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Phase IB Study of Sorafenib and Evofosfamide in Patients with Advanced Hepatocellular and Renal Cell Carcinomas (NCCTG N1135, Alliance)

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Phase IB Study of Sorafenib and Evofosfamide in Patients with Advanced Hepatocellular and Renal Cell Carcinomas (NCCTG N1135, Alliance) Phase IB Study of Sorafenib and Evofosfamide in Patients with Advanced Hepatocellular and Renal Cell Carcinomas (NCCTG N1135, Alliance) Nguyen Tran Mayo Clinic https://orcid.org/0000-0002-6104-6489 Nathan Foster Mayo Clinic Minnesota Amit Mahipal Mayo Clinic Minnesota Thomas Byrne Mayo Clinic Arizona Joleen Hubbard Mayo Clinic Minnesota Alvin Silva Mayo Clinic Arizona Kabir Mody Mayo Clinic's Campus in Florida Steven Alberts Mayo Clinic Rochester: Mayo Clinic Minnesota Mitesh Borad ( [email protected] ) Mayo Clinic Arizona Research Article Keywords: evofosfamide, hypoxia activated pro-drug (HAP), hepatocellular cancer Posted Date: February 24th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-234613/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published at Investigational New Drugs on March 1st, 2021. See the published version at https://doi.org/10.1007/s10637-021-01090-w. Page 1/16 Abstract Background: Sorafenib (Sor) remains a rst-line option for hepatocellular carcinoma (HCC) or refractory renal cell carcinomas (RCC). PLC/PRF/5 HCC model showed upregulation of hypoxia with enhanced ecacy when Sor is combined with hypoxia-activated prodrug evofosfamide (Evo). Methods: This phase IB 3 + 3 design investigated 3 Evo dose levels (240, 340, 480 mg/m2 on days 8, 15, 22), combined with Sor 200 mg orally twice daily (po bid) on days 1-28 of a 28-day cycle. Primary objectives included determining maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Sor + Evo. Results: Eighteen patients were enrolled (median age 62.5 years; 17 male /1 female; 12 HCC/6 RCC) across three dose levels (DL0: Sor 200 mg bid/Evo 240 mg/m2 [n=6], DL1:Sor 200 mg bid/Evo 480 mg/m2 [n=5], DL1a: Sor 200 mg bid/Evo 340 mg/m2 [n=7]). Two dose-limiting toxicities (DLTs) were reported with Evo 480 mg/m2 (grade 3 mucositis, grade 4 hepatic failure). Grade 3 rash DLT was observed in one patient at Evo 240 mg/m2. No DLTs were observed at Evo 340 mg/m2. MTD and RP2D were established as Sor 200 mg/Evo 340 mg/m2 and Sor 200/Evo 240 mg/m2, respectively. The most common treatment-related adverse events included fatigue, hand-foot syndrome, hypertension, and nausea/vomiting. Two partial responses were observed, one each at DL0 and DL1a.; disease control rate was 55%. Conclusions: RP2D was established as sorafenib 200 mg bid + Evo 240 mg/m2. While preliminary anti-tumor activity was observed, future development must account for advances in immunotherapy in HCC/RCC. NCT01497444 Date of registration December 20, 2011 Introduction Hepatocellular carcinoma (HCC) remains one of the deadliest cancers globally. Currently, it is the fourth leading cause of cancer death worldwide.(1) Patients often present with advanced disease when rst diagnosed. Since 2007, sorafenib, an oral multikinase inhibitor, has been established as rst line systemic therapy for patients with advanced HCC. This is based on the results of a phase III clinical trial (SHARP) where Llovet and colleagues randomized 602 patients to sorafenib or placebo. Patients on the sorafenib arm demonstrated an improvement in overall survival (OS) (10.7 versus 7.9 months; hazard ratio (HR), 0.69; 95% CI, 0.55-0.87; P<0.001).(2) Survival benets were observed in a separate trial in patients in the Asia-Pacic region.(3) Recent advances in systemic treatments have led to longer survival; the combination atezolizumab and bevacizumab resulted in 12-month survival rates of 67.2% compared to 54.6% in the sorafenib arm.(4) However, responses remain short for the majority of patients with refractory disease.(5-7) Additional therapeutic options in this setting are urgently needed. New cases of renal cell carcinoma (RCC) affect more than 70,000 individuals in the US(8) and 300,000 individuals worldwide yearly.(9) The 5-year survival for patients with distant metastatic disease is low at 13%.(10) Since 2005, targeted therapies utilizing tyrosine kinase inhibitors (TKIs), anti-VEGF antibodies as well as mammalian target of rapamycin (mTOR) have been used in rst- and second-line treatments. The addition of immune checkpoint inhibitors has further improved the overall response rate and progression-free survival (PFS) in selected Page 2/16 populations.(11, 12) However, the majority of patients progress on these therapies and as such, there remains a signicant unmet need. Hypoxia has been well characterized in HCC(13) and RCC(14) and is associated with worsening prognosis. Hypoxia has been postulated to promote genomic instability, acceleration and accumulation of mutations(15) that confer drug resistance and lead to invasive and metastatic potential. High proportions of solid tumors with hypoxic regions showed resistance to radiation and conventional chemotherapy due to inability to penetrate beyond 50-100 µm from capillaries.