Investigator-Initiated Drug Research Program 2016 REQUEST for PROPOSALS

Investigator-Initiated Drug Research Program 2016 REQUEST FOR PROPOSALS

Update 4/12/2016

Investigator-Initiated Drug Research Program (IIDRP) – Request for Proposals

SUMMARY Academic-based investigator-initiated clinical research has been the foundation to the translation of biomedical and basic science discoveries into improvements in the clinical outcome for patients with early stage and advanced breast cancer [1], but fewer funding opportunities for this type of work over the last 15 years have become a barrier to the development of new therapies and the training of the next generation of clinical investigators [2, 3].

The Investigator-Initiated Drug Research Program (IIDRP) is a new BCRF initiative that invites proposals for preclinical research (laboratory science) or for therapeutic clinical trials (clinical science) in all stages of breast cancer. This new BCRF program provides support for high-quality, independent, academic- initiated research aimed at accelerating the pace of discovery to significantly impact outcomes in breast cancer care. Inaugural support for this round of preclinical research and for therapeutic clinical trials as part of the BCRF IIDRP is provided by Pfizer, Inc. and independently managed by BCRF.

Funded proposals for preclinical in vitro and in vivo studies will be selected by a Special Review Committee and managed by the BCRF Scientific Advisory Board and staff. Funded proposals for therapeutic clinical trials will be selected by a Special Review Committee and managed by the BCRF in partnership with the Translational Breast Cancer Research Consortium. In addition to financial support, Pfizer is providing free- of-charge access to a select list of its commercial and investigational drugs for basic and clinical trial proposals funded by this initiative.

COMPOUNDS AVAILABLE FOR STUDY

Appendix 1 contains a list of Pfizer drugs that are available including FDA-approved drugs in oncology and investigational pipeline drugs undergoing human studies. Some of the sixteen agents available at the launch of this program include cell cycle inhibitors, immune-modulatory agents (some in limited supply), antibody-drug conjugates, tyrosine kinase inhibitors, and hedgehog and notch pathway inhibitors. Additional drugs ready for human studies may become available in future rounds of funding.

Proposed laboratory studies must (a) use one or more of the available drugs or (b) study a pathway that is relevant to one of the listed drugs. Clinical trials must use one or more of the listed drugs (alone, in sequence, or in combination). Clinical trials may also include a listed drug plus another drug that is FDA- approved in the US commercialized by another pharmaceutical company for any clinical indication. Studies combining a listed Pfizer drug with an investigational drug from another company are also eligible for this award, but may require further agreements with the 3rd party.

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KEY DATES for 2016 proposal submissions  Application submission opens: April 4  Letter of Interest (LOI) due date: May 6 o Scientific review of LOIs: May 6 – June 10 o Invitation to submit full proposals: Notifications by June 15  Full Proposal due: August 15 (invited LOI’s only) o Scientific review of full proposals: August 15 – November 1 o Award notification date: November 1  Post-Award Activation o Negotiation of contract, payment terms and reporting requirements o Regulatory document submission (IRB/ IACUC approvals) by January 1, 2017

FUNDING LEVELS While general guidelines on the ranges of funding are stated below, BCRF also solicits big, bold ideas that do not fit within these restrictions.

CATEGORY OF STUDY APPROXIMATE RANGE OF FUNDING (per grant award) Clinical/Correlative Science Studies Therapeutic Clinical trials $750,000 – $2,000,000 per study over 3 years. Award amounts dependent upon phase, sample size, specimen acquisition, and correlative science proposed. Nonclinical studies Preclinical In Vitro studies Up to $150,000 per award over 3 years

Preclinical In Vivo studies Up to $500,000 per award over 3 years

GENERAL PRINCIPLES OF THE IIDRP

The goal of the IIDRP is to bring new treatment options for all stages of breast cancer to patients by funding innovative and high-quality, independent, investigator-initiated research on a broad spectrum of oncology agents currently in development. Academic investigators are encouraged to submit proposals for:  Nonclinical and translational studies (with or without available agent) in research laboratories to investigate mechanisms of action; biochemical, cellular, molecular and genetic endpoints; predictive and prognostic markers; and underlying biological effects of the agent.  Innovative clinical trials in the neoadjuvant, adjuvant, or advanced disease settings (but not traditional phase I studies limited to dose-discovery, toxicity-setting clinical trials) that have as main endpoints (a) biological measures (DNA, RNA, protein, or full cells) or modulation of biological targets, (b) measures of clinical parameters such as response, recurrence, or survival as assessed through imaging, pathology, or analysis of biospecimens, and/or (c) measures of quality, toxicity, and/or patient-reporting.

