Phase I/II and Phase II Clinical Trials of Axitinib for Selected Cancers ...

NCCN Axitinib RFP: 20DEC10NCCN Request for Proposals (RFP): Phase I/II and Phase II Clinical Trials ofAxitinib for Selected Cancers1.0 PurposeThe National Comprehensive Cancer Network (NCCN) has received a 2.1 Million Dollarresearch grant from Pfizer, Inc. (hereafter, “Pfizer”) to support NCCN Member Institutionfaculty for the performance of clinical studies of axitinib in the treatment of specific solidtumors. NCCN will serve as the funding organization for these grants that are availableonly to NCCN investigators.The proposed clinical trials should focus on developing innovative studies of axitinib witha particular emphasis on:• Renal cell carcinoma (RCC)• Melanoma• Sarcoma• Neuroendocrine cancer• Head and neck cancer• Thyroid cancer• Other rare solid tumors will be considered with compelling scientificrationaleThe overall aim is to develop innovative studies to help determine the possible role ofaxitinib in the treatment of the select group of solid tumors noted above. It is hoped thatproposals submitted in response to this RFP will be useful in guiding furtherdevelopment of axitinib. Studies with correlative endpoints will be encouraged.The NCCN Request for Proposals Development Team (RFPDT) has developed thisRequest for Proposals (RFP) with a formalized review procedure to accept applicationsand select proposals of highest scientific merit. The NCCN RFPDT has overseen thedevelopment of the RFP and a NCCN Scientific Review Committee composed of somemembers of this group and other NCCN clinical leaders will perform the review ofapplications.2.0 Background2.1 Structure and Mechanism of ActionThe structure of axitinib and its binding affinity in vitro to various targets are shownbelow.CONFIDENTIALPage 1 of 16

NCCN Axitinib RFP: 20DEC10Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelialgrowth factor (VEGF) receptors 1, 2 and 3. In kinase assays, axitinib was shown to be apotent and ATP-competitive inhibitor of receptor tyrosine kinases (RTK) of VEGFreceptors 1, 2 and 3 , but not a potent inhibitor of the closely related kinases of FGFR-1,Flt-3, Tie-2 or CSFR-1 and was inactive against most kinases of distant families in thekinome (1, 2).Table 1. Receptor tyrosine kinase affinities and selectivity of axitinib (2)TargetVEGFR-2VEGFR-1VEGFR-3PDGFR-βKITPDGFR-αCSF-1RFGFR-1Flt3Cell potency(IC 50 , nM)0.20.10.1-0.31.61.75.073231>1000Axitinib has no measurable kinase activity against RET, cMet, EGFR, and many otherRTKs at ≥ 1 uM. Key metabolites of axitinib do not have significant activity againstVEGF and PDGF RTKs.2.2 Clinical Pharmacology and Safety Experience in HumansHuman studies have shown that axitinib is absorbed within 4 hours following oral dosingwith a mean absolute bioavailability of 58%. Axitinib is highly protein bound (>99%), withno change in protein binding with hepatic impairment. Both the major human circulatingplasma metabolites (the sulfoxide and glucuronide) are inactive. The elimination ofaxitinib is predominantly hepatobiliary and the drug has a short plasma half-life (2.5-6.1hours) (1, 3).Common adverse events observed in patients treated with axitinib include fatigue,hypertension, proteinuria, hoarseness and diarrhea.CONFIDENTIALPage 2 of 16

