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This is a Phase I Trial evaluating the safety of the dietary supplement honokiol for lung cancer chemoprevention. Female or male patients aged 18 years, or older, with early stage lung cancer who have been scheduled for curative surgery will be eligible for participation in the study. The study will only enroll patients with stage I lung cancers less than 4 cm, given the recent approval of neoadjuvant chemotherapy and nivolumab for stage IB tumors > 4 cm. Approximately, 15 patients will be enrolled in the study. They will take the study drug, honokiol, for 2 weeks prior to the surgery. The primary endpoint will be the Maximum Tolerated Dose (MTD) of honokiol.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Honokiol | Experimental | Approximately, 15 patients will be enrolled in the study. They will take the study drug, honokiol, for 2 weeks prior to the surgery. The primary endpoint will be the maximum tolerated dose (MTD) of honokiol and this will be determined using Bayesian Optimal Interval Design (BOIN) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Honokiol | Drug | Honokiol will be given orally at a starting dose of 1 capsule (250 mg/ capsule) per day for 2 weeks. Dose levels will escalate based on dose-limiting toxicity occurrence. We will start at one capsule (250 mg) once daily, dose 0 would be one capsule (250 mg) twice daily, dose +1 would be 500mg in the AM and 250mg in the evening, and +2 would be 500 mg twice daily. |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Tolerated Dose of Honokiol therapy | To determine the maximum tolerated dose (MTD) of honokiol therapy in patients with stage I NSCLC, less than 4 cm, who will undergo surgical resection. Review the safety data to determine the dose level at which the maximum tolerable level of toxicity is observed and select as the MTD the dose for which the isotonic estimate of the DLT rate is closest to the target DLT rate. | From treatment initiation of each patient, assessed up to 21 days after treatment initiation of final patient, up to 2 years after first enrollment. |
| Measure | Description | Time Frame |
|---|---|---|
| Dose Limiting Toxicities of Honokiol therapy | To determine the dose-limiting toxicity (DLT) and other toxicities associated with honokiol therapy, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0; | DLT period will start with initial treatment dose until 21 days after. |
| Measure | Description | Time Frame |
|---|---|---|
| Tissue immune correlative biomarkers of honokiol therapy | To evaluate tissue immune correlative biomarkers of honokiol therapy, including but not limited to Ki67, a good standard for the measurement of cell proliferation. | From pre-intervention blood collection to post-intervention blood collection, an average of 2 weeks. |
Inclusion Criteria:
The patient provides written informed consent for the trial. Spanish speaking patients will be included and translation services will be provided as needed.
Male or female, 18 years of age or older, on the day of informed consent signing.
Early stage NSCLC eligible for upfront definitive surgical resection
Measurable disease according to the Response evaluation criteria in solid tumors (RECIST 1.1) within 30 days of treatment.
Expected life expectancy of at least 6 months
Adequate organ and marrow function as defined below:
Hemoglobin ≥9.0 g/dl (without blood transfusion within 2 weeks of laboratory test used to determine eligibility) Absolute neutrophil count ≥1000/μL (without granulocyte colony stimulating factor support within 2 weeks of laboratory test used to determine eligibility) Platelet count ≥100,000/μL (without transfusion within 2 weeks of laboratory test used to determine eligibility)- Serum total bilirubin (TB) ≤1.5 x institutional upper limit of normal (ULN; In the case of known Gilbert's syndrome, a higher serum TB [>1.5 x ULN] is allowed), Aspartate transaminase/alanine transaminase ≤5 x institutional ULN Creatinine ≤1.5X the ULN or measured creatinine clearance ≥ 60 mL/min/1.
Willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits and examinations.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jun Zhang, MD | Contact | 713-441-6698 | jzhang22@houstonmethodist.org |
| Name | Affiliation | Role |
|---|---|---|
| Jun Zhang, MD | Houston Methodist Neal Cancer Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Houston Methodist Neal Cancer Center | Recruiting | Houston | Texas | 77030 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18775299 | Background | Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008 Sep 5;134(5):703-7. doi: 10.1016/j.cell.2008.08.021. | |
| 20699334 | Background | Barger JF, Plas DR. Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis. Endocr Relat Cancer. 2010 Sep 23;17(4):R287-304. doi: 10.1677/ERC-10-0106. Print 2010 Dec. |
| Label | URL |
|---|---|
| Honokiol, magnolia bark, A miracle cure for cancer? | View source |
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| ID | Term |
|---|---|
| D002289 | Carcinoma, Non-Small-Cell Lung |
| ID | Term |
|---|---|
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D008175 | Lung Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
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| ID | Term |
|---|---|
| C005499 | honokiol |
| D019587 | Dietary Supplements |
| ID | Term |
|---|---|
| D005502 | Food |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |
| D019602 | Food and Beverages |
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| Recommended Phase 2 Dose of Honokiol therapy |
To determine the recommended Phase II dose (RP2D) of honokiol; Bayesian Optimal Interval (BOIN) design will be used for dose finding. |
| From initial treatment dose until 21 days after. |
| Number of participants with tumor necrosis | To assess for any evidence of tumor necrosis. | From screening tissue collection to post-intervention tissue collection, an average of 3 months. |
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | To determine the safety and tolerability of honokiol therapy prior to surgery as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. | The safety period will start at baseline and will be assessed through study completion, up to 2 months |
| 22431711 | Background | Cheng G, Zielonka J, Dranka BP, McAllister D, Mackinnon AC Jr, Joseph J, Kalyanaraman B. Mitochondria-targeted drugs synergize with 2-deoxyglucose to trigger breast cancer cell death. Cancer Res. 2012 May 15;72(10):2634-44. doi: 10.1158/0008-5472.CAN-11-3928. Epub 2012 Mar 19. |
| 11331019 | Background | Liu H, Hu YP, Savaraj N, Priebe W, Lampidis TJ. Hypersensitization of tumor cells to glycolytic inhibitors. Biochemistry. 2001 May 8;40(18):5542-7. doi: 10.1021/bi002426w. |
| 19072739 | Background | Kurtoglu M, Lampidis TJ. From delocalized lipophilic cations to hypoxia: blocking tumor cell mitochondrial function leads to therapeutic gain with glycolytic inhibitors. Mol Nutr Food Res. 2009 Jan;53(1):68-75. doi: 10.1002/mnfr.200700457. |
| 6848187 | Background | Lampidis TJ, Bernal SD, Summerhayes IC, Chen LB. Selective toxicity of rhodamine 123 in carcinoma cells in vitro. Cancer Res. 1983 Feb;43(2):716-20. |
| 19716393 | Background | Pathania D, Millard M, Neamati N. Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism. Adv Drug Deliv Rev. 2009 Nov 30;61(14):1250-75. doi: 10.1016/j.addr.2009.05.010. Epub 2009 Aug 27. |
| 15526365 | Background | Chen F, Wang T, Wu YF, Gu Y, Xu XL, Zheng S, Hu X. Honokiol: a potent chemotherapy candidate for human colorectal carcinoma. World J Gastroenterol. 2004 Dec 1;10(23):3459-63. doi: 10.3748/wjg.v10.i23.3459. |
| 8061832 | Background | Tsai TH, Chou CJ, Cheng FC, Chen CF. Pharmacokinetics of honokiol after intravenous administration in rats assessed using high-performance liquid chromatography. J Chromatogr B Biomed Appl. 1994 Apr 22;655(1):41-5. doi: 10.1016/0378-4347(94)00031-x. |