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o Clinical studies should preferentially be designed as collaboration across various research groups and institutions, and strongly consider biospecimen acquisition for current and future studies. o Clinical investigators are encouraged to consider the inclusion of parallel arms as appropriate for numerical or statistical comparisons in studies that evaluate measures of therapeutic activity.  Applicants are encouraged to consider clinical studies that are multidisciplinary (clinical disciplines and lab disciplines)

About BCRF BCRF was established in 1993 with a mission to prevent and cure breast cancer by advancing the world's most promising research. BCRF is unique in that it is the only breast cancer non-profit dedicated solely to research. The goal of the BCRF research program is to facilitate and spur innovative and important directions in clinical and/or translational research on breast and related cancers. Since its founding, BCRF has raised and awarded $600 million to advance laboratory and clinical research to improve prevention and treatment of breast cancer. BCRF’s commitment to reducing the barriers to clinical and translational research is evidenced by its initial and sustained support of the Translational Breast Cancer Research Consortium (TBCRC) since 2005.

About the TBCRC The primary goal of the TBCRC is to conduct innovative, high impact, biologically-driven translational and clinical research. This goal fulfills its mission to lessen the burden of breast cancer by using a multidisciplinary approach to discover novel mechanisms of breast cancer pathogenesis and test innovative, science-based therapeutic strategies. TBCRC members work collaboratively to speed the completion of clinical trials, share biologic specimens and clinical data, and conduct tissue-based investigation with cutting-edge molecular approaches that can be applied to clinical investigation and, eventually, clinical practice.

IIDRP PROCESS, REVIEW AND SELECTION Funding through the IIDRP is by a competitive, peer-reviewed request for proposal process summarized in the diagram below. BCRF and TBCRC is establishing a Steering Committee to guide the entire program and a Special Review Committee for application review. Ad hoc reviewers may be added, as needed, to ensure appropriate scientific expertise for rigorous evaluation of all letters-of-intent and full proposals.

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ELIGIBILITY REQUIREMENTS: The lead investigators should have a primary academic appointment in clinical or basic science department as assistant professor or higher and have a demonstrable record of innovative and collaborative research. The nonclinical laboratory science awards are open to all BCRF investigators. The clinical science awards are open to all BCRF investigators in US and Canadian institutions and all TBCRC investigators. Co-leadership across institutions is encouraged for the therapeutic clinical trial proposals and at least one of the proposal PIs should be at or below the rank of associate professor.

INSTITUTION REQUIREMENTS: Applicant institutions must be non-profit research institutions with the appropriate resources and support required to execute the proposed research. All subcontracted institutions must meet the same criteria and agree to the award conditions and policies and procedures of BCRF as outlined in the award contract.

NONCLINICAL PROPOSAL REQUIREMENTS: All nonclinical trial proposals funded by this program will be managed by BCRF. BCRF investigators must be in good standing with BCRF. BCRF-funded investigators are encouraged to seek out and include expert collaborators in the design and implementation of the study.

CLINICAL TRIAL REQUIREMENTS: All clinical trials funded by this program will be conducted in the TBCRC. 1) TBCRC investigators are strongly encouraged to develop their proposals through one or more of the TBCRC Working Groups (WGs). Institutions must have experience with multisite trial coordination or should consider using centralized trial management done with TBCRC’s preferred CRO partner, the Hoosier Cancer Research Network (HCRN), as the data from the clinical trials will be shared with BCRF and Pfizer to ensure timely public reporting.

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2) All TBCRC investigators are eligible to submit an LOI, and if invited, subsequent applications. BCRF investigators based in the US or Canada who are not based at a TBCRC institution are also eligible to submit an LOI in partnership with one or more TBCRC institutions. All LOIs must be reviewed/discussed with the relevant TBCRC WG co-chairs in advance of submission. 3) Participation of institutions that are part of regional networks of TBCRC institutions is allowed if those institutions are under the direct legal umbrella of a participating TBCRC institution (single contracting for the clinical trial) and under the jurisdiction of the same TBCRC institution IRB.

