Genistein in Treatment of Metastatic Colorectal Cancer

Genistein Combined With FOLFOX or FOLFOX-Avastin for Treatment of Metastatic Colorectal Cancer: Phase I/II Pilot Study

Colorectal neoplasms are the third most common malignancies in the United States. Patients with metastatic (stage IV) colorectal cancer have a median life expectancy of 2 years. The response rates to chemotherapy range from 35-40%.

Epidemiologic evidence suggests that soy compounds may reduce the incidence of colorectal cancers. Laboratory analyses demonstrate that genistein, a soy-derived compound, may inhibit Wnt signaling, a pathway activated in majority of colorectal cancers. Laboratory observations also demonstrate that genistein may augment growth inhibition when combined with chemotherapeutic agents of 5-Fluorouracil and platinum compounds.

Based on pre-clinical data the investigators hypothesize that combining genistein with the standard of care chemotherapeutic regimens will reduce chemotherapy resistance and improve response rates in patients. The aim of the study is to add genistein to the regimens of FOLFOX or FOLFOX-Avastin in patients with newly diagnosed stage IV colon or rectal neoplasms.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Rectal Cancer; Colon Cancer
• Intervention / Treatment: Drug: Genistein

Detailed Description

OBJECTIVES:

Primary

• Evaluate the tolerability of genistein when combined with chemotherapy

Secondary:

• Evaluate Response Rate (RR) as measured by the radiologic RECIST criteria
• Evaluate Progression Free Survival (PFS)

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult male and female patients ≥18 years old
• Have pathologically confirmed colon or rectal carcinoma
• Have metastatic (stage IV) disease
• Have a plan by treating physician to receive FOLFOX or FOLFOX-Avastin
• Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2

• Have adequate hematopoietic, hepatic and renal function

  1. Hematopoietic function

     • Hemoglobin ≥10g/dL
     • Absolute Neutrophil Count(ANC) ≥1,500cells/mm2
     • Platelet Count ≥100,000/µL

  2. Hepatic Function

     • Total bilirubin ≤ 1.5x the upper limit of normal
     • ALT and AST must each be ≤2,5x the upper limits of normal

  3. Renal Function

     • Estimated creatinine clearance (Clcr) ≥30 mL/minute
• Are not pregnant and do not plan to become pregnant

Exclusion Criteria:

• Prior systemic chemotherapy for metastatic disease
• History of breast cancer, endometrial cancer or ovarian cancer or taking aromatase inhibitors or selective estrogen receptor modulators
• Patients taking MAO-inhibitors
• History of myocardial infarctions or cardiac stent placement less than 1 year before recruitment into the study
• Unable to give informed consent or comply with clinical trial requirements
• Uncontrolled hypertension
• History of clinically significant GI bleeding within prior 2 months prior to enrollment
• Presence of GI fistula
• Prior history of bowel perforation
• History of CNS thrombotic/embolic or ischemic events
• Have past or current, acute or chronic concurrent medical condition/illness or therapy that, in the opinion of the investigator, would make the subject unsuitable for the clinical trial or unable to comply with the follow up visits.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Genistein; Genistein combined with FOLFOX or FOLFOX-Avastin Genistein 60mg/day orally for 7 days every 2 weeks. Genistein will be administered beginning 4 days prior to FOLFOX or FOLFOX-Avastin and continuing the 3 days of chemotherapy.	Drug: Genistein; Genistein combined with FOLFOX or FOLFOX-Avastin; Other Names: Bonistein

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Adverse Events	Number of adverse events to assess tolerability of genistein treatment. Evaluation of side effects conducted every 14 days before each chemotherapy/genistein cycle.	up to 6 months
Percent Change in Tumor Size	Percent change in tumor size after cycle 6. Each cycle is 21 days.	end of Cycle 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate RECIST Criteria	Response Rate (RR) as measured by radiologic RECIST criteria. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.	end of Cycle 6
Number of Participants With an Overall Response Rate (ORR)	Number of participants with an ORR - the portion of patients with a tumor size reduction of a predefined amount for a minimum time period	up to 50 months
Best Overall Response Rate RECIST Criteria	Best Overall Response Rate (ORR) as measured by radiologic RECIST criteria. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. SD - target lesion SD, non target lesions Non-PD, and no new lesions. PR - target lesion CR, non target lesions Incomplete response/SD and no new lesions; or target lesion PR, non target lesions Non-PD, and no new lesions. PD - target lesions PD, non target lesions Any, can have new lesions; or target lesions Any, non target lesions PD, can have new lesions; or target lesions Any, non target lesions Any, have new lesions.	up to 50 months
Number of Participants With Best Overall Response Rate (ORR)	The number of participants with best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.	up to 50 months
Progression Free Survival (PFS)	Patients monitored for progression. Progression-free survival (PFS) is the length of time during and after the treatment that a patient lives with the disease but it does not get worse.	up to 50 months
Percent of Patients With Progression Free Survival (PFS) at 6 Months and 12 Months	Patients monitored for progression during the study period and 1 year following. Progression-free survival (PFS) is the length of time during and after the treatment that a patient lives with the disease but it does not get worse.	6 month and 12 month
Overall Survival (OS)	Overall Survival - Number of months still living since baseline	up to 50 months