NCCN Axitinib RFP: 20DEC10Safety Review of Pooled Single Agent Axitinib Studies:Table 2 summarizes the treatment-emergent adverse events in (≥10%) cancer subjectswho received single agent axitinib regardless of whether the event was reported asrelated to axitinib treatment or other cause. The combined results are summarized,including Phase I studies in subjects with various solid tumors, thyroid cancermelanoma, non-small cell lung cancer (NSCLC), and RCC. Only data from thepreviously treated (2 nd line) patients with advanced RCC was included. No data from astudy of treatment-naïve (1 st line) patients were included. One study was excluded sinceit involved subjects with hematological malignancies, and the first-in-human (FIH) PhaseI study was excluded since a number of patients received starting doses above therecommended starting dose of 5 mg BID.Overall, the adverse events reported in axitinib clinical studies are consideredmanageable, generally reversible and expected for this class of agents. For singleagentaxitinib, the most common adverse events reported from 515 cancer subjectsregardless of causality included fatigue (284 subjects, 55.1%), diarrhea (254 subjects,49.3%), hypertension (246 subjects, 47.8%), anorexia (197 subjects, 38.3%), nausea(177 subjects, 34.4%), dysphonia (175 subjects, 34.0%), palmar-plantarerythrodysaesthesia syndrome (134 subjects, 26.0%), weight decreased (132 subjects,25.6%), headache (122 subjects, 23.7%), cough (113 subjects, 21.9%), and constipation(109 subjects, 21.2%). Additionally, proteinuria and hypothyroidism were reported asadverse events in 95 subjects (18.4%) and 71 subjects (13.8%), respectively. Grade 3+events occurred most frequently for hypertension (92 subjects, 17.9%) and fatigue(56 subjects, 10.9%).CONFIDENTIALPage 3 of 16

NCCN Axitinib RFP: 20DEC10Table 2 Treatment-Emergent, All-Causality Adverse Events Summarized byDescending Frequency Occurring in at Least 10% of Subjects with Solid TumorsReceiving Single-Agent AxitinibSolid TumorSingle-Agent(N =515)MedDRA Preferred TermAll Gradesn (%)Grade 3+n (%)Fatigue 284 (55.1) 56 (10.9)Diarrhoea 254 (49.3) 29 (5.6)Hypertension 246 (47.8) 92 (17.9)Anorexia 197 (38.3) 12 (2.3)Nausea 177 (34.4) 6 (1.2)Dysphonia 175 (34.0) 0 (0.0)Palmar-plantar erythrodysaesthesiasyndrome 134 (26.0) 33 (6.4)Weight decreased 132 (25.6) 19 (3.7)Headache 122 (23.7) 8 (1.6)Cough 113 (21.9) 5 (1.0)Constipation 109 (21.2) 2 (0.4)Dyspnoea 102 (19.8) 32 (6.2)Arthralgia 100 (19.4) 11 (2.1)Proteinuria 95 (18.4) 15 (2.9)Vomiting 93 (18.1) 6 (1.2)Pain in extremity 91 (17.7) 11 (2.1)Stomatitis 81 (15.7) 7 (1.4)Rash 79 (15.3) 2 (0.4)Mucosal inflammation 78 (15.1) 3 (0.6)Back pain 75 (14.6) 9 (1.7)Dyspepsia 75 (14.6) 1 (0.2)Abdominal pain 71 (13.8) 16 (3.1)Hypothyroidism 71 (13.8) 0 (0.0)Dizziness 62 (12.0) 2 (0.4)Dysgeusia 61 (11.8) 0 (0.0)Dry skin 57 (11.1) 1 (0.2)Epistaxis 55 (10.7) 0 (0.0)Insomnia 53 (10.3) 0 (0.0)Musculoskeletal pain 53 (10.3) 5 (1.0)Oedema peripheral 53 (10.3) 0 (0.0)Pyrexia 53 (10.3) 0 (0.0)Data in Table 2 represents combined safety data from individual studiesLaboratory test results, summarized by maximum grade for subjects with solid tumorswho received single-agent axitinib are presented in Table 3. Grade 3 or 4 hyponatremiawas reported in 22 subjects (4.8%), elevations in SGOT (AST) in 13 subjects (2.9%),hyperglycemia in 22 subjects (4.8%), proteinuria in 14 subjects (2.9%), creatinineincreases in 4 subjects (0.9%), lymphopenia in 36 subjects (8.5%), thrombocytopenia in2 subjects (0.4%), and neutropenia in 5 subjects (1.1%).CONFIDENTIALPage 4 of 16