| 10688873 | Background | Sporn MB, Suh N. Chemoprevention of cancer. Carcinogenesis. 2000 Mar;21(3):525-30. doi: 10.1093/carcin/21.3.525. |
| 9790544 | Background | Lippman SM, Lee JJ, Sabichi AL. Cancer chemoprevention: progress and promise. J Natl Cancer Inst. 1998 Oct 21;90(20):1514-28. doi: 10.1093/jnci/90.20.1514. No abstract available. |
| 10711244 | Background | Kelloff GJ, Sigman CC, Greenwald P. Cancer chemoprevention: progress and promise. Eur J Cancer. 1999 Dec;35(14):2031-8. doi: 10.1016/s0959-8049(99)00299-3. |
| 22466367 | Background | Xu HL, Tang W, Du GH, Kokudo N. Targeting apoptosis pathways in cancer with magnolol and honokiol, bioactive constituents of the bark of Magnolia officinalis. Drug Discov Ther. 2011 Oct;5(5):202-10. doi: 10.5582/ddt.2011.v5.5.202. |
| 16807544 | Background | Chiang CK, Sheu ML, Hung KY, Wu KD, Liu SH. Honokiol, a small molecular weight natural product, alleviates experimental mesangial proliferative glomerulonephritis. Kidney Int. 2006 Aug;70(4):682-9. doi: 10.1038/sj.ki.5001617. |
| 25245764 | Background | Pan J, Zhang Q, Liu Q, Komas SM, Kalyanaraman B, Lubet RA, Wang Y, You M. Honokiol inhibits lung tumorigenesis through inhibition of mitochondrial function. Cancer Prev Res (Phila). 2014 Nov;7(11):1149-59. doi: 10.1158/1940-6207.CAPR-14-0091. Epub 2014 Sep 22. |
| 19880244 | Background | Chen YJ, Wu CL, Liu JF, Fong YC, Hsu SF, Li TM, Su YC, Liu SH, Tang CH. Honokiol induces cell apoptosis in human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress. Cancer Lett. 2010 May 1;291(1):20-30. doi: 10.1016/j.canlet.2009.08.032. Epub 2009 Oct 31. |
| 17938262 | Background | Hahm ER, Singh SV. Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity. Mol Cancer Ther. 2007 Oct;6(10):2686-95. doi: 10.1158/1535-7163.MCT-07-0217. |
| 18594009 | Background | Garcia A, Zheng Y, Zhao C, Toschi A, Fan J, Shraibman N, Brown HA, Bar-Sagi D, Foster DA, Arbiser JL. Honokiol suppresses survival signals mediated by Ras-dependent phospholipase D activity in human cancer cells. Clin Cancer Res. 2008 Jul 1;14(13):4267-74. doi: 10.1158/1078-0432.CCR-08-0102. |
| 19483651 | Background | Crane C, Panner A, Pieper RO, Arbiser J, Parsa AT. Honokiol-mediated inhibition of PI3K/mTOR pathway: a potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function. J Immunother. 2009 Jul-Aug;32(6):585-92. doi: 10.1097/CJI.0b013e3181a8efe6. |
| 16181613 | Background | Tse AK, Wan CK, Shen XL, Yang M, Fong WF. Honokiol inhibits TNF-alpha-stimulated NF-kappaB activation and NF-kappaB-regulated gene expression through suppression of IKK activation. Biochem Pharmacol. 2005 Nov 15;70(10):1443-57. doi: 10.1016/j.bcp.2005.08.011. Epub 2005 Sep 21. |
| 18507762 | Background | Deng J, Qian Y, Geng L, Chen J, Wang X, Xie H, Yan S, Jiang G, Zhou L, Zheng S. Involvement of p38 mitogen-activated protein kinase pathway in honokiol-induced apoptosis in a human hepatoma cell line (hepG2). Liver Int. 2008 Dec;28(10):1458-64. doi: 10.1111/j.1478-3231.2008.01767.x. Epub 2008 May 26. |
| 21935912 | Background | Steinmann P, Walters DK, Arlt MJ, Banke IJ, Ziegler U, Langsam B, Arbiser J, Muff R, Born W, Fuchs B. Antimetastatic activity of honokiol in osteosarcoma. Cancer. 2012 Apr 15;118(8):2117-27. doi: 10.1002/cncr.26434. Epub 2011 Sep 20. |
| 16115372 | Background | Hu H, Zhang XX, Wang YY, Chen SZ. Honokiol inhibits arterial thrombosis through endothelial cell protection and stimulation of prostacyclin. Acta Pharmacol Sin. 2005 Sep;26(9):1063-8. doi: 10.1111/j.1745-7254.2005.00164.x. |
| Bayesian Optimal Interval Designs for Phase I Clinical Trials | View source |
| D013899 |
| Thoracic Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |