008), squamous cell carcinoma of the head and neck (SCCHN) (Choong et al., 2008), hepatocellular carcinoma (HCC) (Zhu et al., 2008), colorectal carcinoma (CRC) (Saltz et al. 2007; Starling et al., 2008; Pfeiffer et al., 2009) and uveal melanoma (Chan et al., 2008). Results from these trials have been summarized in Gan et al., 2009.
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safety profile

Sunitinib is reasonably well tolerated, with asthenia, hypertension, dermatitis, and mild myelosuppression as the most common AEs (Stadler, 2006). Additionally, the inhibition of TK receptors by agents such as sunitinib can result in cutaneous AEs such as acral erythema, subungal splinter hemorrhages, modification of hair and skin pigmentation, mucositis, and (occasionally) periocular edema (Robert et al., 2005; Suwattee, 2008). Hand-foot skin reaction, a group of signs and symptoms that can affect, usually bilaterally, the hands and/or feet of patients, has occurred in patients receiving sunitinib (Porta et al., 2007; Suwattee, 2008). A recent analysis of dermatological AEs in patients receiving sunitinib therapy has reported that all-grade hand-foot skin reactions occurred in 19% of patients (5% grades 3-4), skin discoloration in 28% (no grades 3-4), dry skin in 16% (1% grades 3-4), skin rash in 13% (1% grades 3-4), dermatitis in 8% (2% grades 3-4), hair color changes in 10% (no grades 3-4), alopecia in 6% (no grades 3-4), and phototoxicity in <0.1% (no grades 3-4) (Rosenbaum et al., 2008).  
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Cardiotoxicity, including congestive heart failure (3%-8%) and left ventricular dysfunction (12%-14%), has been reported in patients undergoing treatment with sunitinib (Chu et al., 2007; Khakoo et al., 2008; Schmidinger et al., 2008; Telli et al., 2008). More subjects treated with sunitinib experienced decline in left ventricular ejection fraction (LVEF) than subjects receiving either placebo or IFN-α (Investigator's Brochure, 2009). In a phase 3 GIST study in subjects with imatinib-resistant or -intolerant GIST, 22 of 209 (11%) subjects on sunitinib and 3 of 102 (3%) subjects on placebo had treatment-emergent LVEF values below the lower limit of normal (LLN). In a phase 3 study treatment-naive RCC patients, 27% and 15% of subjects on sunitinib and IFN-α, respectively, had an LVEF value below the LLN. Among 461 patients enrolled in CDUS-monitored trials with sunitinib alone, 2% of patients experienced left ventricular systolic dysfunction (CDUS data). It is unknown whether patients with concurrent cardiac conditions may be at a higher risk for developing drug-related LVEF. Baseline and periodic evaluations of LVEF should be considered while these patients are on sunitinib treatment. In patients without cardiac risk factors, a baseline evaluation of LVEF should be considered.  
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Sunitinib has been shown to prolong the QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes. This condition has been reported in <0.1% of sunitinib-exposed patients. The DCTD, NCI, issued an IND AE Action Letter to all investigators using sunitinib describing the occurrence of QTc prolongation and Torsade de pointes (ventricular tachycardia) in patients on clinical trials utilizing sunitinib. As a result of this Action Letter, DCTD, NCI-sponsored sunitinib protocols were amended to include the requirement for a baseline EKG prior to study treatment, exclude patients with histories of serious ventricular arrhythmias or prolonged QTc, and exclude patients with certain cardiac conditions.  
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Among 8054 solid tumor subjects treated with single-agent sunitinib, Grade 3 hypertension was reported in 6.1% of patients and was one of the most commonly reported Grade 3 AEs. Of subjects receiving sunitinib for treatment-naive MRCC, 34% receiving sunitinib experienced hypertension, compared with 4% on IFN-α. Grade 3 hypertension was reported in 13% of treatment-naive metastatic RCC subjects on sunitinib compared to <1% on IFN-α. Severe  
hypertension occurred in 4% GIST subjects on sunitinib, 1% GIST subjects on placebo, 9% RCC subjects on sunitinib and 1% RCC subjects on IFN-α (Investigator's Brochure, 2009). Among 461 patients enrolled in CDUS-monitored trials with sunitinib alone, 28% experienced hypertension (CDUS data). In subjects receiving sunitinib for treatment-naive MRCC, 37% had bleeding events compared with 8% receiving IFN-α (Investigator's Brochure, 2009). Bleeding events occurred in 18% of patients receiving sunitinib in the double-blind treatment phase of the GIST phase 3 study, compared with 17% receiving placebo. Among 461 patients enrolled in CDUS-monitored trials with sunitinib alone or in combination with other agents, there were 103 reported bleeding events (CDUS data). Epistaxis was the most common hemorrhagic AE reported. Tumor-related hemorrhage can occur with sunitinib and in the case of pulmonary tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage.  
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Hypothyroidism has been reported in 71% patients with RCC (Rini et al., 2007) and in 36% of those with GIST (Desai et al, 2006) treated with sunitinib. Among subjects treated with singleagent sunitinib, hyperthyroidism was reported in 0.6% and thyroiditis in 0.1% (Investigator's Brochure, 2009). Baseline measurement of thyroid function is recommended, and patients with thyroid dysfunction should be treated appropriately prior to starting sunitinib therapy.  
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Nonclinical evidence of adrenal toxicity following sunitinib exposure led the company to perform specialized safety assessments in clinical studies, including computed tomography or MRI in 336 subjects to specifically identify any change in adrenal gland structure or the presence of adrenal gland hemorrhage (Investigator's Brochure, 2009). Neither event was observed. Adrenocorticotropic hormone (ACTH) stimulation testing was done in 400 patients across multiple sunitinib trials. One subject developed consistently abnormal test results during treatment that were unexplained and may be related to sunitinib treatment. Eleven additional subjects had abnormailities in the final test, with low peak cortisol levels. None of these patients had clinical evidence of adrenal insufficiency. However, based on the nonclinical findings, patients receiving sunitinib should be clinically followed for signs and symptoms of adrenal insufficiency, especially in (1) patients with comorbidities associated with adrenal dysfunction,
(2) patients with preexisting adrenal insufficiency (primary or secondary), and (3) patients with concomitant stress (e.g., fever, infection, bleeding, serious accident, surgery) that may precipitate overt adrenal insufficiency in the presence of subclinical sunitinib-induced adrenal toxicity.  
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Diarrhea, nausea, abdominal pain, vomiting, constipation and dyspepsia are some of the most frequent AEs reported with sunitinib (Investigator's Brochure, 2009). Serum chemistries including phosphate should be performed at the beginning of each treatment cycle. Supportive care may include anti-emetic premedication, supportive oral care products, and analgesics. Serious complications due to degeneration or shrinkage of tumors, including gastrointestinal perforation and tracheoesophageal fistula, have occurred rarely in patients with abdominal, head and neck, thyroid, and other malignancies treated with sunitinib, believed to be the result of the antitumor effect of sunitinib. Other serious effects include thromboembolic events, rare reversible posterior leukoencephalopathy syndrome (RPLS), proteinuria with rare nephrotic syndrome, and rare microangiopathic hemolytic anemia.  