NCCN Axitinib RFP: 20DEC10Table 3 Laboratory Test Results Reported for Subjects with Solid TumorsReceiving Single-Agent Axitinibn (%) a at Maximum GradeGroup/Parameter b N Grade 1 Grade 2 Grade 3 Grade 4 TotalChemistryAmylase 88 16 (18.2) 3 (3.4) 2 (2.3) 0 (0.0) 21 (23.9)Aspartate Aminotransferase(AST) 456 131 (28.7) 28 (6.1) 13 (2.9) 0 (0.0) 172 (37.7)Alanine Aminotransferase(ALT) 456 109 (23.9) 36 (7.9) 10 (2.2) 0 (0.0) 155 (34.0)Bilirubin (Total) 456 58 (12.7) 23 (5.0) 1 (0.2) 1 (0.2) 83 (18.2)Alkaline Phosphatase 456 141 (30.9) 30 (6.6) 7 (1.5) 0 (0.0) 178 (39.0)Bicarbonate 342 101 (29.5) 9 (2.6) 1 (0.3) 0 (0.0) 111 (32.5)Creatinine 456 141 (30.9) 31 (6.8) 1 (0.2) 3 (0.7) 176 (38.6)Creatine Kinase 7 2 (28.6) 0 (0.0) 0 0.0) 0 (0.0) 2 (28.6)Hypoalbuminemia 456 132 (28.9) 43 (9.4) 13 (2.9) 0 (0.0) 188 (41.2)Hypernatremia 456 22 (4.8) 1 (0.2) 0 (0.0) 0 (0.0) 23 (5.0)Hyponatremia 456 119 (26.1) 0 (0.0) 22 (4.8) 0 (0.0) 141 (30.9)Hyperkalemia 456 90 (19.7) 29 (6.4) 9 (2.0) 0 (0.0) 128 (28.1)Hypokalemia 456 58 (12.7) 0 (0.0) 7 (1.5) 0 (0.0) 65 (14.3)Hypercalcemia 240 31 (12.9) 2 (0.8) 1 (0.4) 1 (0.4) 35 (14.6)Hypocalcemia 240 40 (16.7) 12 (5.0) 2 (0.8) 2 (0.8) 56 (23.3)Hyperglycemia 456 200 (43.9) 63 (13.8) 16 (3.5) 6 (1.3) 285 (62.5)Hypoglycemia 456 55 (12.1) 13 (2.9) 2 (0.4) 1 (0.2) 71 (15.6)Hypophosphatemia 69 0 (0.0) 6 (8.7) 2 (2.9) 0 (0.0) 8 (11.6)-Lipase 88 10 (11.4) 3 (3.4) 3 (3.4) 1 (1.1) 17 (19.3)HematologyHemoglobin 456 170 (37.3) 36 (7.9) 1 (0.2) 11 (2.4) 218 (47.8)Platelets 454 100 (22.0) 4 (0.9) 1 (0.2) 1 (0.2) 106 (23.3)White Blood Cells 456 74 (16.2) 15 (3.3) 0 (0.0) 2 (0.4) 91 (20.0)Neutrophils (Abs) 454 40 (8.8) 9 (2.0) 4 (0.9) 1 (0.2) 54 (11.9)Lymphocytes (Abs) 423 85 (20.1) 75 (17.7) 33 (7.8) 3 (0.7) 196 (46.3)UrinalysisUrine Protein 476 73 (15.3) 88 (18.5) 14 (2.9) 0 (0.0) 175 (36.8)Data in Table 3 represents combined laboratory data from individual studiesa Number of subjects at their maximum after-dosing gradeOnly laboratory values which fall within CTCAE grading criteria are includedAxitinib chemotherapy combination studies:No pharmacokinetic interactions have been observed when axitinib was administered incombination with the following chemotherapy drugs: paclitaxel, cisplatin, carboplatin,oxaliplatin, 5-fluorouracil, irinotecan, pemetrexed or gemcitabine (1).There has been limited experience with axitinib in combination with other agents.Appendix A summarizes the experience to date of axitinib combination studies.2.3 Experience in Specific DiseasesIn the Phase I study of axitinib, the maximum tolerated dose and recommended Phase IIdose of axitinib was 5 mg bid. Objective radiographic responses were seen in renal cellcarcinoma (n = 2) and adenoid cystic carcinoma (n=1) (3). In subsequent Phase IICONFIDENTIALPage 5 of 16