INSTITUTIONAL ASSURANCES Clinical Trials/Human Subjects Research: As a condition of support, institutions and investigators must provide documentation of both the initial IRB/Ethical Committee approval and annual renewals of that approval, as applicable. IRBs must include date of approval and expiration, project title, primary investigator name and list BCRF as a funder. No award can be initiated without documented IRB approval and patient informed consent documentation (ICD), as applicable.

Research involving animals: The USDA Animal Welfare Act and the NIH Public Health Service Policy on the Humane Care and Use of Animals require that institutions conducting research with animals establish an Institutional Animal Care and Use Committee (IACUC). Institutions and Investigators must provide documentation of IACUC approval and annual reviews of animal use protocols. Approval letters must include the date of approval and expiration, project title, primary investigator name and name BCRF as a funder. No award can be initiated without documented IACUC approval, as applicable.

PUBLICATION: All abstracts and manuscripts of a study conducted under an approved award must be shared with the BCRF and Pfizer before submission, though the BCRF and Pfizer do not have a veto privilege over the reporting of study results. All reporting of clinical trial results will be guided by both the BCRF and TBCRC Policies & Procedures regarding clinical trial reporting and publications.

For more information, please refer to the Frequently Asked Questions or contact BCRF directly.

BCRF IIDRP Contacts: Maneesh Kumar, MD, PhD BCRF Scientific Program Manager: [email protected] (646-497-2637) Marc Hurlbert, PhD, BCRF Chief Mission Officer: [email protected] Margaret Flowers, PhD, BCRF Associate Director, Grants: [email protected]

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PROPOSAL COMPONENTS

Letter of Intent: The Letter of Intent (LOI) and full proposal are submitted through the BCRF grants portal: https://www.grantinterface.com/bcrfcure/Common/LogOn.aspx.

The online letter of intent form requires the following information:

 Applicant details  Type of research and requested agents  Amount requested and expected duration of project  Study title  Study concept: A narrative of no more than 2 pages describing the rationale for the proposed work, study design, endpoints, expertise, and planned resources  Proposed budget and justifications  Investigator biosketches of PI (or co-PIs) and lead investigators in NIH format

Full proposal. The full proposal is divided into clinical trial and laboratory research sections. Applicants submitting proposals that include both research components will complete both sections. Detailed instructions will be provided when online full application system opens.

CLINICAL TRIAL PROPOSAL

Title

Sponsoring institution protocol number

Study Chair (principle investigator) details

Clinical trial details (type of trial, study personnel contact details)

Selected compound and any other “off list” compound that will be used in the study

Lay abstract: No more than 250 words, written for review by a patient advocate and to be shared with BCRF donors and constituents. The lay abstract should succinctly outline the reason for the trial and how it will impact patient outcomes.

Proposal: The proposal section should be no more than 10 pages including references and must include the following sections under separate headings:

 Background/Rationale: This section should state the need and scientific rationale supporting the proposed research and study design and explain why the trial is important  Hypothesis  Objectives  Eligibility Criteria: Include rationale for selecting or excluding particular cohorts  Study Design: Include schema showing arms/regimens of each cohort  Study Calendar: Detailed schedule of clinical assessments, laboratory tests/imaging, treatments, correlative blood/tissue studies, other assessment  Planned Correlative Studies: Include additional studies such as companion laboratory or imaging studies, biomarker analysis or quality of life studies

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 Statistical Design: Detailed statistical design describing endpoints (including secondary and other descriptive endpoints, clinical or lab correlative), stratification plans as applicable, sample size with power justifications (especially for primary endpoints), analysis (including plans for formal interim analysis), expected accrual rate, and expected time to accrual.  Trial Recruitment Plans: Including development of recruitment tools in collaboration with the TBCRC Patient Advocate WG  Feasibility: Discuss as appropriate, the size of eligible population, anticipated acceptance of trial by patients and referring physicians and experience with accrual to similar trials. Include any competing trials at your institution or other sites within the US or international groups.

Budget: Designed in consultation with the TBCRC Budget Specialist

NIH biosketches: PI (or Co-PIs) and for key investigators responsible for primary and secondary endpoints

Supplemental documents: Additional documents to support the proposal

LABORATORY RESEARCH PROPOSAL

Project title

Selected study compound(s) that is relevant to the proposed research

Proposal: The proposal section should be no more than 10 pages including references and must include the following sections under separate headings:

Budget and Justifications: Prepared on the BCRF/IIDRP template. (If this is a multi-year study, provide a multi-year budget.)