(16, 17) Therapeutics designed to target these areas may augment and complement the anti-tumor activity of standard drugs by exploiting tumor hypoxia through activation of a pro- drug. This class of drug is designated as hypoxia activated prodrugs (HAPs). TH-302 or evofosfamide (Evo), a second generation of HAPs, is a nitroimidazole-linked prodrug of a brominated version of isophosphoramide mustard (Br-IPM).(18) When exposed to hypoxic conditions, Evo is reduced at the nitroimadazole site by intracellular reductase leading to subsequent release of Br-IPM. Br-IPM then acts as a DNA crosslinking agent. In areas of normoxia, evofosfamide remains intact as prodrug and toxicity is minimized. Numerous preclinical and clinical studies have demonstrated its effect across different cancer types including HCC and RCC.(19-24) Preclinical studies using sorafenib in the PLC/PRF/5 HCC model showed upregulation of hypoxia in both HCC and RCC.(25) The addition of TH-302 to sorafenib showed delayed tumor growth compared to TH-302 or sorafenib alone. The current phase IB study was designed to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of TH-302 and sorafenib in patients with advanced HCC and RCC. Methods Study Design North Central Cancer Treatment Group (NCCTG) study N1135 was a phase I single-arm trial that used a classical 3+3 dose escalation, followed by a maximum tolerated dose (MTD) dose-expansion design in patients with advanced HCC and RCC. The starting regimen was given as follows: sorafenib 200 mg orally twice a day on days 1 to 28 and Evo 240 mg/m2 on days 8, 15 and 22 every 28 days. Dose escalation entailed Evo dosed at 340 mg/m2 and 480 mg/m2. Three patients were treated at each dose level, and were observed for a minimum of 4 weeks to assess for toxicities before new patients were treated. DLT was dened as adverse event attributed to the study treatment in the rst four weeks of combination therapy. DLTs included febrile neutropenia, any grade 4 neutropenia lasting more than 7 days, grade 4 thrombocytopenia, grade 5 toxicity attributed to study treatment, any grade ischemic events and any nonhematologic adverse events grade 3 or greater lasting 14 days or more. Table S1 includes the full denition. Patients were treated until disease progression, unacceptable toxicity as dened by DLT, withdrawal of consent for treatment, physician decision or death. NCCTG is now part of the Alliance for Clinical Trials in Oncology. Patients Patients recruited were age 18 years and older, had cytological or histological conrmed diagnosis of advanced hepatocellular or renal cell carcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. HCC patients had Child Pugh A or B7 liver disease and were not amenable to surgery or orthotopic liver transplant. Patients with prior rst-line treatment with sorafenib were allowed. RCC patients had received standard Page 3/16 approved rst-line therapy only. Adequate blood and organ function, as well as measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were required for inclusion. Patients were excluded if they had active malignancy within 3 years prior to registration, were pregnant or nursing women, had inadequately controlled hypertension, prolonged QTc >500 msec on baseline electrocardiogram, brolamellar histology HCC or mixed hepatocholangiocarcinoma, hepatic sarcomas and other non-HCC primary liver tumors (See S2 for full protocol). The study protocol was approved by the institutional review board at each study site. All patients signed an IRB-approved, protocol-specic written informed consent document in accordance with federal and institutional guidelines. Assessments The primary end-point was the incidence of DLTs assessed in cycle 1 (DLTs are dened in Supplementary Table S1). A minimum of 3 patients were enrolled in each consecutive dosing cohort. If DLTs occurred in more than or equal to two of 6 patients, the dose was de-escalated. Safety was continuously evaluated by incidence and severity of treatment emergent adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. After treatment discontinuation, each patient was followed for disease progression and survival for up to 3 years after registration. The objective response rate was assessed by computed tomography or magnetic resonance imaging according to RECIST v1.1 criteria. Statistical Methodology Primary objectives were to determine the MTD and recommended phase II dose (RP2D) of combination sorafenib and Evo. Secondary objectives included assessment of overall safety prole, conrmed response rate based on RECIST 1.1 criteria, progression-free survival (PFS) and overall survival (OS). PFS was dened as the time from registration to death due to any cause or disease progression. OS was dened as the time from registration to death due to any cause. Kaplan-Meier methodology(26) and the log-rank test were used to describe the distribution of PFS and OS by dose level.
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