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A Phase 1/2 Study of Evofosfamide, a Hypoxia-Activated Prodrug with Or Without Bortezomib 2 in Subjects with Relapsed/Refractory Multiple Myeloma 3

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A Phase 1/2 Study of Evofosfamide, a Hypoxia-Activated Prodrug with Or Without Bortezomib 2 in Subjects with Relapsed/Refractory Multiple Myeloma 3 Author Manuscript Published OnlineFirst on October 2, 2018; DOI: 10.1158/1078-0432.CCR-18-1325 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 A Phase 1/2 Study of evofosfamide, A Hypoxia-Activated Prodrug with or without Bortezomib 2 in Subjects with Relapsed/Refractory Multiple Myeloma 3 4 Jacob P. Laubach, MD1,2, Chia-Jen Liu, MD, PhD1, Noopur S. Raje, MD3, Andrew J. Yee, MD3, 5 Philippe Armand, MD, Ph.D.1,2, Robert L. Schlossman, MD1,2, Jacalyn Rosenblatt, MD2,4, 6 Jacquelyn Hedlund, MD2,5, Michael Martin, MD2,6, Craig Reynolds, MD2,7, Kenneth H. Shain, MD, 7 PhD8, Ira Zackon, MD2,9, Laura Stampleman, MD2,10, Patrick Henrick BS1,2, Bradley Rivotto, BS1, 8 Kalvis T.V. Hornburg BA1, Henry J. Dumke BS1, Stacey Chuma, BSN1,2, Alexandra Savell1,2, 9 Damian R. Handisides11, Stew Kroll11, Kenneth C. Anderson, MD1,2, Paul G. Richardson, MD1,2*, 10 Irene M. Ghobrial MD1,2* 11 1Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber 12 Cancer Institute, Harvard Medical School, Boston, MA; 2Blood Cancer Research Partnership 13 (BCRP), Boston, MA; 3Massachusetts General Hospital, Boston, MA; 4Beth Israel Deaconess, 14 Boston, MA; 5Maine Center For Cancer Medicine, Scarborough, ME; 6The West Clinic, Memphis, 15 TN; 7Ocala Oncology Center, Ocala, FL; 8Moffitt Cancer Center, Tampa, FL; 9New York Oncology 16 Hematology, Albany, NY; 10Pacific Cancer Care, Salinas, CA; 11Threshold Pharmaceuticals, South 17 San Francisco, CA 18 *Paul Richardson and Irene Ghobrial are co-senior authors 19 Correspondence: 20 21 Irene M. Ghobrial, MD and Paul G. Richardson, MD 22 Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology 23 Dana-Farber Cancer Institute, Harvard Medical School 24 Boston, MA USA. 25 Email: [email protected] 26 Email: [email protected] 27 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 2, 2018; DOI: 10.1158/1078-0432.CCR-18-1325 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Running title: Phase I/2 Study of evofosfamide in multiple myeloma 2 Key words: multiple myeloma, hypoxia-activated pro-drug, hypoxic bone marrow 3 microenvironment 4 Funding source: Threshold Pharmaceuticals funded the study in partnership with Merck KGaA, 5 Darmstadt, Germany. This was partially supported by R01 CA181683-01A1 and the Leukemia 6 and Lymphoma Society. 7 Conflicts of interest: IMG is on the advisory board of Celgene, Takeda, BMS, Janssen, and 8 Amgen and research support from Celgene, Takeda, BMS and Janssen. PGR: Research support 9 from Takeda and Celgene; member of advisory committees for Takeda, Celgene, Janssen, and 10 Amgen. All others have no conflict of interest. 11 12 Word count: abstract: 248, word count for main text: 3,892 13 14 15 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 2, 2018; DOI: 10.1158/1078-0432.CCR-18-1325 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Translational Relevance: 2 Evofosfamide is an investigational 2-itroimidazole prodrug of the DNA alkylator bromo- 3 isophosphoramide (Br-IPM) designed to be selectively activated under hypoxic conditions. 4 Evofosfamide exhibited activity in both in vitro and in vivo preclinical multiple myeloma (MM) 5 models. Additionally, in vitro synergism was seen when evofosfamide was combined with the 6 proteasome inhibitor bortezomib. Therefore, targeting the hypoxic microenvironment in 7 combination with anti-MM agents, such as bortezomib, represents a novel anti-MM treatment 8 strategy. We conducted a Phase 1/2 study to determine the maximum tolerated dose (MTD), 9 dose-limiting toxic effects (DLT), safety, tolerability, and clinical activity of evofosfamide plus 10 low-dose dexamethasone with or without bortezomib in patients with relapsed and/or 11 refractory multiple myeloma. Clinical activity has been noted in these heavily treated patients. Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 2, 2018; DOI: 10.1158/1078-0432.CCR-18-1325 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Abstract 2 Introduction. The presence of hypoxia in the diseased bone marrow presents a new 3 therapeutic target for multiple myeloma (MM). Evofosfamide (formerly TH-302) is a 2- 4 nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard that is 5 selectively activated under hypoxia. A phase 1/2 study investigating evofosfamide in 6 combination with dexamethasone (EvoD) and in combination with bortezomib and 7 dexamethasone (EvoBorD) in relapsed/refractory MM. 8 Experimental Design: 59 patients initiated therapy, 31 received EvoD and 28 received EvoBorD. 