Study Personnel and Expertise: Detail study personnel, level of effort and how each will contribute to the study.

Biosketches: For key personnel only

Institution letter of support

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REFERENCES

1. Piccart, M.J. and I. Gingras, Breast cancer in 2015: Academic research sheds light on issues that matter to patients. Nat Rev Clin Oncol, 2016. 13(2): p. 67-8. 2. Bergmann, L., et al., Investigator-initiated trials of targeted oncology agents: why independent research is at risk? Ann Oncol, 2010. 21(8): p. 1573-8. 3. Hemminki, A. and P.L. Kellokumpu-Lehtinen, Harmful impact of EU clinical trials directive. BMJ, 2006. 332(7540): p. 501-2.

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Appendix 1: Investigator-Initiated Drug Research Program (IIDRP) Pfizer Study Drugs Available

DRUG INDICATION OR TARGET MECHANISM OF ACTION CURRENT STUDIES Bosulif™ Indication: CML Abl and Src kinase kinase inhibitor; Src, Lyn, (bosutinib) Hck family members [1-3]

Inlyta™ (axitinib) Indication: Renal (RCC) VEGF-R1,2, 3, Receptor tyrosine kinase PDGF-R, cKIT inhibitor [4, 5] Ibrance™ Indication: MBC: ER+, CDK4/CDK6 Cell cycle inhibitor (G1 to S (palbociclib) HER2- first line of phase blockade) [6, 7] endocrine Rx Sutent™ (sunitinib) Indication: Multi-Receptor Receptor tyrosine kinase Ph III Renal (RCC), Tyrosine Kinase inhibitor [8-12] Ph II GIST (PDGF-R, VEGF-R, cKIT, RET, CD114, CD135) Torisel™ Indication: Advanced renal mTOR mTOR inhibitor [13-15] (temsirolimus) cell carcinoma (RCC) Xalkori™ Indication: Metastatic Anaplastic Receptor tyrosine kinase (crizotinib) NSCLC whose tumors are Lymphoma Kinase inhibitor [16-18] ALK- positive (ALK)/c- MET/ROS1 4-1BB Ph I: combinations non- 4-1BB/CD137 Membrane-spanning TNFR Hodgkin’s lymphoma (NHL; super family; Immuno- Ph IB: combinations in oncology [19, 20] advanced solid tumors Avelumab* limited Ph III: NSCLC Programmed Fully humanized IgG1 quantities Ph II: Merkel cell carcinoma death-ligand 1 monoclonal antibody; Ph 1: RCC (PD-L1) Immuno-oncology [21-24] Ph 1: advanced solid tumors EFNA4 (PF- Ph I: combinations in Ephrin-A4 (EFNA4) ADC; ephrin-ligands and Eph 06647263) advanced solid tumors RTK [25-27] Gedatolisib Ph Ib: combinations in PI3K/Akt/mTOR Dual inhibitor of PI3Ka, advanced cancer PI3Kg, mTOR [28-30]

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Glasdegib Ph II: AML, MDS and Smoothened Hedgehog signaling pathway myelofibrosis (Smo) [31, 32] Ph I: BC HER2 ADC HER2 Antibody-Drug Conjugate. Additional details coming soon. Lorlatinib Ph II: ALK+ or ROS1+ NSCLC ALK, ROS1 Receptor tyrosine kinase [18, 33, 34]

Notch3 ADC Ph I: BC NOTCH3 Non-inhibitory anti-NOTCH3 ADC (PF-06650808) [35-37] OX40 Ph I: select advanced solid OX40/CD134 Cell surface glycoprotein of tumors TNF; immune-modulation of T cells [38, 39] PTK7 Ph I: advanced solid tumors Protein-tyrosine ADC [40-43] pseudokinase 7 (PTK7)

*Provided, however, that in no event will more than 2000g be made available to a single institution/investigator.