Collaborators and Investigators

• Sponsor: Sofya Pintova
• Collaborators: DSM Nutritional Products, Inc.
• Investigators: Principal Investigator: Sofya Pintova, MD, Icahn School of Medicine at Mount Sinai

Publications and helpful links

General Publications

• Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26(12):2013-9. doi: 10.1200/JCO.2007.14.9930. Erratum In: J Clin Oncol. 2008 Jun;26(18):3110. J Clin Oncol. 2009 Feb 1;27(4):653.
• DeCosse JJ, Ngoi SS, Jacobson JS, Cennerazzo WJ. Gender and colorectal cancer. Eur J Cancer Prev. 1993 Mar;2(2):105-15. doi: 10.1097/00008469-199303000-00003.
• Hebert-Croteau N. A meta-analysis of hormone replacement therapy and colon cancer in women. Cancer Epidemiol Biomarkers Prev. 1998 Aug;7(8):653-9.
• Haenszel W, Berg JW, Segi M, Kurihara M, Locke FB. Large-bowel cancer in Hawaiian Japanese. J Natl Cancer Inst. 1973 Dec;51(6):1765-79. doi: 10.1093/jnci/51.6.1765. No abstract available.
• Hu JF, Liu YY, Yu YK, Zhao TZ, Liu SD, Wang QQ. Diet and cancer of the colon and rectum: a case-control study in China. Int J Epidemiol. 1991 Jun;20(2):362-7. doi: 10.1093/ije/20.2.362.
• Nishi M, Yoshida K, Hirata K, Miyake H. Eating habits and colorectal cancer. Oncol Rep. 1997 Sep-Oct;4(5):995-8. doi: 10.3892/or.4.5.995.
• Kono S, Imanishi K, Shinchi K, Yanai F. Relationship of diet to small and large adenomas of the sigmoid colon. Jpn J Cancer Res. 1993 Jan;84(1):13-9. doi: 10.1111/j.1349-7006.1993.tb02777.x.
• Witte JS, Longnecker MP, Bird CL, Lee ER, Frankl HD, Haile RW. Relation of vegetable, fruit, and grain consumption to colorectal adenomatous polyps. Am J Epidemiol. 1996 Dec 1;144(11):1015-25. doi: 10.1093/oxfordjournals.aje.a008872.
• Pereira MA, Barnes LH, Rassman VL, Kelloff GV, Steele VE. Use of azoxymethane-induced foci of aberrant crypts in rat colon to identify potential cancer chemopreventive agents. Carcinogenesis. 1994 May;15(5):1049-54. doi: 10.1093/carcin/15.5.1049.
• Helms JR and Gallaher DD, The effect of dietary soy protein isolate and genistein on the development of preneoplastic lesions (aberrant crypts) in rats. 1995 Cancer Lett:125
• Thiagarajan DG, Bennink MR, Bourquin LD, Kavas FA. Prevention of precancerous colonic lesions in rats by soy flakes, soy flour, genistein, and calcium. Am J Clin Nutr. 1998 Dec;68(6 Suppl):1394S-1399S. doi: 10.1093/ajcn/68.6.1394S.
• Li Y, Ahmed F, Ali S, Philip PA, Kucuk O, Sarkar FH. Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells. Cancer Res. 2005 Aug 1;65(15):6934-42. doi: 10.1158/0008-5472.CAN-04-4604. Erratum In: Cancer Res. 2005 Dec 1;65(23):11228.
• Linsalata M, Russo F, Notarnicola M, Guerra V, Cavallini A, Clemente C, Messa C. Effects of genistein on the polyamine metabolism and cell growth in DLD-1 human colon cancer cells. Nutr Cancer. 2005;52(1):84-93. doi: 10.1207/s15327914nc5201_11.
• Qi W, Weber CR, Wasland K, Savkovic SD. Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity. BMC Cancer. 2011 Jun 3;11:219. doi: 10.1186/1471-2407-11-219.
• Miyaki M, Konishi M, Kikuchi-Yanoshita R, Enomoto M, Igari T, Tanaka K, Muraoka M, Takahashi H, Amada Y, Fukayama M, et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 1994 Jun 1;54(11):3011-20.
• Zhang Y, Chen H. Genistein attenuates WNT signaling by up-regulating sFRP2 in a human colon cancer cell line. Exp Biol Med (Maywood). 2011 Jun 1;236(6):714-22. doi: 10.1258/ebm.2011.010347. Epub 2011 May 13.
