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For Conducting Clinical Trials Using Selinexor (Nsc 781780)

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For Conducting Clinical Trials Using Selinexor (Nsc 781780) REQUEST FOR PROJECT TEAM MEMBER APPLICATIONS FOR CONDUCTING CLINICAL TRIALS USING SELINEXOR (NSC 781780) The National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) is accepting Project Team Member Applications for a project using selinexor, a selective small-molecule inhibitor of the nuclear export protein XPO1 being developed by CTEP as an anticancer agent in collaboration with Karyopharm Therapeutics. Selinexor inhibits nuclear export by binding the nuclear export protein XPO1, leading to the accumulation of tumor suppressor proteins in the cell nucleus. This is believed to reinitiate and amplify their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells; the precise mechanism by which XPO1 inhibition leads to cancer cell death is uncertain. Selinexor (XPOVIO) is approved for treatment of patients with relapsed or refractory diffuse large B-cell lymphoma and, in combination with dexamethasone, for treatment of patients with relapsed or refractory multiple myeloma. At the present time, the preliminary CTEP drug development plan is for Phase I development of combinations of selinexor with venetoclax, venetoclax plus DNA methyltransferase inhibitors, and venetoclax plus flt-3 inhibitors in myeloid malignancy; Phase I combinations of selinexor with proteasome inhibitors in soft tissue sarcomas, and Phase I combinations of selinexor with temozolomide in glioblastoma multiforme. Preclinical models suggest synergistic activity of these combinations in these disease settings. The role of the project team is to evaluate all available evidence to modify and refine this initial plan or suggest an alternative project. It is anticipated that CTEP will activate 3 – 6 different combination trials with selinexor. The project team will include: 1. Clinician Scientists with expertise in phase I and II studies and with an interest in myeloid malignancies, sarcoma, and glioblastoma (fill out Part A of the attached Application; Clinician Scientists must belong to a qualifying NCI grant funded institution as defined at the end of this letter); 2. Translational scientists with an interest in biomarker development in nuclear export, tumor suppressor genes and/or apoptosis, and acquired mechanisms of resistance (fill out Part B of the attached Application and see the submission instructions at the end of this letter); and 3. Basic scientists with expertise in nuclear export and mechanisms of carcinogenesis or apotosis (fill out Part C of the attached Application and see the submission instructions at the end of this letter). Prospective team members may apply for multiple roles using a single application form by completing all the appropriate Parts. The project team will be recruited nationally and will prioritize the research questions regarding selinexor in combination trials, including prioritization of biomarker studies. It is anticipated that the clinicians on the drug project team will be tasked with writing the Letters of Intent describing the study design, based upon the team’s recommendations, for CTEP approval, and that these clinicians will ultimately lead the clinical studies. It is also anticipated that other extramural members of the drug project team will stay involved in the subsequent design and execution of the proposed trials. It is anticipated that the project team will complete its work in 6 – 8 weeks or less. Background/Rationale Exportin 1 (XPO1) is the major nuclear export protein of tumor suppressor proteins (TSPs; e.g., p53, pRb, IκB, p27, p21, FOXOs) and eIF4E-bound proto-oncogene mRNAs (e.g., c-Myc, Bcl2, Bcl6, BclxL). Elevated XPO1 expression inactivates TSPs by mislocalization, enhances proto-oncoprotein translation, and correlates with poor patient prognosis in a variety of cancers, including multiple myeloma, soft tissue sarcoma, and glioblastoma. Mechanism of Action Selinexor is an oral small-molecule selective inhibitor of XPO1. This inhibition leads to the accumulation and reactivation of TSPs in the cell nucleus and is also associated with blockage of proto-oncoprotein translation and of DNA damage repair. Ultimately, inhibition of XPO1 by selinexor is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. Synergy has been reported in vitro and in vivo in combination studies of selinexor plus DNA damage-inducing therapies, proteasome inhibitors, and conventional chemotherapy. Nonclinical Studies of Selinexor and Analogues Selinexor and/or its congeners have shown broad anti-tumor activity in acute myeloid leukemia (AML) cell lines and murine xenograft models of AML and glioblastoma multiforme (GBM), both as single agents and in