ADC=Antibody-Drug conjugate; AML=Acute Myeloid Leukemia; BC=Breast Cancer; CML=Chronic Myelogenous Leukemia; ER=Estrogen Receptor; GIST=Gastrointestinal Stromal Tumor; MBC=Metastatic Breast Cancer; MDS=Myelodysplastic Syndromes; NHL=Non-Hodgkin’s Lymphoma; NSCLC=Non-Small Cell Lung Cancer; RCC=Renal Cell Carcinoma; Rx=Therapeutic

REFERENCES

1. Isakoff, S.J., et al., Bosutinib plus capecitabine for selected advanced solid tumours: results of a phase 1 dose-escalation study. Br J Cancer, 2014. 111(11): p. 2058-66. 2. Moy, B., et al., Bosutinib in combination with the aromatase inhibitor letrozole: a phase II trial in postmenopausal women evaluating first-line endocrine therapy in locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer. Oncologist, 2014. 19(4): p. 348-9. 3. Moy, B., et al., Bosutinib in combination with the aromatase inhibitor exemestane: a phase II trial in postmenopausal women with previously treated locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer. Oncologist, 2014. 19(4): p. 346-7. 4. Rugo, H.S., et al., Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer. J Clin Oncol, 2011. 29(18): p. 2459-65. 5. Schneider, B.P. and G.W. Sledge, Jr., Anti-vascular endothelial growth factor therapy for breast cancer: can we pick the winners? J Clin Oncol, 2011. 29(18): p. 2444-7. 6. Finn, R.S., et al., The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2- negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol, 2015. 16(1): p. 25-35.

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7. Finn, R.S., A. Aleshin, and D.J. Slamon, Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res, 2016. 18(1): p. 17. 8. Crown, J.P., et al., Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol, 2013. 31(23): p. 2870-8. 9. Curigliano, G., et al., Randomized phase II study of sunitinib versus standard of care for patients with previously treated advanced triple-negative breast cancer. Breast, 2013. 22(5): p. 650-6. 10. Bachelot, T., et al., Sunitinib in combination with trastuzumab for the treatment of advanced breast cancer: activity and safety results from a phase II study. BMC Cancer, 2014. 14: p. 166. 11. Ahluwalia, M.S., et al., Phase II trial of sunitinib as adjuvant therapy after stereotactic radiosurgery in patients with 1-3 newly diagnosed brain metastases. J Neurooncol, 2015. 124(3): p. 485-91. 12. Yardley, D.A., et al., Phase I/II trial of neoadjuvant sunitinib administered with weekly paclitaxel/carboplatin in patients with locally advanced triple-negative breast cancer. Breast Cancer Res Treat, 2015. 152(3): p. 557-67. 13. Wolff, A.C., et al., Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol, 2013. 31(2): p. 195-202. 14. Ma, C.X., et al., A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat, 2013. 139(1): p. 145-53. 15. Gandhi, L., et al., Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol, 2014. 32(2): p. 68-75. 16. Grande, E., M.V. Bolos, and E. Arriola, Targeting oncogenic ALK: a promising strategy for cancer treatment. Mol Cancer Ther, 2011. 10(4): p. 569-79. 17. Robertson, F.M., et al., Presence of anaplastic lymphoma kinase in inflammatory breast cancer. Springerplus, 2013. 2: p. 497. 18. Siraj, A.K., et al., ALK alteration is a frequent event in aggressive breast cancers. Breast Cancer Res, 2015. 17: p. 127. 19. Kohrt, H.E., et al., CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood, 2011. 117(8): p. 2423-32. 20. Kohrt, H.E., et al., Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest, 2012. 122(3): p. 1066-75. 21. Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med, 2012. 366(26): p. 2455-65. 22. Topalian, S.L., C.G. Drake, and D.M. Pardoll, Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol, 2012. 24(2): p. 207-12. 23. Sznol, M. and L. Chen, Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res, 2013. 19(5): p. 1021-34. 24. Creelan, B.C., Update on immune checkpoint inhibitors in lung cancer. Cancer Control, 2014. 21(1): p. 80-9. 25. Pasquale, E.B., Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer, 2010. 10(3): p. 165-80. 26. Burleigh, A., et al., A co-culture genome-wide RNAi screen with mammary epithelial cells reveals transmembrane signals required for growth and differentiation. Breast Cancer Res, 2015. 17: p. 4.