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Clinical Pharmacokinetics  
Orally-administered sunitinib is well absorbed in humans, with linear pharmacokinetics (PK) at doses of 50-150 mg/day (Sakamoto, 2004). Sunitinib is highly protein-bound and metabolized through N-de-ethylation by cytochrome P450 (CYP) 3A4 to SU12662 (Investigator's Brochure, 2009). SU12662 has a similar inhibitory profile to sunitinib in vitro and similar protein binding properties. SU12662 is further metabolized by CYP3A4 to a minor inactive metabolite (Investigator's Brochure, 2009).  
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The PK of sunitinib was studied in a variety of company-sponsored studies in both healthy volunteers (n=135) and in patients with solid tumors (n=266), including GIST and metastatic RCC; the PK was similar in the volunteers and in those with solid tumors. Terminal half-lives (t1/2) of sunitinib and SU12662 are 40-60 hours and 80-110 hours, respectively, with a time to maximum concentration (Tmax) of 6-12 hours for sunitinib and its primary active metabolite, followed by a biexponential decline in concentrations. The PK of sunitinib and SU12662 were measured in a phase 1 dose-escalation study in patients with advanced solid malignancies (Faivre et al., 2006). Twenty-eight patients received doses ranging from 15 mg/m2 to 59 mg/m2 (ranging from 50 mg every other day to 150 mg/day), on a 4 weeks on, 2 weeks off (4/2) schedule. Concentration-versus-time data were analyzed using a noncompartmental analytic technique. Overall, sunitinib displayed a long half-life and a large volume of distribution with moderate interpatient variability. Trough plasma concentrations of sunitinib and SU12662 increased with increasing doses. However, area under the concentration-time curve (AUC) values increased less than proportionally with dose. Accumulation ratios of sunitinib were >1, with detectable trough drug levels, suggesting drug accumulation over time. At the recommended dose, maximum plasma concentration (Cmax) occurred approximately 5 hours after administration and t1/2 ranged from 41-86 hours. Doses of 50 mg daily led to plasma concentrations ranging from 50-100 ng/mL. Most patients with DLTs had combined (sunitinib plus SU12662) trough plasma concentrations ≥100 ng/mL (Faivre et al., 2006).  
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PK values determined from body surface area (BSA)-based doses were adjusted to reflect fixed doses of 50, 75-100, and 100-150 mg doses to determine if there was a need for BSA-based dosing to be employed. AUC sum values obtained using BSA-normalized and fixed dosing were found to be comparable, suggesting that normalizing the dose based on BSA would not improve variability. Therefore, fixed dosing on a milligram basis was considered appropriate for phase 2 studies (Faivre et al., 2006). To determine the effect of food on the PK of sunitinib and its active metabolite SU12662, 16 healthy subjects received a single dose of sunitinib 50 mg under fasting conditions and 14 subjects received a single dose of sunitinib 50 mg under fed conditions (Bello et al., 2006). Subjects were randomized to one of two treatment sequences each comprising two treatment periods (fasted and fed). In Sequence 1, the fasted treatment period was followed by the fed treatment period, and for Sequence 2, the fasted period followed the fed period. For the fasted period, a single oral (PO) dose of sunitinib 50 mg was administered after a 10-hour fast. For the fed period, a single PO dose of sunitinib 50 mg was administered within 30 minutes of a highfat, high-calorie meal. A washout period of at least 4 weeks separated sunitinib dosing between the two treatment periods. Two subjects in Sequence 1 discontinued prematurely due to grade 1 and 2 rash, but PK information was collected and included in the analysis. Only a negligible difference in Tmax of sunitinib was observed between fed and fasted treatment periods; D  
SU12662 Tmax was prolonged by 2 hours (median difference) in the fed compared with the fasted state. The 90% confidence intervals (CIs) for Cmax and AUC were within the 80-125% bioequivalence range, indicating the absence of food effect. Sunitinib exposure increased slightly in the fed compared with the fasted state (ratios of fed/fasted geometric least square means: Cmax 104%, AUC0-last and AUC0-∞ both 112%). There was a delay in the formation/absorption of the active metabolite SU12662 in the fed state (mean Cmax decreased 23%), but exposure remained unaffected (90% CIs for AUC 0-last and AUC0-∞ were within 80125%). Sunitinib and SU12662 half-lives, and oral clearance of sunitinib, were not affected by food (Bello et al., 2006).  
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A study of sunitinib PK in patients with AML indicated that a plasma concentration of 50-100 ng/mL of combined sunitinib and SU12662 could be achieved on the first cycle of a 50 mg/day 4/2 regimen, similar to that achieved in studies with patients having other tumor types (Fiedler et al., 2005). In a phase 1 trial of sunitinib given on the 4/2 schedule in pediatric patients with relapsed or refractory solid tumors, the median day 21 steady-state trough sunitinib plasma concentration was 24.6 ng/mL (range, 6.0-37.7 ng/mL) at the 15 mg/m2 dose and 37.4 (range, 24.2-62.9 ng/mL) at the 20 mg/m2 dose (DuBois et al., 2008).  
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Population PK methods indicated that the covariates of weight, gender, race, ethnicity, ECOG score, and tumor type had no clinically significant effects on drug exposure, and that adjustments of starting doses based on these covariates were not required (Investigator's Brochure, 2009). Concurrent administration of a single dose of sunitinib with ketoconazole (a CYP3A4 inhibitor) in healthy volunteers resulted in 49% and 51% increases in the combined (sunitinib + SU12662) Cmax and AUC0-∞ values, respectively, compared with sunitinib alone (Washington et al., 2003). Concurrent administration of sunitinib and rifampin (a potent CYP3A4 inducer) in healthy subjects resulted in 23% and 46% reduction in combined Cmax and AUC0-∞, respectively, compared with sunitinib alone (Bello et al., 2005). Thus, dose adjustments for sunitinib should be considered when coadministered with CYP3A4 inhibitors and inducers.  
I
Proposed Dose and Schedule for Phase 2 Clinical Trials Starting doses in multiple-dose studies were 25, 50, 75, and 100 mg administered orally once daily with the majority of patients receiving the 50-mg dose. Patients in sunitinib studies have been treated on four different schedules: schedules 4/1 and 4/2 comprised 4 consecutive weeks of daily dosing followed by a 1- or 2-week rest period, respectively, while schedules 2/1 and 2/2 comprised 2 consecutive weeks of daily dosing followed by a 1- or 2-week rest period, respectively. The majority of subjects were treated on schedules 4/2 or 2/2 in phase 1 studies. Schedule 4/2 has been well tolerated with generally mild to moderate adverse effects at a 50 mg daily dose. Alternate regimens of sunitinib are being explored; 50 mg of sunitinib daily for 2 weeks followed by a 1-week off-treatment period (sunitinib 2/1) (Britten et al., 2008), while another schedule is sunitinib 37.5 mg as a CDD (George et al., 2008). Both schedules were welltolerated, achieved therapeutic plasma concentrations and showed no significant accumulation of the drug.  
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18.2 appendix b medication diaries