combination with sorafenib, quizartinib, nutlin-3a, venetoclax, decitabine, temozolomide, and radiation. In in vitro AML models, selinexor treatment led to reductions of flt-3, c- kit and MCL-1 expression; enhanced therapeutic index in killing AML cells versus normal hematopoietic cells; and AML cell differentiation. In xenograft models of AML and diffuse large B cell lymphoma (DLBCL), combinations of selinexor with venetoclax synergized. In vitro augmentation of activity with MDM2 inhibition was demonstrated in p53 wild-type AML. In flt-3 ITD AML xenografts, flt-3 inhibitors augmented activity; synergy was particularly impressive with quizartinib. In animal models of glioblastoma multiforme, addition of selinexor to radiation alone improved survival, and selinexor synergized with temozolomide in inhibition of tumor growth. Selinexor appears to be particularly active against NPM-1 mutated leukemia: selinexor restored nuclear localization of the cytoplasmically mis-localized mutant NPM1 protein and restored HOX expression programs. In multiple myeloma, selinexor inhibited bone marrow stromal cell protection and osteoclast differentiation. Clinical Studies of Selinexor Selinexor (XPOVIO) has been approved by the Food and Drug Administration (FDA) for treatment of patients with relapsed or refractory diffuse large B-cell lymphoma and, in combination with dexamethasone, for treatment of patients with relapsed or refractory multiple myeloma. Clinical trials are currently testing Selinexor in Phase II and III clinical development, alone or in combination regimens, for the treatment of patients with liposarcoma, endometrial cancer, diffuse large B-cell lymphoma, and glioblastoma. The following active studies are being conducted as part of the Karyopharm clinical development program for selinexor (Table 1): Table 1: Active Karyopharm-sponsored selinexor clinical trial listings on ClinicalTrials.gov NCT Number Phase Agent(s) Disease/ Sponsor Study Planned Abstract Indication Start- Accrual End NCT02091245 1 Selinexor Relapsed/ Karyopharm and 3/2014 – 16 Place et al., refractory Dana-Farber 6/2020 2018 childhood leukemias NCT02228525 2 Selinexor Myelodysplastic Karyopharm, Sloan 8/2014 – 26 Taylor et al., syndrome Kettering, MD 8/2021 2018 Anderson, and Columbia University Page 2 of 7 NCT Number Phase Agent(s) Disease/ Sponsor Study Planned Abstract Indication Start- Accrual End NCT02186834 1/2 Selinexor + Relapsed/ Karyopharm and H. 9/2014 – 28 Baz et al., liposomal refractory Lee Moffitt Cancer 12/2020 2016 doxorubicin + multiple Center dexamethasone myeloma NCT02227251 2 Selinexor Diffuse large B- Karyopharm 11/2014 129 Maerevoet et cell lymphoma – al., 2020 12/2020 NCT02403310 1 Selinexor + Leukemia Karyopharm and H. 6/2015 – 21 Sweet et al., daunorubicin + Lee Moffitt Cancer 12/2020 2020 cytarabine Center NCT02343042 1/2 Selinexor + Multiple Karyopharm 10/2015 437 Bahlis et al. dexamethasone myeloma – 5/2020 2018 + backbones (pomalidomide, bortezomib, lenalidomide, pomalidomide + bortezomib, daratumumab, carfilzomib, ixazomib, or pomalidomide + elotuzumab) NCT02471911 1 Selinexor + Diffuse large B- Karyopharm and 11/2015 23 RICE (rituximab, cell lymphoma Weill-Cornell – 1/2021 etoposide, carboplatin, ifosfamide, dexamethasone) NCT02606461 2/3 Selinexor vs. Advanced Karyopharm 12/2015 334 Gounder et placebo liposarcoma – al., 2018 11/2020 NCT02831686 1 Selinexor + Multiple Karyopharm, Sloan 7/2016 – 18 Salcedo et ixazomib + myeloma Kettering, and 7/2020 al., 2020 dexamethasone Millennium Pharmaceuticals NCT02741388 1 Selinexor + R- B-cell lymphoma Karyopharm and 10/2016 60 DHAOx Lymphoma Academic – 6/2021 (rituximab, Research dexamethasone, Organisation oxaliplatin, cytarabine); selinexor + R- GDP (rituximab, dexamethasone, gemcitabine, cisplatin) NCT03042819 1 Selinexor + Soft tissue Karyopharm and 5/2017 – 25 Malone et doxorubicin sarcoma University Health 11/2020 al., 2018 Network, Toronto NCT03110562 3 Selinexor + Multiple Karyopharm 5/2017 – 402 bortezomib + myeloma 6/2020 dexamethasone vs. bortezomib + dexamethasone NCT02780609 1/2 Selinexor + high- Multiple Karyopharm and H. 6/2017 – 46 Nishihori et dose melphalan myeloma Lee Moffitt Cancer 8/2022 al., 2019 + Center dexamethasone + hematopoietic cell transplant Page 3 of 7 NCT Number Phase Agent(s) Disease/ Sponsor Study Planned Abstract Indication Start- Accrual End NCT03466827 2 Selinexor Thymic cancers Karyopharm, Institut 10/2017 25 Curie, Gustave – 7/2020 Roussy, Hospices Civils de Lyon, and GSO Global NCT03555422 3 Selinexor vs. Endometrial Karyopharm, BGOG, 1/2018 – 192 placebo cancer NOGGO, MITO, 3/2023 GEICO, CEEGOG, and ISGO NCT03095612 1/2 Selinexor + Non-small cell Karyopharm and UT 3/2018 – 59 docetaxel lung cancer Southwestern 5/2021 NCT03193437 2 Selinexor
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