{
  "abstract": "Background Despite significant advances in cancer therapeutics, many patients with advanced/metastatic cancer fail to respond, underscoring the need for novel therapeutic strategies. Bioactive natural products, such as paclitaxel 1 2 have long served as anticancer agents. In recent years, derivatives of Nigella sativa (N.sativa), particularly thymoquinone (TQ), have demonstrated apoptotic and antiproliferative effects in preclinical studies3–10 and favorable safety profiles in non-cancerous conditions.11 12 NP-101 is a novel enteric formulation that contains oil derived from the seeds of N. sativa and includes TQ and associated fatty acids as the main bioactive ingredients.13 In preclinical studies, NP-101 demonstrated significant antitumor activity in pancreatic neuroendocrine tumor (pNET) cell lines (p<0.001) and in NRAS-mutant pNET (p<0.001) and hepatocellular carcinoma models (p=0.0002). A double-blind, randomized, placebo-controlled trial in COVID-19 patients14 demonstrated that NP-101 led to a faster decline in the total symptom burden (p<0.001) and a significant increase in CD8+ cytotoxic (p=0.042) and CD4+ helper (p=0.042) T lymphocytes, suggesting an immunomodulatory effect. Furthermore, emerging results15 16 suggest that intense immunologic response stimulated by anti-COVID treatments promote antitumor response. Therefore, we hypothesize that NP-101 may modify the tumor microenvironment and improve outcomes in patients with solid tumors.Methods This open-label Phase I study ( NCT06563375) is evaluating NP-101 in adult patients with advanced/metastatic solid tumors. Patients must have an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy ≥3 months.The primary objective is to determine the safety and tolerability of NP-101. The secondary objective is to assess the preliminary antitumor activity. The exploratory objectives are characterization of the pharmacokinetic (PK) profile and evaluation of the immune activation potential of NP-101. The overall objective is to establish a recommended phase II dose (RP2D) for larger late-stage trials.The study consists of two parts (figure 1): dose escalation (Part 1) and dose expansion (Part 2). In Part 1 (n=15), three dose levels (3.0, 4.8 [starting dose], and 6.0 g/day BID) will be evaluated using the Bayesian optimal interval (BOIN) design to determine the maximum tolerated dose (MTD). We will conduct comprehensive PK studies. Part 2 will further evaluate the safety and preliminary antitumor activity of NP-101 at the MTD and possibly a dose lower than the MTD. The RP2D of NP-101 will be determined at the end of the study based on the totality of safety, tolerability, clinical activity, pharmacodynamic, and PK data.Results Enrollment is ongoing.Acknowledgements Novatek Pharmaceuticals is providing the study drug and is funding the study. This work is also supported in part by the NIH/NCI under award number 1R01CA279749-01A1 (Dr. Aung Naing)Trial Registration NCT06563375References National Cancer Institute: A Story of Discovery: Natural Compound Helps Treat Breast and Ovarian Cancers National Cancer Institute, 2015.Weaver BA. How taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25:2677–81.Shoieb AM, Elgayyar M, Dudrick PS, Bell JL, Tithof PK: in vitro inhibition of growth and induction of apoptosis in cancer cell lines by thymoquinone. Int J Oncol. 2003;22:107–13.Taha MM, Sheikh BY, Salim LZ, Mohan S, Khan A, Kamalidehghan B, Ahmadipour F, Abdelwahab SI: Thymoquinone induces apoptosis and increase ROS in ovarian cancer cell line. Cell Mol Biol (Noisy-le-grand). 2016;62:97–101.Gali-Muhtasib H, Diab-Assaf M, Boltze C, Al-Hmaira J, Hartig R, Roessner A, Schneider-Stock R. Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53-dependent mechanism. Int J Oncol. 2004;25:857–66.Zhang L, Bai Y, Yang Y. Thymoquinone chemosensitizes colon cancer cells through inhibition of NF-kappaB. Oncol Lett. 2016;12:2840–5.Yi T, Cho SG, Yi Z, Pang X, Rodriguez M, Wang Y, Sethi G, Aggarwal BB, Liu M. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther. 2008;7:1789–96.Samarghandian S, Azimi-Nezhad M, Farkhondeh T. Thymoquinone-induced antitumor and apoptosis in human lung adenocarcinoma cells. J Cell Physiol. 