NCCN Axitinib RFP: 20DEC10studies, axitinib has been evaluated in renal cell carcinoma, non-small cell lung cancer,thyroid cancer, melanoma, and colorectal carcinoma. A brief overview of the clinicaldata from these trials is outlined below.2.3.1 Renal cell carcinomaThe design of axitinib trials in metastatic renal cell carcinoma (mRCC) aredisplayed in Appendix A.A Phase II trial of axitinib in 52 patients with cytokine refractory RCCdemonstrated an objective response rate of 44.2%, with a time to treatmentfailure of 15.7 months. The overall survival in this trial was 29.9 months (4).In a Phase II trial of axitinib in sorafenib-refractory mRCC showed an objectiveresponse rate of 22.6%. The progression-free and overall survival in this trialwere 7.4 and 13.6 months respectively (5).The three randomized trials in mRCC are shown in Appendix A. A November 19,2010, press release reported a Phase III trial that randomized patients withmRCC, who had failed one prior line of systemic therapy, to receive eitheraxitinib or sorafenib had met its primary endpoint of progression free survival(PFS).2.3.2 MelanomaA Phase II trial of axitinib in 32 patients with metastatic melanoma demonstratedan objective response rate of 15.6% and a median PFS of 2.3 months. Themedian overall survival was 6.8 months.2.3.3 Thyroid cancerA Phase II trial of axitinib in 60 patients with advanced thyroid cancer showed anobjective response rate of 30% with a median progression-free survival of 18.1months. In this trial 8 patients (13%) discontinued axitinib due to adverse events.Notably, objective responses were observed in all histological subtypes (6).2.3.4 Neuroendocrine cancer, Sarcoma and Head and Neck CancersData is lacking in neuroendocrine cancer, sarcoma and head and neck cancers,but these tumor types are of interest.2.3.5 Potential biomarkersPharmacokinetic data from two Phase II trials in cytokine-refractory mRCC and 8single dose healthy volunteer trials have been studied (9). For the 109 RCCpatients, mean steady-state area under the plasma concentration-time curve(AUC) at the end of cycle one and the diastolic blood pressure during axitinibtherapy were evaluated as predictors of clinical efficacy. The median overallsurvival for patients with at least one diastolic blood pressure measurement ≥90mmHg during axitinib treatment (n=59) was 130 weeks compared to 42 weeks inthose who did not experience diastolic blood pressure elevation greater than 90CONFIDENTIALPage 6 of 16

NCCN Axitinib RFP: 20DEC10mmHg (n=50), p

NCCN Axitinib RFP: 20DEC103.2. In diseases where extensive clinical research has already been performed toaccess efficacy (e.g. mRCC), studies focusing on evaluation of mechanism, identificationof predictive markers, evaluation of resistance, and management of drug toxicities areencouraged. Alternatively, studies focusing on particular sub-populations (e.g. patientswith brain metastases or patients with renal insufficiency) are also encouraged.3.3. Since axitinib is not FDA approved at the time of this RFP, the investigator will berequired to hold an IND and cross file against Pfizer’s IND (See Section 6.2.1). Singlecenterstudies may be preferable for reasons of expedience; however, multi-centercollaboration may be necessary for studies of rare cancers or rare cancer-subsets.Collaboration with non-NCCN institutions is permitted.If you need additional information regarding whether a concept is already planned orfunded, please send an email to ORPProposals@nccn.org.4.0 Study Time FramesAll approved studies are expected to commence, which is defined as the first patientreceiving the first dose of study drug(s), within six (6) months and no later than nine (9)months of notice of study approval by NCCN and are to be completed within two (2)years of commencement. A manuscript must be submitted to NCCN for review no laterthan six (6) months after study endpoint achieved or termination of the study. Thesestudies will be given as described in Section 9.0 and should be designed with subjectnumber commensurate with study time frames and funding.Studies for rare cancers or those that require larger number of patients for statisticalpower should consider being a multi-institutional trial. Stand-alone Phase I studies willnot be accepted.The following types of studies will be accepted for review:• Single-arm Phase II studies are expected to explore new approaches that can betested in larger confirmatory studies if positive results are obtained. It isexpected that these studies will complete accrual within 2 years ofcommencement. To meet this accrual goal, single-arm Phase II trials may bemulti-institutional. Data management and monitoring of studies should becoordinated by the applying institution. Additional funding for the lead institutionmay be requested to support the additional resources required for this activity, ifthe study involves multi-institutional participation.• Phase I/II studies are expected to explore new approaches that can be tested inlarger confirmatory studies if positive results are obtained. Phase I/II studiescombining axitinib with other targeted agents will be considered. It is expectedthat these studies will complete accrual within 2 years of commencement.• Randomized Phase II multi-institutional studies with an estimated 2-yearcompletion. Multi-institutional data management and monitoring of these studiesshould be coordinated by the lead institution. Additional funding for the leadinstitution may be requested to support the additional resources required for thisactivity.CONFIDENTIALPage 8 of 16

