Genistein in Treatment of Metastatic Colorectal Cancer

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01985763
• Other study ID #: GCO 13-1697
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 2013
• Est. completion date: October 31, 2018

Study information

• Verified date: April 2019
• Source: Icahn School of Medicine at Mount Sinai
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 13
• Est. completion date: October 31, 2018
• Est. primary completion date: January 19, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colon Cancer
• Colonic Neoplasms
• Colorectal Cancer
• Colorectal Neoplasms
• Rectal Cancer
• Rectal Neoplasms

Intervention

Drug:
• Genistein
Genistein combined with FOLFOX or FOLFOX-Avastin

Locations

Country	Name	City	State
United States	Icahn School of Medicine at Mount Sinai	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Sofya Pintova	DSM Nutritional Products, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (25)

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. — View Citation

DeCosse JJ, Ngoi SS, Jacobson JS, Cennerazzo WJ. Gender and colorectal cancer. Eur J Cancer Prev. 1993 Mar;2(2):105-15. Review. — View Citation

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. — View Citation

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. — View Citation

Hébert-Croteau N. A meta-analysis of hormone replacement therapy and colon cancer in women. Cancer Epidemiol Biomarkers Prev. 1998 Aug;7(8):653-9. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum in: Cancer Res. 2005 Dec 1;65(23):11228. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Nishi M, Yoshida K, Hirata K, Miyake H. Eating habits and colorectal cancer. Oncol Rep. 1997 Sep-Oct;4(5):995-8. — View Citation

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. — View Citation

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. — View Citation

Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Percent Change in Tumor Size	Percent change in tumor size after cycle 6. Each cycle is 21 days.	end of Cycle 6
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Overall Survival (OS)	Overall Survival - Number of months still living since baseline	up to 50 months