18.2.1 AZD6244 hydrogen sulfate PATIENT'S MEDICATION DIARY Today's date _________________________ Agent______AZD6244_____________  
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1. Complete one form for each cycle of treatment. 2. AZD6244 should be stored at room temperature. 3. You will take AZD6244 by mouth twice each day about 12 hours apart. Take the medicine on an empty stomach (no food or drink other than water for 1 hour before or 2 hours after dosing).  
Morning dose: take _____ mg (____capsules) AZD6244. *********** Evening dose: take _____ mg
(____capsules) AZD6244.  
O  
  
4. Record the date, the number of AZD6244 capsules you swallowed in the morning and again in the evening, and when you swallowed the medicine.  
5. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If you vomit after taking the tablets, the dose is replaced only if the tablets can actually be seen and counted. If you miss a dose, you should resume with the next scheduled dose.  
6. If you have any comments or notice any side effects, please record them in the Comments column.  
| I          |                                                                                                                                                                        |              |              |
|------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|--------------|
| 7.         | Please bring this form and your bottles of AZD6244 when you return for each appointment.  Time of Dose taken Comments Dose taken evening  dose  Time of  morning  dose |              |              |
| Day        | Date                                                                                                                                                                   | # of capsule | # of capsule |
| taken      | taken                                                                                                                                                                  | D            |              |
| 1  2  3  4 |                                                                                                                                                                        |              |              |  
CTEP-assigned Protocol \#___________
Patient Name_____________________(initials acceptable) Patient Study ID____________________  
| Version Date: 01/07/2020   |    |
|----------------------------|----|
| 5  6  7                    | V  |
| 8  9  10  11  12           | O  |
| 13  14  15  16  17         | I  |
| 18  19  20  21             |    |  
| D                                                                                                                                                                                                                                                                                                                                                                                                                             |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Patient's signature __________________________________________________________                                                                                                                                                                                                                                                                                                                                                |
| Physician's Office will complete this section: 1. Date patient started protocol _____________________________________________________  2. Date patient was removed from __________________________________________________________  3. Patient's planned total daily dose________________________________________________________  4. Total number of capsules taken this month _____________________________________________ |  
5. Physician/Nurse/Data Manager's Signature ______________________________________________  
  
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CTEP-assigned Protocol \#___________
untitled h1
instructions to the patient

1. Complete one form for each cycle of treatment.  
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2. You will take MK-2206 tablets by mouth once every week. You should take the tablets 2 hours before or after a meal.  
3. Dose: take _______5 mg tablet(s), _______25 mg tablet(s), and/or ________ 200 mg tablet(s)
once every week.  
4. Record the date, the number of tablets of each size of tablet that you took, and when you took them.  
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5. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If you vomit after taking the tablets, the dose is replaced only if the tablets can actually be seen and counted. If you miss a dose, you should resume with the next scheduled dose.  
6. If you have any comments or notice any side effects, please record them in the Comments column.  
| 7.        | Please bring this form and your bottles of MK-2206 tablets when you return for each appointment.  I # of tablets taken Comments   |               |      |       |         |
|-----------|-----------------------------------------------------------------------------------------------------------------------------------|---------------|------|-------|---------|
| Day       | Date                                                                                                                              | Time of  dose | 5 mg | 25 mg | 200  mg |
| 1  2-7    | Days 2-7 drug holiday                                                                                                             |               |      |       |         |
| 8         | D                                                                                                                                 |               |      |       |         |
| 9-14      | Days 9-14 drug holiday                                                                                                            |               |      |       |         |
| 15  16-21 | Days 16-21 drug holiday                                                                                                           |               |      |       |         |
| 22  23-28 | Days 23-28 drug holiday                                                                                                           |               |      |       |         |  
Today's date _____________________ Agent: MK-2206 Patient's signature _________________________________________________________________________
Physician's Office will complete this section:  
  
1. Date patient started protocol treatment __________________________________________  
  
5. Physician/Nurse/Data Manager's Signature ______________________________________ V  
  
2. Date patient was removed from study ________________________________________  
 3. Patient's planned total daily dose ____________________________________________ 4. Total number of tablets taken this month _____________________________________  
  
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CTEP-assigned Protocol \#___________
18.2.3 Sunitinib PATIENT'S MEDICATION DIARY Today's date _______________________________ Agent: Sunitinib Patient Name___________________ (initials acceptable) Patient Study ID _______________  
1. Complete one form for each 4 week-period while you take sunitinib.  
V
2. You will take your dose of sunitinib by mouth each day in the morning. You will take ____12.5 mg capsule(s), and/or ____ 25 mg capsule(s); or ___ 50 mg capsule. You may take the capsules with or without food as you wish.  
3. Record the date, the number of capsules of each size you took, and when you took them. 4. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If you vomit after taking the tablets, the dose is replaced only if the tablets can actually be seen and counted. If you miss a dose, you should resume with the next scheduled dose.  
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5. If you have any comments or notice any side effects, please record them in the Comments column. 6. Wash your hands with soap and water after touching the capsule(s). Do not share this medication with anyone.  
7. Please return unused sunitinib capsules (or empty bottles) and this form to your physician when you go for your next appointment.  
| # of capsules  taken   | Comments   |            |               |       |
|------------------------|------------|------------|---------------|-------|
| I                      |            |            |               |       |
| Time of                |            |            |               |       |
| Day                    | Date       | daily dose | 12.5 mg 25 mg | 50 mg |
| 1  2  3                | D          |            |               |       |
| 4  5  6  7  8          |            |            |               |       |  
| Version Date: 01/07/2020   |                                                                            |
|----------------------------|----------------------------------------------------------------------------|
| 9  10  11                  | V                                                                          |
| 12  13  14  15  16         | O                                                                          |
| 17  18  19  20  21         | I                                                                          |
| 22  23  24  25             | D                                                                          |
| 26  27  28  29-42          | Days 29-42 drug holiday                                                    |
|                            | Patient's signature ______________________________________________________ |  
Physician's Office will complete this section:  
| 1.   | Date patient started protocol treatment __________________________________________   |                                     |
|------|--------------------------------------------------------------------------------------|-------------------------------------|
| 2.   | Date patient was removed from study ________________________________________         |                                     |
| 3.   | Patient's planned total daily dose ____________________________________________      |                                     |
| 4.   | Total number of tablets taken this month                                             | ___________________________________ |  
5. Physician/Nurse/Data Manager's Signature ______________________________________ V  
  