NCCN Axitinib RFP: 20DEC105.0 ProposalsIn order to respond to the RFP, investigators will submit a proposal in the formatdelineated below to NCCN, which will be evaluated by the NCCN Scientific ReviewCommittee (SRC).Proposals are required to be submitted by the institution’s Office of SponsoredResearch and include a letter of support from the governing groups of theinstitution verifying:1) The proposal has Department Chair/Division approval;2) Institutional budgetary review and approval;3) Verification of the priority status of the research (there are no competing trials ofhigher priority);4) The study includes a statistical co-investigator;5) Contact information for the contract representative assigned to the study;6) Documentation to support feasibility with at least one of the following:• Letter from institution’s Feasibility Committee• Documentation by previous studies and accrual (if available, publications andabstractsLetters should be addressed to William T. McGivney, PhD, CEO, NationalComprehensive Cancer Network, 275 Commerce Drive, Suite 300, Fort Washington, PA19034.Proposals will provide concise documentation of the research plan and are to bemodeled after the NCI Letter of Intent. The proposal is expected to contain sufficientinformation to allow the reviewers to fully assess the scientific rigor of the proposedstudy. A full research project plan may be submitted as an attachment to a proposal.The proposal should contain detailed information regarding the following areas:5.1 Clinical Trials (Maximum 5 Pages)A. Title/Tumor TypeB. Investigators and institutional affiliationsC. Hypothesis with primary and secondary objectivesD. Background InformationE. Research designF. Study populationi. Stageii. Major inclusions/exclusionsG. Treatment planH. Endpoints/Statistical analysisI. Feasibilityi. Estimated time of completion/monthly accrualii. Previous experience with trials that had similar tumor type,phase of study or prior therapyiii. Collaborators’ experience, including affiliatesiv. Competing trials: List all active, approved or in-review studiesat your institution for which the same patient population iseligibleCONFIDENTIALPage 9 of 16

NCCN Axitinib RFP: 20DEC10v. Projected Accrual Dates (Month/Year)vi. Information listed in 5.0(6)5.2 Correlative Studies (Maximum 3 Pages)A. Hypothesis (include relevant background studies)B. Preliminary dataC. Study design (include methods for obtaining samples, administeringforms, or performing radiologic studies)D. Study populationE. MethodologyF. Analytic planG. Feasibilityi. Accrualii. Specimen acquisition5.3 Budget using NCI formatA. Breakdown by major cost categories.B. Justification of major costs with enough detail to demonstrate howfunding for major elements in the study will be allocated.C. For combined clinical and correlative studies, separate budgets foreach component should be submitted.5.4 Ancillary DocumentationA. An NCI format BioSketch of the Principal InvestigatorB. An appendix of supportive literature may be provided6.0 Proposal Requirements6.1 SubmissionAll proposals must be submitted via email to ORPProposals@nccn.organd are due to the NCCN office by close of business, 5:00 PM (EST) onFebruary 14, 2011.Studies that have safety issues, are already well-funded concepts,or are not consistent with the strategy for investigation as written inthis RFP, will not be reviewed by the SRC.For questions or issues, please send an email toORPProposals@nccn.org or call Doreen Walker at (215) 690-0565.NCCN will seek to provide information to potential investigators regardingongoing or completed studies of axitinib in order to avoid the submissionof a proposal that is already a well-studied concept.6.2 Requirements6.2.1 IND: Investigators are required to hold INDs for studies and willbe allowed to cross-reference a filing to Pfizer’s IND as stated in Section3.3.CONFIDENTIALPage 10 of 16