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27. Damelin, M., et al., Anti-EFNA4 Calicheamicin Conjugates Effectively Target Triple-Negative Breast and Ovarian Tumor-Initiating Cells to Result in Sustained Tumor Regressions. Clin Cancer Res, 2015. 21(18): p. 4165-73. 28. Mallon, R., et al., Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res, 2011. 17(10): p. 3193-203. 29. Jansen, V.M., I.A. Mayer, and C.L. Arteaga, Is There a Future for AKT Inhibitors in the Treatment of Cancer? Clin Cancer Res, 2016. 30. Toska, E. and J. Baselga, Pharmacology in the Era of Targeted Therapies: The Case of PI3K Inhibitors. Clin Cancer Res, 2016. 31. Wagner, A.J., et al., A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin Cancer Res, 2015. 21(5): p. 1044-51. 32. Justilien, V. and A.P. Fields, Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells. Clin Cancer Res, 2015. 21(3): p. 505-13. 33. Mosse, Y.P., A. Wood, and J.M. Maris, Inhibition of ALK signaling for cancer therapy. Clin Cancer Res, 2009. 15(18): p. 5609-14. 34. Wu, J., J. Savooji, and D. Liu, Second- and third-generation ALK inhibitors for non-small cell lung cancer. J Hematol Oncol, 2016. 9(1): p. 19. 35. Park, J.T., et al., Notch3 overexpression is related to the recurrence of ovarian cancer and confers resistance to carboplatin. Am J Pathol, 2010. 177(3): p. 1087-94. 36. Capaccione, K.M. and S.R. Pine, The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis, 2013. 34(7): p. 1420-30. 37. Sansone, P., et al., Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer. Nat Commun, 2016. 7: p. 10442. 38. Morris, A., et al., Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo. Breast Cancer Res Treat, 2001. 67(1): p. 71-80. 39. Moran, A.E., M. Kovacsovics-Bankowski, and A.D. Weinberg, The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol, 2013. 25(2): p. 230-7. 40. Golubkov, V.S., et al., Protein-tyrosine pseudokinase 7 (PTK7) directs cancer cell motility and metastasis. J Biol Chem, 2014. 289(35): p. 24238-49. 41. Ataseven, B., et al., PTK7 expression in triple-negative breast cancer. Anticancer Res, 2013. 33(9): p. 3759-63. 42. Gartner, S., et al., PTK 7 is a transforming gene and prognostic marker for breast cancer and nodal metastasis involvement. PLoS One, 2014. 9(1): p. e84472. 43. Ataseven, B., et al., PTK7 as a potential prognostic and predictive marker of response to adjuvant chemotherapy in breast cancer patients, and resistance to anthracycline drugs. Onco Targets Ther, 2014. 7: p. 1723-31.

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Investigator-Initiated Drug Research Program (IIDRP) Frequently Asked Questions

1. What is Pfizer’s role in proposal approval or IIDRP program administration? None. Pfizer has no role in the selection of grantees or in oversight of the program. While the IIDRP RFP and policies and procedures are governed by a contractual agreement with Pfizer, BCRF will exercise full control over the program and selection of grantees, and in partnership with the TBCRC for the selection and conduct of clinical trials. BCRF must provide summary reports to Pfizer every 6 months regarding all funding disbursements. BCRF will coordinate drug disbursements with Pfizer. The BCRF IIDRP Steering Committee and staff will interact with Pfizer on an as needed basis.

2. What is the goal of the IIDRP program? The goal of the IIDRP is to accelerate treatments for patients and to serve as a bridge between academic investigators and access to drugs in development for early and advanced breast cancer. It will allow researchers to test applications for targeted therapies, or combinations of agents against multiple targets that will hopefully translate into more effective and more meaningful therapies for people with all types of breast cancer as well as other cancers.

3. What is unique about the IIDRP program? It will encourage independent, high-quality academic- driven research and give more patients access to clinical trials. Researchers will have the freedom to design and implement clinical trials and correlative studies that might not otherwise be completed. This unique approach has the potential to greatly accelerate and impact research progress, and ultimately, will lead to more treatment discoveries.