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CTEP-assigned Protocol \#___________
18.2.4 Erlotinib PATIENT'S MEDICATION DIARY Today's date _____________________ Agent: Erlotinib Patient Name_____________________(initials acceptable) Patient Study ID ________________  
1. Complete one form for each cycle of treatment.  
V
2. You will take theErlotinib tablets by mouth once every day. You will take ____ 25mg tablets,
____100mg tablet, ____150mg tablet. You should take the tablets either 1 hour before or two hours after a meal. Take the tablets with 8 ounces of water.  
3. Record the date, the number of tablets of each size of tablet that you took, and when you took them. 4. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If you vomit after taking the tablets, the dose is replaced only if the tablets can actually be seen and counted. If you miss a dose, you should resume with the next scheduled dose.  
5. If you have any comments or notice any side effects, please record them in the Comments column.  
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| 6.            | Please bring this form and your bottles of Erlotinib tablets when you return for each appointment.  # of tablets taken Comments   |               |    |    |    |
|---------------|-----------------------------------------------------------------------------------------------------------------------------------|---------------|----|----|----|
| Day           | Date                                                                                                                              | Time of  dose | mg | mg | mg |
| I             |                                                                                                                                   |               |    |    |    |
| 1  2  3  4    | D                                                                                                                                 |               |    |    |    |
| 5  6  7  8  9 |                                                                                                                                   |               |    |    |    |  
| 10  11  12         | V                   |
|--------------------|---------------------|
| 13  14  15  16  17 | O                   |
| 18  19  20  21     | Patient's signature |  
Patient's signature _________________________________________________________________________  
| I   |                                                |                                                                                   |
|-----|------------------------------------------------|-----------------------------------------------------------------------------------|
|     | Physician's Office will complete this section: |                                                                                   |
|     | 1.                                             | Date patient started protocol treatment ______________________________________    |
|     | 2.                                             | Date patient was removed from study _______________________________________       |
|     | 3.                                             | Patient's planned total daily dose __________________________________________     |
|     | 4.                                             | Total number of tablets taken this month ________________________________________ |
|     | 5.                                             | Physician/Nurse/Data Manager's Signature ______________________________________   |  
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18.2.5 Lapatinib PATIENT'S MEDICATION DIARY
CTEP-assigned Protocol \#___________
Patient Name_____________________(initials acceptable) Patient Study ID _______________ INSTRUCTIONS TO THE PATIENT: 1. Complete one form for each cycle of treatment.  
V
2. You will take Lapatinib tablets by mouth once every day. You should take the tablets 1 hours before or after a meal Dose: take ___ mg tablets.  
3. Record the date, the number of tablets of each size of tablet that you took, and when you took them.  
4. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If you vomit after taking the tablets, the dose is replaced only if the tablets can actually be seen and counted. If you miss a dose, you should resume with the next scheduled dose.  
5. If you have any comments or notice any side effects, please record them in the Comments column.  
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| 6.             | Please bring this form and your bottles of Lapatinib tablets when you return for each appointment.  # of tablets taken Comments   |               |    |     |     |
|----------------|-----------------------------------------------------------------------------------------------------------------------------------|---------------|----|-----|-----|
| Day            | Date                                                                                                                              | Time of  dose | mg | N/A | N/A |
| I              |                                                                                                                                   |               |    |     |     |
| 1  2  3  4  5  | D                                                                                                                                 |               |    |     |     |
| 6  7  8  9  10 |                                                                                                                                   |               |    |     |     |  
Today's date _____________________ Agent: Lapatinib  
| 11  12  13         | V                   |
|--------------------|---------------------|
| 14  15  16  17  18 | O                   |
| 19  20  21         | Patient's signature |  
Patient's signature _________________________________________________________________________  
| I   |                                                |                                                                                    |
|-----|------------------------------------------------|------------------------------------------------------------------------------------|
|     | Physician's Office will complete this section: |                                                                                    |
|     | 1.                                             | Date patient started protocol treatment __________________________________________ |
|     | 2.                                             | Date patient was removed from study ________________________________________       |
|     | 3.                                             | Patient's planned total daily dose ____________________________________________    |
|     | 4.                                             | Total number of tablets taken this month ______________________________________    |
|     | 5.                                             | Physician/Nurse/Data Manager's Signature _______________________________           |  
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| 18.3                                                                                                                                                                                       | Appendix C: Performance Status Criteria                       |                                                                           |                                                                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|---------------------------------------------------------------------------|------------------------------------------------------------------------|
| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                   |                                                                           |                                                                        |
| V                                                                                                                                                                                          |                                                               |                                                                           |                                                                        |
| Grade                                                                                                                                                                                      | Descriptions                                                  | Percent                                                                   | Description                                                            |
| 100                                                                                                                                                                                        | Normal, no complaints, no evidence  of disease.               |                                                                           |                                                                        |
| Normal activity. Fully active, able                                                                                                                                                        |                                                               |                                                                           |                                                                        |
| 0                                                                                                                                                                                          | to carry on all pre-disease  performance without restriction. | 90                                                                        | Able to carry on normal activity;  minor signs or symptoms of disease. |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). | 80                                                            | Normal activity with effort; some  signs or symptoms of disease.          |                                                                        |
| 1                                                                                                                                                                                          | 70                                                            | Cares for self, unable to carry on  normal activity or to do active work. |                                                                        |
| O                                                                                                                                                                                          |                                                               |                                                                           |                                                                        |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                             | Requires occasional assistance, but                           |                                                                           |                                                                        |
| 60                                                                                                                                                                                         | is able to care for most of his/her  needs.                   |                                                                           |                                                                        |
| 2                                                                                                                                                                                          | 50                                                            | Requires considerable assistance and  frequent medical care.              |                                                                        |
| 40                                                                                                                                                                                         | Disabled, requires special care and  assistance.              |                                                                           |                                                                        |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                     |                                                               |                                                                           |                                                                        |
| 3                                                                                                                                                                                          | 30                                                            | Severely disabled, hospitalization  indicated. Death not imminent.        |                                                                        |
| I                                                                                                                                                                                          |                                                               |                                                                           |                                                                        |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                            | Very sick, hospitalization indicated.  Death not imminent.                |                                                                        |
| 4                                                                                                                                                                                          | 10                                                            | Moribund, fatal processes  progressing rapidly. Dead.                     |                                                                        |
| 5                                                                                                                                                                                          | Dead.                                                         | 0                                                                         |                                                                        |  
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18.4 appendix d new york