NCCN Axitinib RFP: 20DEC106.2.2 Human Biological Specimens – All specimens must be obtainedunder informed consent and IRB approval appropriate for the study. Aletter of assurance must be provided to NCCN that the PI’s academicinstitution owns and has full rights to the tissue without conflicting claimsfrom a non-Pfizer commercial entity. Compliance with all federalregulations is required.6.2.3 IRB:6.2.3(a) Draft protocols will be reviewed by NCCN and Pfizer priorto IRB review. A copy of the draft protocol must be submitted to NCCNwithin 4-6 weeks after the study approval letter. The protocol must beconsistent with the approved proposal and all reviewer comments mustbe addressed.6.2.3(b) All investigators will submit protocols for IRB review anddocument approval to NCCN prior to study activation and all collaboratorswill furnish evidence of IRB approval. It is expected that IRB review andapproval be completed within 120 days following NCCN notification offunding for the project.6.2.3(c) IRB approval documents must be submitted to NCCNprior to study activation and all collaborators will also furnish evidence ofIRB approval.6.2.4 Serious Adverse Event Reporting: All serious adverse events willbe reported to NCCN and Pfizer in addition to local regulatory authorities.6.2.5 Institutional Monitoring: All studies will be internally monitored inaccordance with appropriate committees (e.g. institutional Data Safetyand Monitoring Plan in the case of human studies). A copy of the DataMonitoring Plan for the study must be submitted to NCCN prior to NCCNapproval of study activation.6.2.6 Progress Reports: Investigators will provide interim progressreports to NCCN detailing the progress of studies quarterly, and uponstudy completion. These reports will be used administratively forgenerating investigator payments. If study progress or accrual lagsbehind the expected rate, the Scientific Review Committee (SRC) may beasked for suggestions to improve study progress, or alternatively, toterminate the study and any further funding.6.2.7 Specimen Transmittal: If specimens are to be transportedextramurally for collaborative laboratory studies, all institutionalrequirements for safety and confidentiality will be met.6.2.8 Investigators Meeting: All studies will be presented by institutionalrepresentatives at an annual NCCN investigator meeting. The purpose ofthis meeting will be to discuss preliminary results and develop newresearch initiatives and further collaborative activities between NCCNinvestigators and Pfizer’s scientific staff. Separate funds will be providedCONFIDENTIALPage 11 of 16

NCCN Axitinib RFP: 20DEC107.0 Drug Supplyfor attendance at this meeting. Participation by the PIs in these meetingsis a requirement of a funded study.6.2.9 Abstracts and Publications: Abstracts for presentation at scientificmeetings and all publications of study results will be submitted to NCCNand Pfizer for review related to protection of company’s intellectualproperty and confidential information prior to any submission.Abstracts must be submitted at least 10 days prior to submission andmanuscripts at least 30 days prior to submission. Pfizer may delaypublication and disclosure of the manuscript or abstract for up to anadditional sixty (60) days so as to seek patent protection of intellectualproperty rights.6.2.10 NCCN institutions and investigators will be responsible forconducting all studies in accordance with the applicable research plan,GCP Guidelines, and all applicable laws and regulations. NCCNinstitutions and investigators will be responsible for all data collection,statistical analysis and safety reporting.6.2.11 Investigators must provide reasonable assurance that submittedstudies will be able to reach completion within the time frames specified inSection 4.0.6.2.12 Final protocols must be consistent with approved proposals.Funds will be rescinded if there are significant changes without priorNCCN approval. There will be no exceptions.Axitinib will be supplied and distributed to sites for all approved and funded studies byPfizer. No drug will be shipped until NCCN receives all required regulatory documents.8.0 Selection CriteriaProposals will be judged based on the following criteria:1. Scientific value2. Soundness of study design3. Feasibility including reasonable assurance of achieving intended and fullaccrual4. Budgetary reasonableness5. Expected applicability in the evaluation of and the appropriate use ofaxitinib in selected solid tumors9.0 FundingNCCN and its member institutions have an agreement to include a maximum of 25%indirect costs for trials funded by the NCCN. Direct funding will include all costsincluding investigators’ salaries. For example, $80,000 direct costs, $20,000 indirectcosts for a total grant of $100,000. Any funds in excess of the limits stipulated in thissection for direct funding will require detailed justification and review.CONFIDENTIALPage 12 of 16