4. Are there restrictions to publishing data resulting from these studies? No. The publication rules follow standard industry-academic investigator-initiated research. All clinical trial reporting is subject to the BCRF IIDRP and the TBCRC Policies & Procedures regarding Publications. The full publishing policy is included in the BCRF IIDRP Policies and Procedures. a. BCRF encourages you to submit abstract(s), poster(s) and/or otherwise publish as soon as possible the results of your studies conducted hereunder after review by BCRF. Study results are expected to be delivered throughout the period of funding, but no later than a 2020 congress presentation. b. BCRF must review and approve all publications prior to public disclosure. c. BCRF requires investigators to use reasonable efforts to generate, propose and supply drafts of publications no later than twelve (12) months after the conclusion of the study. d. BCRF will give Pfizer the opportunity to review draft publications prior to public disclosure. Pfizer cannot block any publication, but is given the opportunity to review before public disclosure. Pfizer will complete its review of any manuscript publication within thirty (30) days of receipt and any abstract or poster within ten (10) days of receipt. During this review period, Pfizer may

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request in writing an additional thirty (30) days so that the parties may discuss whether or not to seek patent protection. If Pfizer believes that the publication contains any confidential information other than data or information required to support the results, conclusions and recommendations of such publication, then Pfizer shall notify BCRF, and Investigator shall remove or cause to be removed such confidential information.

5. What are the reporting requirements to BCRF? At minimum, you must submit a progress report or update to BCRF annually. We welcome more frequent updates of particularly interesting or exciting results.

6. Are there restrictions on the development of new intellectual property? No. However, per contractual agreement between BCRF and Pfizer, any new invention, development or discovery, whether patentable or not, must be disclosed to BCRF, who shall in turn disclose such invention to Pfizer. The BCRF intellectual property policy will apply to all contracts (and subcontracts) in this program. Contact BCRF if you would like to see the IP language in the BCRF IIDRP Policies and Procedures.

7. Can non-TBCRC investigators submit proposals for clinical trial studies? Yes. Non-TBCRC BCRF investigators based in the US or Canada are eligible to submit an LOI and, if selected, a full proposal, but must work in partnership with one or more TBCRC institutions.

8. Do all investigators on the grant need to be members of BCRF? For clinical trial studies, the PI must be a BCRF member but can include additional investigators that are not BCRF members. For laboratory studies, the PI need not be a BCRF member but the application must include at least one additional investigator that is a BCRF member.

9. Are studies that combine a Pfizer drug listed in Appendix 1 with an FDA-approved drug from another company eligible for this award? Yes. However, no funds from this BCRF program may be used to secure agents from other companies or purchase commercial drugs.

10. Are studies that combine a Pfizer drug listed in Appendix 1 with an investigational drug from another company eligible for this award? Yes. However, no funds from this BCRF program may be used to obtain the investigational drugs from a third party, which may require an agreement with the third party. In addition, if the terms of the agreement with the third party conflict with our terms, the investigator may also need to negotiate with BCRF, Pfizer, and the third party.

11. Is this RFP open to non-US investigators? The BCRF welcomes LOIs for lab-based studies from all BCRF investigators. However, only TBCRC investigators and BCRF investigators based in the US or Canada are eligible to submit LOIs for clinical projects to avoid any competition with a similar program in Europe managed by Breast Cancer Now based in the UK.

12. Can proposals include both clinical and laboratory research components? Yes. Proposals including both clinical and laboratory studies are allowed. Applicants will complete both the clinical and laboratory studies sections of the application form.

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13. What if my proposed research is outside the funding levels or duration limits described in the RFP? BCRF welcomes innovative proposals regardless of funding amount or time requested, as long as the scientific rationale and budget is justified.

14. Can proposals include more than one Pfizer agent? Yes.

15. What is the selection process of LOI and full proposals? A Steering Committee is being established to oversee the IIDRP program. A Special Review Committee is being established by BCRF and the TBCRC to review LOI and full proposals. Each LOI and full proposal will be reviewed by at least two scientific or clinical experts, an advocate and an expert in trial design or biostatistics. Ad hoc reviewers may be added, as needed, to ensure appropriate scientific expertise for rigorous evaluation of all letters-of-intent and full proposals. The Steering Committee will consider the reviews from the Special Review Committee and make final decisions.

16. How do I submit my letter of intent? All letters-of-intent and full proposals are submitted through the BCRF Grants Portal at: https://www.grantinterface.com/bcrfcure/Common/LogOn.aspx.

17. What if my project exceeds the three-year limit? The current limit is three years based on the contractual agreement between BCRF and Pfizer. No cost extensions of one year are allowed per BCRF policy.

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