9 Pts were heavily pre-treated with a median number of prior therapies of 7 (range: 2–15). All 10 had previously received bortezomib and immunomodulators. The maximum tolerated dose 11 (MTD), treatment toxicity, and efficacy were determined. 12 Results: The MTD was established at 340 mg/m2 Evo+D with dose limiting mucositis at higher 13 doses. For EVOBorD, no patient had a dose limiting toxicity and the recommended phase 2 dose 14 was established at 340 mg/m2. The most common ≥ Gr 3 adverse events were 15 thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients) and 16 leukopenia (9 patients). Skin toxicity was reported in 42 (71%). Responses included 1 VGPR, 3 17 PR, 2 MR, 20 SD and 4 PD for EvoD and 1 CR, 2 PR, 1 MR, 18 SD and 5 PD for EvoBorD. Disease 18 stabilization was observed in over 80% and this was reflective of the prolonged overall survival 19 of 11.2 months. 20 Conclusions: Evofosfamide can be administered at 340 mg/m2 twice a week with or without 21 bortezomib. Clinical activity has been noted in patients with heavily pre-treated relapsed 22 refractory MM. 23 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 2, 2018; DOI: 10.1158/1078-0432.CCR-18-1325 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Introduction 2 Multiple Myeloma (MM) is a plasma cell malignancy characterized by clonal evolution and 3 resistance to therapy at end stages of the disease(1). In recent years, combinations of therapy 4 using the cornerstone classes of agents in MM including proteasome inhibitors (e.g., 5 bortezomib and carfilzomib) and immunomodulatory agents (e.g., lenalidomide and 6 pomalidomide), have significantly improved response rates and survival in MM(2). Despite 7 significant advances in the treatment of MM, including the FDA approval of several novel 8 agents (3-5), most patients with relapsed/refractory MM succumb to their disease. In fact, the 9 median overall survival of patients refractory to immunomodulatory agents and proteasome 10 inhibitors is estimated to be about 9 months, with a median event-free survival of 5 months (6). 11 Therefore, there is an urgent need to develop therapeutic agents with new mechanisms of 12 action that can overcome drug resistance in MM. 13 Alkylators and DNA targeting agents remain essential in the treatment of patients with MM. 14 However, the use of melphalan, cyclophosphamide and benadmustine is associated with 15 significant toxicities, especially at high doses(7-9). A novel method of delivering higher doses of 16 alkylator therapy while eliminating the associated side effects could potentially optimize the 17 effectiveness of these agents. 18 Tumors are more than insular masses of proliferating cancer cells (10). Instead, they are 19 complex tissues composed of multiple distinct cell types that participate in heterotypic 20 interactions with one another as previously described(11). Growing evidence supports a pivotal 21 role of the microenvironment in tumorigenesis and tumor progression (12). Cancer niches have 22 been shown to promote tumor proliferation, metastasis, resistance to therapy and eventually 23 recurrence/relapse in a number of cancers, including MM (13). 24 Hypoxia is an imbalance between oxygen supply and consumption that deprives cells or tissues 25 of oxygen. Decreases in oxygen levels are observed in certain types of pathological situations, 26 such as cancer. Hypoxic regions arise in tumors because of rapid cell division and aberrant 27 blood vessel formation(14, 15). In solid tumors, it has been shown that the hypoxic 5 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 2, 2018; DOI: 10.1158/1078-0432.CCR-18-1325 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 microenvironment contributes to cancer progression by activating adaptive transcriptional 2 programs, thereby promoting tumor-cell survival, motility, and metastasis leading to a worse 3 prognosis(16-18). Specifically, it has been shown that the BM of MM mouse models and MM 4 patients is hypoxic compared to healthy controls(19-21). Therefore, targeting hypoxia niches 5 should be considered as a novel approach for the treatment of MM. 6 Evofosfamide is an investigational 2-nitroimidazole prodrug of the DNA alkylator bromo- 7 isophosphoramide (Br-IPM) designed to be selectively activated under hypoxic conditions. 8 Evofosfamide exhibited activity in both in vitro and in vivo preclinical MM models (20, 22). 9 Additionally, in vitro synergism was seen when evofosfamide was combined with the 10 proteasome inhibitor bortezomib (23). Therefore, targeting the hypoxic microenvironment in 11 combination with other novel anti-MM agents, such as bortezomib, represents a novel anti-MM 12 treatment strategy.
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