NCCN Axitinib RFP: 20DEC10Phase I /II clinical trials will be funded at a cost of up to $250,000 (total costs includingdirect costs and 25% indirect costs) per trial. Per patient costs will not exceed $8,000per patient. Multi-institutional data management and monitoring of these studies shouldbe coordinated by the lead institution. Additional funding for the lead institution may berequested to support the additional resources required for this activity.The Correlative Laboratory studies section of the clinical trial will be funded up to a totalcost of $100,000 including up to 25% indirect costs.Funding will be disbursed according to the following:Phase I/II trials:• 25% of total award after IRB approval and implementation of the Phase I Study• 35% of total award after 50% accrual of Study subjects are enrolled in the PhaseII Study,• 30% of total award after 100% accrual of Study subjects to the Phase II Study• 10% of funds will be awarded after submission of manuscript for publication or afinal summary report of the StudyPhase II trials 25% of total award for such Study after IRB approval and implementation• 35% of total award after 50% accrual• 30% of total award after 100% accrual• 10% of funds will be awarded after submission of a final summary report ormanuscript for publicationThe goal is to have rapid submission of a manuscript so as to have the data available tothe wider scientific community.Studies that do not meet the time frame requirements as stipulated in Section 4.0will have funds rescinded and will be required to return any and all unused fundspreviously disbursed.10.0 Study AgreementA study agreement will be signed between NCCN and each participating institution.All aforementioned points between NCCN and the participating institution must be strictlyadhered to.CONFIDENTIALPage 13 of 16

NCCN Axitinib RFP: 20DEC10APPENDIX ATable A1 Pfizer Clinical Development of AxitinibTumor type Trial design Recruitment statusAdvanced Non-Small Cell LungCancerAdvanced Non-Small Cell LungCancerMetastatic colorectal carcinomaMetastatic colorectal carcinomaThyroid cancerRenal cell carcinoma Phase II CompletedHepatocellular carcinomaPhase II study of second-line Scheduled to opensingle agent axitinib after failure ofone prior antiangiogenic therapyAdvanced Non-Small Cell LungCancerPhase II study of first-line axitinib+ paclitaxel/carboplatin vs.bevacizumab +paclitaxel/carboplatin in non-Completedsquamous NSCLCPhase I/ II study of first-linepemetrexed/cisplatin +/– axitinibin non-squamous NSCLCPhase II study of first-line axitinib+ gemcitabine/cisplatin insquamous NSCLCPhase I/ II study of first-lineaxitinib + FOLFOX +bevacizumab vs. axitinib +FOLFOX vs. bevacizumab +FOLFOXPhase II study of second-lineaxitinib + FOLFOX or FOLFIRI vs.bevacizumab + FOLFOX orFOLFIRIPhase II study in refractory,metastatic or locally advanceddiseaseCompletedCompletedCompletedCompletedCompletedThyroid cancer Phase II trial in 2 nd -line OngoingAdvanced solid tumors Phase I study of axitinib +chemotherapy in patientswith relapsed, advanced solidtumorsCompletedAdvanced solid tumorsAdvanced solid tumorsClear cell Renal Cell Carcinoma(RCC) -failed one prior systemictherapyClear cell RCC with no priorsystemic therapyClear cell RCC with no priortherapy or failed one linePhase I study of axitinib inJapanese patients with relapsed,advanced solid tumorsPhase I study of single andmultiple doses of axitinibPhase III trial of axitinib vs.sorafenibPhase II study:Axitinib 5mg bid vs. axitinib 5mgbid + DT vs. axitinib 5mg bid +placebo DTPhase II trial of axitinib vs.sorafenibCompletedCompletedCompletedCompletedEnrolling in the 1 st line part ofstudyMetastatic RCC with failed 1 priorline cytokine-based therapy (Noother systemic therapy)Metastatic RCC-status postnephrectomy. Failed priorsorafenib-based therapyClear cell RCC/Postnephrectomy/Failed first-linecytokine therapyPhase II trial of axitinib 5mg bidwith dose titrationPhase II trial of axitinib 5mg bidwith dose titrationPhase II study of axitinib 5mg bidto 10 mg bidCompletedCompletedCompletedCONFIDENTIALPage 14 of 16