2019; 234:10421–31.Xu D, Ma Y, Zhao B, Li S, Zhang Y, Pan S, Wu Y, Wang J, Wang D, Pan H, Liu L, Jiang H: Thymoquinone induces G2/M arrest, inactivates PI3K/Akt and nuclear factor-kappaB pathways in human cholangiocarcinomas both in vitro and in vivo. Oncol Rep. 2014; 31:2063–70.Imran M, Rauf A, Khan IA, Shahbaz M, Qaisrani TB, Fatmawati S, Abu-Izneid T, Imran A, Rahman KU, Gondal TA. Thymoquinone: a novel strategy to combat cancer: a review. Biomed Pharmacother. 2018;106:390–402.Kaatabi H, Bamosa AO, Badar A, Al-Elq A, Abou-Hozaifa B, Lebda F, Al-Khadra A, Al-Almaie S. Nigella sativa improves glycemic control and ameliorates oxidative stress in patients with type 2 diabetes mellitus: placebo controlled participant blinded clinical trial. PLoS One. 2015;10:e0113486.Barakat EM, El Wakeel LM, Hagag RS. Effects of nigella sativa on outcome of hepatitis C in Egypt. World J Gastroenterol. 2013;19:2529–36.Maen A, Gok Yavuz B, Mohamed YI, Esmail A, Lu J, Mohamed A, Azmi AS, Kaseb M, Kasseb O, Li D, Gocio M, Kocak M, Selim A, Ma Q, Kaseb AO. Individual ingredients of NP-101 inhibit SARS-CoV-2 pseudovirus infection. Front Pharmacol. 2024;15:1291212.Bencheqroun H, Ahmed Y, Kocak M, Villa E, Barrera C, Mohiuddin M, Fortunet R, Iyoha E, Bates D, Okpalor C, Agbosasa O, Mohammed K, Pondell S, Mohamed A, Mohamed YI, Gok Yavuz B, Kaseb MO, Kasseb OO, Gocio MY, Tu PT, Li D, Lu J, Selim A, Ma Q, Kaseb AO. A randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and efficacy of thymoquinone formula for treating outpatient SARS-CoV-2. Pathogens. 2022;11:551Huang W, Liu W, Yu T, Zhang Z, Zhai L, Huang P, Lu Y. Effect of anti-COVID-19 drugs on patients with cancer. Eur J Med Chem. 2024;268:116214.Sousa LG, McGrail DJ, Li K, Marques-Piubelli ML, Gonzalez C, Dai H, Ferri-Borgogno S, Godoy M, Burks J, Lin SY, Bell D, Ferrarotto R: Spontaneous tumor regression following COVID-19 vaccination. J Immunother Cancer. 2022;10.Ethics Approval This study was approved by The University of Texas MD Anderson Cancer Center’s Institutional Review Board. OHRP IRB Registration Number: IRB00000121 FWA #: 00000363Abstract 532 Figure 1NP-101 Phase 1 study design (Created in https://BioRender.com). Abbreviations: BID, twice daily; MTD, maximum tolerated dose; PO, orally; PD, pharmacodynamics; PK, pharmacokinetics; RP2D, recommended phase II dose",
  "authors": [
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Camila Braganca Xavier"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Bettzy Stephen"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Serdar A Gurses"
    },
    {
      "affiliations": [
        "Novatek Pharmaceuticals, Pearland, TX, USA"
      ],
      "name": "Michelle Y Gocio"
    },
    {
      "affiliations": [
        "Novatek Pharmaceuticals, Pearland, TX, USA"
      ],
      "name": "Mohamed Kaseb"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Yali Yang"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Ann M Cimo"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Mohamed H Derbala"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Tin-Yun Tang"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Stephane Champiat"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Paula R Pohlmann"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Mohamed A Gouda"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Harold N Tan"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Carlos Torrado Martin"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Jordi Rodon"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Timothy A Yap"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Ecaterina E Dumbrava"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Sarina A Piha-Paul"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Apostolia M Tsimberidou"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Siqing Fu"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "David S Hong"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Funda Meric-Bernstam"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Aung Naing"
    }
  ],
  "title": "532 A phase 1 dose escalation and dose expansion trial of NP-101 in patients with advanced solid tumors",
  "uid": "c0dabc63-c6a3-5435-9ca7-afecf6111b5b"
}