Clinical Evaluation of Functional Capacity of Patients with Heart Disease in Relation to Ordinary Physical Activity  
| V        | Need for                                                              |             |                                     |                                |
|----------|-----------------------------------------------------------------------|-------------|-------------------------------------|--------------------------------|
| Class    | Cardiac Symptoms                                                      | Limitations | Additional  Rest*                   | Physical Ability   to work**__ |
| I        | None                                                                  | None        | None                                | Full time                      |
| II       | Only moderate                                                         | Slight      | Usually only  slight or  occasional | Usually full  time             |
| O        |                                                                       |             |                                     |                                |
| III      | Defined, with  less than  ordinary activity                           | Marked      | Usually                             | Usually part                   |
| moderate | time                                                                  |             |                                     |                                |
| IV       | May be present  even at rest,  and any activity  increases discomfort | Extreme     | Marked                              | Unable to work                 |  
I
* To control or relieve symptoms, as determined by the patient, rather than as advised by the physician. ** At accustomed occupation or usual tasks. Reference: Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956. (Modified from New York Heart Association, 1953).  
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18.5 appendix e medications that

The following table presents a list of drugs that prolong, may prolong or are unlikely to prolong the QTc. These drugs are prohibited during the treatment with some study agents. Please note that this list is frequently updated. For the most current list of medications, users should be directed to the following website: *http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm*.  
| website: http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.  V   | Possible                                                                   |                          |                                   |
|-----------------------------------------------------------------------------|----------------------------------------------------------------------------|--------------------------|-----------------------------------|
| Compound                                                                    | Compound Half Life                                                         | Washout  Period -  Hours | Possible  Washout  Period -  Days |
| Alfuzocin                                                                   | ~10 hours                                                                  | 7                        |                                   |
| Amantadine                                                                  | 17 +/- 4 hours (10-25)                                                     | 4                        |                                   |
| Amiodarone (cordarone)                                                      | 58 days (15-142)                                                           | 180                      |                                   |
| 36 days (active metabolite)                                                 |                                                                            |                          |                                   |
| Amitriptyline*                                                              | > 24 hours, wide interpatient  variability                                 |                          |                                   |
| Arsenic trioxide                                                            | Not characterized                                                          |                          |                                   |
| Azithromycin                                                                | 40 hours                                                                   |                          |                                   |
| Bepridil                                                                    | 42 hr (26-64)                                                              | 10                       |                                   |
| Chloral hydrate                                                             | Readily converted to  Trichloroethanol (active metabolite  T1/2=7-10 hour) |                          |                                   |
| O                                                                           | 48                                                                         |                          |                                   |
| Chloroquine                                                                 | Prolonged (days to weeks)                                                  |                          |                                   |
| Chlorpromazine                                                              | 30 +/- 7 hours                                                             | 7                        |                                   |
| Cisapride                                                                   | 6 - 12 hour, up to 20 hour                                                 | 60                       |                                   |
| Clarithromycin                                                              | Non linear PK3-4 hr (250mg Q12)                                            | 36                       |                                   |
| 5-7 hr (500mg Q12) I                                                        |                                                                            |                          |                                   |
| Cloroquine                                                                  | 6 to 60 days; mean 20 days                                                 |                          |                                   |
| Desipramine*                                                                | > 24 hours, wide interpatient  variability                                 |                          |                                   |
| Disopyramide                                                                | 6.7 hr (4-10)                                                              | 36                       |                                   |
| Dofetilide                                                                  | 10 hr                                                                      | 48                       |                                   |
| Dolesetron                                                                  | 8.1 hr                                                                     |                          |                                   |
| Domperidone                                                                 | 7-8 hr                                                                     | 48                       |                                   |
| Doxepin*                                                                    | > 24 hours, wide interpatient  variability                                 |                          |                                   |
| Droperidol                                                                  | 2.2 hours                                                                  | 10                       |                                   |
| Erythromycin                                                                | * Each salt form has different Half  life*                                 |                          |                                   |
| Felbamate                                                                   | 20-23 hr                                                                   | 5                        |                                   |
| Flecainide                                                                  | 20 hr (12-27)                                                              | 5                        |                                   |
| Foscarnet                                                                   | 87.5+/-41.8 hours                                                          | 20                       |                                   |
| *distribution and release from bone* D                                      |                                                                            |                          |                                   |  
| Version Date: 01/07/2020 Fosphenytoin   | 12-29 hr                                                                         | 6                        |                                   |
|-----------------------------------------|----------------------------------------------------------------------------------|--------------------------|-----------------------------------|
| Gatifloxacin                            | 7-14 hr                                                                          | 48                       |                                   |
| Gemifloxacin                            | 7 hours                                                                          | 48                       |                                   |
| Grepafloxacin                           | 16 hr                                                                            | 3                        |                                   |
| Halofantrine                            | 6-10 days ( variable among                                                       | 45                       |                                   |
| individual)                             |                                                                                  |                          |                                   |
| V                                       |                                                                                  |                          |                                   |
| Haloperidol                             | 18 +/-5 hr                                                                       | 5                        |                                   |
| Ibutilide                               | 6 hours (2-12) * variable among                                                  | 36                       |                                   |
| subject*                                |                                                                                  |                          |                                   |
| Imipramine*                             | > 24 hours, wide interpatient  variability                                       |                          |                                   |
| Indapamide                              | 14 hours (biphasic elimination)                                                  | 3                        |                                   |
| Isradipine                              | 8 hours ( multiple metabolites)                                                  | 48                       |                                   |
| Levofloxacin                            | 6-8 hours                                                                        | 48                       |                                   |
| Levomethadyl                            | Multiple compartment PK with  active metabolite 2.6 day for LAAM, 2 day for norLAAM, 4 day for dinor-LAAM                                                                                  |                          |                                   |
| O                                       | 20                                                                               |                          |                                   |
| Lithium                                 | 24 hour (10-50)                                                                  | 7                        |                                   |
| Possible                                |                                                                                  |                          |                                   |
| Compound                                | Compound Half Life                                                               | Washout  Period -  Hours | Possible  Washout  Period -  Days |
| Mesoridazine                            | 24-48 hours ( animal study)                                                      | 10                       |                                   |
| Methadone                               | 15-30 hours                                                                      | 7                        |                                   |
| Moexipril/HCTZ                          | 2-9 hour (include active metabolite)  for moexipril; 5.6-14.8 hours for  HCTZ  I | 48                       |                                   |
| Moxifloxacin                            | 12 +/-1.3 hours                                                                  | 72                       |                                   |
| Naratriptan                             | 6 hours                                                                          | 36                       |                                   |
| Nicardipine                             | ~ 2 hour post IV infusion                                                        | 12                       |                                   |
| Nortriptyline*                          | > 24 hours, wide interpatient  variability                                       |                          |                                   |
| Octreotide                              | 1.7 hours                                                                        | 12                       |                                   |
| Ofloxacin                               | 5 to 7.5 hours                                                                   | 2                        |                                   |
| Ondansetron                             | 4 hours (IV/IM); 3 hours (PO)                                                    | 1 to 3                   |                                   |
| Pentamidine                             | 6.4+/-1.3 hours                                                                  | 36                       |                                   |
| Pimozide                                | 55 hours                                                                         | 10                       |                                   |
| Procainamide                            | 3-4 hour for PA and NAPA (active                                                 | 24                       |                                   |
| metabolite)                             | D                                                                                |                          |                                   |
| Protiptyline*                           | > 24 hours, wide interpatient  variability                                       |                          |                                   |
| Quetiapine                              | 6 hours                                                                          | 36                       |                                   |  
| Version Date: 01/07/2020 Quinidine                                                                     | 6-8 hours in adult; 3-4 hours in                                                                                                        | 36   |
|--------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|------|
| children                                                                                               |                                                                                                                                         |      |
| Quinine                                                                                                | 4-5 hours                                                                                                                               |      |
| Risperidone                                                                                            | 3-20 hours (extensive to poor  metabolizer) 9-hydroxyrisperidone (active  metabolite) T ½ =21-30 hours  (extensive to poor metabolizer) | 4    |
| V                                                                                                      |                                                                                                                                         |      |
| Salmeterol                                                                                             | 5.5 hours ( only one datum)                                                                                                             | 36   |
| Sotalol                                                                                                | 12 hours                                                                                                                                | 72   |
| Sparfloxacin                                                                                           | 20 hours (16-30)                                                                                                                        | 4    |
| Sumatriptan                                                                                            | 2.5 hours                                                                                                                               | 12   |
| Tacrolimus                                                                                             | ~34 hours in healthy; ~19 hours in                                                                                                      | 7    |
| Kidney transplant                                                                                      |                                                                                                                                         |      |
| Tamoxifen                                                                                              | 5-7 days (biphasic)                                                                                                                     | 30   |
| Telithromycin                                                                                          | 2-3 hr                                                                                                                                  | 24   |
| Thioridazine                                                                                           | 20-40 hours (Phenothiazines)                                                                                                            | 7    |
| Tizanidine                                                                                             | 2.5 hours                                                                                                                               | 12   |
| Vardenifil                                                                                             | 4 to 5 hours                                                                                                                            |      |
| Venlaflaxine                                                                                           | 5 +/-2 hours for parent comp. 11+-2 hours for OVD (active  metabolite)                                                                  |      |
| O                                                                                                      | 60                                                                                                                                      |      |
| Voriconizole                                                                                           | 6 hours; dose dependent                                                                                                                 |      |
| Ziprasidone                                                                                            | 7 hr                                                                                                                                    | 36   |
| Zolmitriptan                                                                                           | 2.8-3.7 hours (higher in female)                                                                                                        | 18   |
| * Weakly associated with Torsades de Pointes and/or QT prolongation but that are unlikely to be a risk |                                                                                                                                         |      |  
I
* Weakly associated with Torsades de Pointes and/or QT prolongation but that are unlikely to be a risk for Torsades de Pointes when used in usual recommended dosages and in patients without other risk factors (e.g., concomitant QT prolonging drugs, bradycardia, electrolyte disturbances, congenital long QT syndrome, concomitant drugs that inhibit metabolism).  
References:
1. Physician's Desk Reference 2002  
2. Facts and Comparisons ( update to June 2005) 3. The Pharmacological Basis of Therapeutics 9th Edition, 1996
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18.6 appendix f list of