NCCN Axitinib RFP: 20DEC10APPENDIX ATable A2 Axitinib Investigator Initiated StudiesTumor Type Trial Design Recruitment StatusNeuroendocrineMelanomaMelanomaRenal cell carcinomaRenal cell carcinomaMetastatic renal cell carcinomaMelanomaSarcomaPhase II randomized double-blindstudy of Santostatin LAR incombination with Axitinib versusPlacebo in patients withprogressive advanced welldifferentiatedneuroendocrinecarcinomas of non-pancreaticoriginPhase II clinical trial of daily oralaxitinib (5 mg) for the adjuvanttreatment of stage III-IVmelanomaA Phase II Trial of Metformin andAxitinib in BRAF MutatedAdvanced Melanoma (MAXIM)Effect of Neoadjuvant Axitinib OnPrimary Tumor Response InLocally Advanced Clear Cell RCCPhase II study of Axitinib fordownstaging large renal tumorsnot primarily suitable for PartialNephrectomyA Phase II Study Of AxitinibTherapy Before Nephrectomy inMetastatic Renal Cell CancerPilot Phase I trial of sequentialAxitinib+ Carboplatin/Paclitaxel inMelanoma with Correlative FLTPETA clinicopathological phase IIstudy of axitinib in patients withadvanced angiosarcoma andother soft tissue sarcomasApprovedApprovedApprovedApprovedApprovedApprovedOngoingOngoingCONFIDENTIALPage 15 of 16

NCCN Axitinib RFP: 20DEC10References1. Investigator's Brochure: AG-013736. October 2010. Pfizer.2. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis andantitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitorof growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res.2008;14:7272-83.3. Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agentAG-013736 in patients with advanced solid tumors: pharmacokinetic and clinicalresults. J Clin Oncol. 2005;23:5474-83.4. Rixe O, Bukowski R, Michaelson MD, et al. Axitinib treatment in patients withcytokine-refractory metastatic renal cell cancer: a phase II study. Lancet Oncol.2007;8:975-84.5. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenibrefractorymetastatic renal cell carcinoma. J Clin Oncol. 2009;27:4462-8.6. Cohen EE, Rosen LS, Vokes EE, et al. Axitinib is an active treatment for allhistologic subtypes of advanced thyroid cancer: results from a phase II study. JClin Oncol. 2008;26:4708-13.7. Fruehauf JP, Lutzky J, McDermott D Fea. Axitinib (AG-013736) in patients withmetastatic melanoma: a phase II study. J Clin Onco 26:2008 (May 20 suppl;abstr 9006).8. Schiller JH, Larson T, Ou SH, et al. Efficacy and safety of axitinib in patients withadvanced non-small cell lung cancer: results from a phase II study. J Clin Oncol.2009;27:3836-41.9. Rixe O, Dutcher J, Motzer R, Wilding G, Stadler WM, Garrett M, Pithavala Y, KimS, Tarazi J, Rini BI. Diastolic blood pressure (dBP) and pharmacokinetics (PK) aspredictors of axitinib efficacy in metastatic renal cell cancer (mRCC). J Clin Oncol27: 2009 (suppl; abstr 5045).CONFIDENTIALPage 16 of 16