• Hwang JT, Ha J, Park OJ. Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways. Biochem Biophys Res Commun. 2005 Jul 1;332(2):433-40. doi: 10.1016/j.bbrc.2005.04.143.
• Solomon LA, Ali S, Banerjee S, Munkarah AR, Morris RT, Sarkar FH. Sensitization of ovarian cancer cells to cisplatin by genistein: the role of NF-kappaB. J Ovarian Res. 2008 Nov 24;1(1):9. doi: 10.1186/1757-2215-1-9.
• Yanhong H, et al, Genistein sensitizes ovarian carcinoma cells to chemotherapy by switching the cell cycle progression in vitro. J Medical Colleges of PLA:125-135
• Metzner JE, Frank T, Kunz I, Burger D, Riegger C. Study on the pharmacokinetics of synthetic genistein after multiple oral intake in post-menopausal women. Arzneimittelforschung. 2009;59(10):513-20. doi: 10.1055/s-0031-1296435.
• Setchell KD, Faughnan MS, Avades T, Zimmer-Nechemias L, Brown NM, Wolfe BE, Brashear WT, Desai P, Oldfield MF, Botting NP, Cassidy A. Comparing the pharmacokinetics of daidzein and genistein with the use of 13C-labeled tracers in premenopausal women. Am J Clin Nutr. 2003 Feb;77(2):411-9. doi: 10.1093/ajcn/77.2.411.
• Takimoto CH, Glover K, Huang X, Hayes SA, Gallot L, Quinn M, Jovanovic BD, Shapiro A, Hernandez L, Goetz A, Llorens V, Lieberman R, Crowell JA, Poisson BA, Bergan RC. Phase I pharmacokinetic and pharmacodynamic analysis of unconjugated soy isoflavones administered to individuals with cancer. Cancer Epidemiol Biomarkers Prev. 2003 Nov;12(11 Pt 1):1213-21.
• Fischer L, Mahoney C, Jeffcoat AR, Koch MA, Thomas BE, Valentine JL, Stinchcombe T, Boan J, Crowell JA, Zeisel SH. Clinical characteristics and pharmacokinetics of purified soy isoflavones: multiple-dose administration to men with prostate neoplasia. Nutr Cancer. 2004;48(2):160-70. doi: 10.1207/s15327914nc4802_5.
• Ullmann U, Oberwittle H, Grossmann M, Riegger C. Repeated oral once daily intake of increasing doses of the novel synthetic genistein product Bonistein in healthy volunteers. Planta Med. 2005 Oct;71(10):891-6. doi: 10.1055/s-2005-864186.
• Busby MG, Jeffcoat AR, Bloedon LT, Koch MA, Black T, Dix KJ, Heizer WD, Thomas BF, Hill JM, Crowell JA, Zeisel SH. Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men. Am J Clin Nutr. 2002 Jan;75(1):126-36. doi: 10.1093/ajcn/75.1.126.
• Pintova S, Dharmupari S, Moshier E, Zubizarreta N, Ang C, Holcombe RF. Genistein combined with FOLFOX or FOLFOX-Bevacizumab for the treatment of metastatic colorectal cancer: phase I/II pilot study. Cancer Chemother Pharmacol. 2019 Sep;84(3):591-598. doi: 10.1007/s00280-019-03886-3. Epub 2019 Jun 15.

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): January 19, 2017
• Study Completion (Actual): October 31, 2018

Study Registration Dates

• First Submitted: November 9, 2013
• First Submitted That Met QC Criteria: November 14, 2013
• First Posted (Estimate): November 15, 2013

Study Record Updates

• Last Update Posted (Actual): May 10, 2019
• Last Update Submitted That Met QC Criteria: April 18, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: colorectal cancer; rectal cancer; colon cancer; Chemotherapy; metastatic; FOLFOX; Genistein; stage IV; soy supplements; phytoestrogens; FOLFOX-Avastin
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Colonic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Estrogens, Non-Steroidal; Estrogens; Protein Kinase Inhibitors; Anticarcinogenic Agents; Phytoestrogens; Genistein
• Other Study ID Numbers: GCO 13-1697