| HIV Antivirals:                                                         | aprepitant                                             | delaviridine                             |                                  |
|-------------------------------------------------------------------------|--------------------------------------------------------|------------------------------------------|----------------------------------|
| V                                                                       |                                                        |                                          |                                  |
| indinavir                                                               | erythromycin                                           | diethyl-dithiocarbamate                  |                                  |
| nelfinavir                                                              | fluconazole                                            | fluvoxamine                              |                                  |
| ritonavir                                                               | grapefruit juice                                       | gestodene                                |                                  |
| verapamil2                                                              | imatinib                                               |                                          |                                  |
| clarithromycin                                                          | diltiazem                                              | mibefradil                               |                                  |
| itraconazole1                                                           | cimetidine                                             | mifepristone                             |                                  |
| ketoconazole1                                                           | amiodarone                                             | norfloxacin                              |                                  |
| O                                                                       |                                                        |                                          |                                  |
| nefazodone                                                              | NOT azithromycin                                       | norfluoxetine                            |                                  |
| saquinavir                                                              | chloramphenicol                                        | starfruit                                |                                  |
| telithromycin                                                           | ciprofloxacin                                          | voriconazole                             |                                  |
| CYP3A4 Inducers Aminoglutethimide Carbamazepine Fosphenytoin  Nafcillin | Nevirapine  Oxcarbazepine Pentobarbital  Phenobarbital | Phenytoin  Primidone  Rifabutin Rifampin | Rifapentine  St. John's wort (3) |  
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When Study Agent is co-administered with drugs classified as "substrates," the plasma concentration of the substrate is high. When Study Agent is co-administered with drugs classified as 'inhibitors,' plasma concentrations of the Study Agent will be high. When Study Agent is co-administered with drugs classified as "inducers," the plasma concentration of the Study Agent will be low. In general, drug interactions occur significantly between substrates and either inhibitors or inducers of the same enzymes usually classified as "strong" substrates, inhibitors, or inducers.  
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Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; LexiComp Inc. 2007: 1899-1912. Only major substrates and effective inducers are listed. Additional information for drug interactions with cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/. (1) Investigator's Brochure, MK-2206. Merck.. January 2009.  
(2) Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23.
(3) Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249. Frye et al. (2004). Clin Pharmacol Ther. 76:323-329. Updated on May 1, 2007
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18.7 appendix g information on

The patient _________________ is enrolled on a clinical trial using the experimental agent ________. This clinical trial is sponsored by the National Cancer Institute. This form is addressed to the patient, but includes important information for others who care for this patient.  
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_________ interacts with many drugs that are processed by your liver. Because of this, it is very important to tell your study doctors about all of your medicine before you start this study. It is also very important to tell them if you stop taking any regular medicine, or if you start taking a new medicine while you take part in this study. When you talk about your medicine with your study doctor, include medicine you buy without a prescription at the drug store (over-the counter remedy), or anything that you buy from the health food store or grocery store (herbal supplement). Many health care prescribers can write prescriptions. You must also tell your other prescribers (doctors, physicians' assistants or nurse practitioners) that you are taking part in a clinical trial. Bring this paper with you. These are the things that you and they need to know:
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- ________ is metabolized (converted in the body) by a liver enzyme called CYP3A4.  
________ must be used very carefully with other medicines that need this liver enzyme to be effective or to be cleared from your system.  
- You and healthcare providers who prescribe drugs for you must be careful about adding or removing any drug in this category.  
- Before you start the study, your study doctor will work with your regular prescriber to switch any medicines that are considered "strong inducers/inhibitors or substrates of CYP3A4."
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- Your regular prescribers should look at this web site http://medicine.iupui.edu/clinpharm/ddis/table.asp to see if any medicine they want to prescribe is on a list of drugs to avoid.  
- Please be very careful! Over-the-counter drugs have a brand name on the label—it's usually big and catches your eye. They also have a generic name—it's usually small and printed on the ingredient list. Find the generic name (your pharmacist can help) and look at the table on the back of this page. Be careful.  
- You should not take St. John's wort or grapefruit juice with _________. - You should not receive steroids unless they are absolutely necessary; tell your study doctor if you are taking, have a prescription for, or have been given steroids.  
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- You should not take drugs that affect your heart rhythm. Tell your study doctor if you are taking, have a prescription for, or have been given such heart medications.  
- Other medicines can be a problem with your study drugs.
- You should check with your doctor or pharmacist whenever you need to use an over-thecounter medicine or herbal supplement.  
- Your regular prescriber should check a medical reference or call your study doctor before  
  
prescribing any new medicine for you. Your study doctor's name is _______________ and he or she can be contacted at _______________________.  
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18.8 appendix h hypertension management

Oral Antihypertensive Medications  
Agents in bold characters are suggested as optimal choices to avoid or minimize potential druginteractions with sunitinib through CYP450.  
| V Agent                                          | Initial           | Intermediate   | Maximum        | Hepatic                          |                    |
|--------------------------------------------------|-------------------|----------------|----------------|----------------------------------|--------------------|
| class                                            | Agent             | dose           | dose           | dose                             | metabolism         |
| nifedipine XL                                    | 30 mg daily       | 60 mg daily    | 90 mg daily    | CYP 3A4  substrate               |                    |
| Dihydropyridine CalciumChannel  Blockers (DHP CCB)                                                  | amlodipine        | 2.5 mg daily   | 5 mg daily     | 10 mg daily                      | CYP 3A4  substrate |
| felodipine                                       | 2.5 mg daily      | 5 mg daily     | 10 mg daily    | CYP 3A4 substrate  and inhibitor |                    |
| O                                                |                   |                |                |                                  |                    |
| metoprolol                                       | 25 mg             | 50 mg          | 100 mg         |                                  |                    |
| twice daily                                      | CYP 2D6 substrate |                |                |                                  |                    |
| twice daily                                      | twice daily       |                |                |                                  |                    |
| atenolol                                         | 25 mg daily       | 50 mg daily    | 100 mg daily   | No                               |                    |
| Selective β Blockers (BB)                        | acebutolol        | 100 mg         | 200-300 mg     | 400 mg                           | Yes (CYP450        |
| twice daily                                      | twice daily       | twice daily    | unknown)       |                                  |                    |
| bisoprolol                                       | 2.5 mg daily      | 5-10 mg daily  | 20 mg daily    | Yes (CYP450  unknown)            |                    |
| captopril                                        | 12.5 mg 3x  daily | 25 mg 3x daily | 50 mg 3x daily | CYP 2D6 substrate                |                    |
| I                                                |                   |                |                |                                  |                    |
| enalapril                                        | 5 mg daily        | 10-20 mg daily | 40 mg daily    | CYP 3A4 substrate                |                    |
| ramipril                                         | 2.5 mg daily      | 5 mg daily     | 10 mg daily    | Yes (CYP450  unknown)            |                    |
| Angiotensin Converting Enzyme Inhibitors (ACEIs) | lisinopril        | 5 mg daily     | 10-20 mg daily | 40 mg daily                      | No                 |
| fosinopril                                       | 10 mg daily       | 20 mg daily    | 40 mg daily    | Yes (CYP450  unknown)            |                    |
| Rarely used: perindopril                         | 4 mg daily        | none           | 8 mg daily     | Yes, but not  CYP450             |                    |
| D                                                |                   |                |                |                                  |                    |
| Rarely used: quinapril                           | 10 mg daily       | 20 mg daily    | 40 mg daily    | No                               |                    |
| losartan                                         | 25 mg daily       | 50 mg daily    | 100 mg daily   | CYP 3A4 substrate                |                    |
| Angiotensin II  Receptor Blockers (ARBs)         | candesartan       | 4 mg daily     | 8-16 mg daily  | 32 mg daily                      | CYP 2C9 substrate  |
| irbesartan                                       | 75 mg daily       | 150 mg daily   | 300 mg daily   | CYP 2C9 substrate                |                    |
| telmisartan                                      | 40 mg daily       | none           | 80 mg daily    | Yes, but not  CYP450             |                    |  
| valsartan   | 80 mg daily   | none         | 160 mg daily      | Yes, but not  CYP450   |
|-------------|---------------|--------------|-------------------|------------------------|
| Blocker     | labetolol     | 100 mg twice |                   |                        |
| α and β     | 200 mg twice  | 400 mg twice | CYP 2D6 substrate |                        |
| daily       | daily         | daily        | and inhibitor     |                        |  
Collection/Recording of Blood Pressure Information
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1.0 general guidelines

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1.1 Frequency of monitoring. Blood pressure (BP) should be monitored weekly during the first cycle of sunitinib therapy, then at least every 2 weeks for the duration of treatment. More frequent monitoring may be considered on a study by study basis, particularly during the first two cycles of sunitinib therapy. 1.2 Data recording. All required data should be recorded in the appropriate CRF or on the patient's blood pressure monitoring diary, as appropriate. The following data are required at baseline and at each subsequent assessment:
- Assessment date and time  
- Pulse - Systolic and diastolic BP (2 readings/assessment taken 5 minutes apart while patient sitting)
$\mathtt{\text{true}}$ .
$$\sqrt{\mathrm{BP}\left(2\,\mathrm{re}\right)}$$  
  
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1.3 Risk factors for hypertension (assess and record data in baseline history/physical CRF)
- Diabetes (type 1 or type 2)
- Renal disease (specify on CRF)
- Endocrine condition associated with HTN (specify on CRF)
- Use of steroids or NSAIDs (specify all concomitant meds)
- Underlying cardiovascular condition - specify (i.e., ischemic heart disease)
$$\vec{\mathrm{lim}}$$
$$\boxed{\mathrm{\Large~\cal~}}\mathrm{\Large~on~CRF~}$$
$$\boxed{\mathrm{{\ant~meds}}}$$
$\textcolor{red}{\text{ify-}}\textcolor{red}{\text{(i.e.,ischo}}$
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2.0 Baseline data collection (at study arm entry) 2.1 All patients
- Current BP
- Proteinuria, if present
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2.2 Patients with preexisting hypertension (i.e., those for whom "hypertension" is entered as a concomitant condition at study entry, or those who are currently receiving therapy with antihypertensive medication) - also record:
- Date of HTN diagnosis (original)  
- Type HTN (essential or secondary)
- CTCAE grade of HTN (at time of study entry)
- Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the following:
- Antihypertensive agents taken at study entry - Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack of efficacy)
3.0 Follow up BP data collection (during study) 3.1 All patients (at each clinic visit)  
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- Current BP
- Proteinuria, if present 3.2 Patients with treatment-emergent hypertension [defined as BP increase of >20 mmHg (diastolic) OR systolic BP >139 OR diastolic BP > 90 (if previously normal or grade 1 per CTCAE v4) - record at time of hypertension diagnosis and at all subsequent clinic visits:
- BP changes from baseline (or from previous assessment) (specify CTCAE grade changes)
- Hypertension-related symptoms as reported by patient (e.g., headache)
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- Other relevant changes associated with development of hypertension (e.g., ECG
abnormalities)
- Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of currently prescribed antihypertensive agents 3.3 Patients with pre-existing hypertension at study entry - record at each clinic visit
- BP changes from previous clinic visit (specify CTCAE grade changes) - Hypertension-related symptoms reported by patient (e.g., headache)  
- Other relevant changes associated with development of hypertension (e.g., ECG
abnormalities)
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- Changes in antihypertensive medications since last assessment (e.g., dose change, add/discontinue drug)
Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha blockers, beta blockers, diuretics, angiotension II receptor antagonists.  
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18.9 appendix i ctep multicenter

If an institution wishes to collaborate with other participating institutions in performing a CTEP sponsored research protocol, then the following guidelines must be followed. Responsibility of the Protocol Chair  
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- The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office (PIO). The Protocol Chair is responsible for the coordination, development, submission, and approval of the protocol as well as its subsequent amendments. The protocol must not be rewritten or modified by anyone other than the Protocol Chair. There will be only one version of the protocol, and each participating institution will use that document. The Protocol Chair is responsible for assuring that all participating institutions are using the correct version of the protocol.  
- The Protocol Chair is responsible for the overall conduct of the study at all participating institutions and for monitoring its progress. All reporting requirements to CTEP are the responsibility of the Protocol Chair.  
- The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety of the patients.  
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- The Protocol Chair will be responsible for the review of and timely submission of data for study analysis.
Responsibilities of the Coordinating Center  
- Each participating institution will have an appropriate assurance on file with the Office for Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for assuring that each participating institution has an OHRP assurance and must maintain copies of IRB approvals from each participating site.  
- Prior to the activation of the protocol at each participating institution, an OHRP form 310 (documentation of IRB approval) must be submitted to the CTEP PIO.  
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- The Coordinating Center is responsible for central patient registration. The Coordinating Center is responsible for assuring that IRB approval has been obtained at each participating site prior to the first patient registration from that site.  
- The Coordinating Center is responsible for the preparation of all submitted data for review by the Protocol Chair.
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The Coordinating Center will maintain documentation of AE reports. There are two options for AE reporting: (1) participating institutions may report directly to CTEP with a copy to the Coordinating Center, or (2) participating institutions report to the Coordinating Center who in turn report to CTEP. The Coordinating Center will submit AE reports to the Protocol Chair for timely review.  
Audits may be accomplished in one of two ways: (1) source documents and research records for selected patients are brought from participating sites to the Coordinating Center for audit, or (2) selected patient records may be audited on-site at participating sites. If the NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is responsible for having all source documents, research records, all IRB approval documents, NCI Drug Accountability Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the audit.  
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Inclusion of Multicenter Guidelines in the Protocol
- The protocol must include the following minimum information: - The title page must include the name and address of each participating institution and the name, telephone number and e-mail address of the responsible investigator at each participating institution.  
- The Coordinating Center must be designated on the title page. - Central registration of patients is required. The procedures for registration must be stated in the protocol.  
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- Data collection forms should be of a common format. Sample forms should be submitted with the protocol. The frequency and timing of data submission forms to the Coordinating Center should be stated.  
- Describe how AEs will be reported from the participating institutions, either directly to CTEP or through the Coordinating Center.  
- Describe how Safety Reports and Action Letters from CTEP will be distributed to participating institutions.
Agent Ordering I
- Except in very unusual circumstances, each participating institution will order DCTDsupplied agents directly from CTEP. Agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO.  
  
18.10 **Appendix J: Molecular Profiling Follow-Up Worksheet**
Patient Name:______________________________________________________________________
Circle: Living or Deceased If deceased, DOD:____________________
Further Chemotherapy/Biotherapy Treatment(s)
Date of follow up:__________________________ Completed By:____________________________  
  
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Drug Name:_____________________________________________________  
  
Dates of administration: Start:___________ Stop:_____________ Reason Treatment ended: Progression / Other Entered into database by:__________________________Date:____________________________ Date of follow up:__________________________ Completed By:____________________________  
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Drug Name:_____________________________________________________ Dates of administration: Start:___________ Stop:_____________  
Reason Treatment ended: Progression / Other Entered into database by:__________________________Date:____________________________
Date of follow up:__________________________ Completed By:____________________________  
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Drug Name:_____________________________________________________  
Dates of administration: Start:___________ Stop:_____________  
Reason Treatment ended: Progression / Other Entered into database by:__________________________Date:____________________________ Date of follow up:__________________________ Completed By:____________________________  
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Reason Treatment ended: Progression / Other  
Entered into database by:__________________________Date:____________________________  
| Drug Name:_____________________________________________________  Dates of administration: Start:___________ Stop:_____________ Reason Treatment ended: Progression / Other   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
tobacco use history
18.9 appendix i ctep multicenter

Patient Name and the content of the Date Have you ever used any tobacco products? _
If yes, did you smoke cigarettes? If yes, and you can be a smoke and you What is the average number of cigarettes you smoke(d) each day? Dou smoke cigars? How many cigars did you smoke each day? How many D Did you smoke a pipe?  
How many pouches did you use each day? The same D
Design and the content of the How old were you when you started?  
At what age did you stop? _ Do you currently use tobacco?  
Have you been exposed to smoke from other people? _  
  
If yes, who smoked in your presence?  
__
number of cigarettes that other people smoked in your presence on an average day number of years you were exposed to other people smoking in your presence  
  
Provider Signature:  
  
18.12 Appendix L: Acquisition, Storage, Interpretation and Reporting of Low-Dose CT
Scans for Enrolled First-Degree Relatives  
| Low-dose computed tomography acquisition parameters (adapted from NCCN Guidelines  for Lung Cancer Screening, version 1.2012)  V Acquisition Small patient (BMI ≤30) Large patient (BMI >30) Total radiation exposure ≤ 3 mSv ≤ 5 mSv kVp 100-120 120  mAs ≤ 40 ≤ 60 O All patients Gantry rotation speed ≤ 0.5 Detector collimation ≤ 1.5 mm Slice width ≤ slice width; 50% overlap preferred for 3D and CAD  applications  Scan acquisition time ≤ 10 seconds (single breath hold)  I Breathing Maximum inspiration  Contrast No oral or intravenous contrast  Ct scanner detectors ≥ 16 Abbreviations: CAD: computed aided diagnostics; BMI: body mass index   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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