MTD Determination, Safety and Efficacy of the Decitabine-Genistein Drug Combination in Advanced Solid Tumors and Non-Small Cell Lung Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2012 by Uman Pharma
Sponsor:
Collaborators:
DSM Nutritional Products, Inc.
MDEIE Ministry, Québec Government
INRS-Institut Armand Frappier , Université du Québec
Information provided by (Responsible Party):
Uman Pharma
ClinicalTrials.gov Identifier:
NCT01628471
First received: May 9, 2012
Last updated: January 17, 2013
Last verified: November 2012
  Purpose

Lung cancer is one of the most prevalent and lethal neoplasias in the world. Currently used chemotherapy regimens have been disappointing in improving overall survival. Decitabine is a S-phase pyrimidine analog that induces DNA hypomethylation. This drug is currently used to treat Myelodysplastic Syndrome ( MDS) and has been studied for the treatment of leukemia. Genistein, is a soy extracted non-toxic isoflavone and phytoestrogen, which has been shown to inhibit activity of cell signaling pathways, such as those driven by tyrosine kinases. Results from in vitro experiments unambiguously demonstrated that the combination of these two compounds induces a synergistic reduction of the multiplication of lung, colon, breast and leukemic cancer cells. Consequently, clinical evaluation of this drug combination is warranted in Non Small Cell Lung Cancer ( NSCLC), and it is hypothezised that this new regimen will safely improve overall tumor response rate and cancer progression free survival.

The proposed trial is a two part study: The phase I part is an open-label, dose-escalation evaluation in subjects with advanced solid tumors who have failed standard therapies and for whom no curative therapeutic option exists.

A cohort of three subjects will be treated per dose level. One cycle is 28 days. Five different, increasing dose levels ranging from 60 mg/m2 to 500 mg/m2 of IV decitabine combined with a fixed oral dose of 150 mg BID of genistein will be tested. The Maximum Tolerated Dose (MTD) will be determined based on the occurrence of Dose Limiting Toxicities (DLTs).

In the phase IIa part of the study, only Stage IIIb and IV advanced NSCLC patients will be treated at the recommended decitabine MTD dose combined with genistein. Safety and preliminary efficacy will be assessed. It is expected that a maximum sample of 46 patients will be enrolled in this trial.


Condition Intervention Phase
Non Small Cell Lung Cancer
Drug: decitabine in combination with genistein
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/IIa Dose-Escalation Study of the Decitabine-Genistein Drug Combination in Advanced Solid Tumors and Non-Small Cell Lung Cancer (NSCLC) Subjects

Resource links provided by NLM:


Further study details as provided by Uman Pharma:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: 28 day treatment cycle for MTD assessment; 4-6 cycles to be administered ] [ Designated as safety issue: Yes ]
    MTD determination will based on the incidence of reported adverse events (including dose-limiting toxicities) and abnormal laboratory test results.


Secondary Outcome Measures:
  • To determine the drug plasma concentrations of decitabine and genistein. [ Time Frame: Up to 6 , 28 day treatment cycles ] [ Designated as safety issue: No ]
    Plasma drug levels will be used to obtain preliminary PK profile. Up to 11 blood samples to be obtained from each enrolled patient, over several cycles.

  • Preliminary clinical efficacy assessment [ Time Frame: Up to 6, 28 day treatment cycles ] [ Designated as safety issue: No ]
    Preliminary efficacy of the investigational regimen will include the assessment of Overall Response Rate ( ORR) and Progression Free Survival(PFS)


Estimated Enrollment: 46
Study Start Date: November 2012
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Decitabine + genistein single arm
decitabine injectable, by infusion, 5 ascending doses (60 to 500 mg/m2) genisteine capsules, 3 x 50 mg capsules twice a day
Drug: decitabine in combination with genistein
decitabine IV infusion ( 10 hrs total), doses from 60 to 500 mg/m2 + fixed daily oral dose of 300 mg genisteine

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written Informed Consent.
  • Males or females.
  • 18-75 years.
  • Histologically or cytologically confirmed non-estrogen dependent advanced solid malignancy who has failed standard therapies and/or for which no curative therapeutic option exists (phase I) or ;
  • Histologically or cytologically confirmed NSCLC of stage IIIb or IV (phase IIa) that has failed or is ineligible to standard therapies.
  • One or more tumor lesions measurable by RECIST criteria
  • Life expectancy of at least 3 months.
  • ECOG performance of 2 or less.

Exclusion Criteria:

  • Prior decitabine or genistein therapy.
  • Received cytotoxic agent, hormonal therapy, radiation therapy, or other targeted cancer therapies or investigational agent within 4 weeks prior to study entry.
  • Patients with confirmed estrogen receptor-positive cancers, or patients with a primary breast or endometrial cancer for which phenotyping analysis has not been performed.
  • Presence of uncontrolled brain metastases or leptomeningeal disease.
  • Uncontrolled cardiovascular disorders, including symptomatic heart failure, unstable angina and cardiac arrhythmias.
  • Inadequate baseline organ function as shown by following laboratory values :

    • Hemoglobin < 90 g/L
    • Absolute neutrophil count < 1,500 /microliter
    • Platelet count < 100,000 /microliter
    • Total bilirubin > 1.5 ULN
    • AST and ALT > 2.5 ULN
    • Creatinine clearance < 60 ml/min
  • To be dependent of oxygen treatment.
  • Active infections requiring antibiotics.
  • Pregnancy or breastfeeding. All women of child-bearing potential must have a negative pregnancy test prior to first receiving protocol therapy.
  • Known allergic reactions to soy derivatives or deoxycytidine derivatives.
  • Active alcohol or drug abuse.
  • Any co-morbid condition that in the judgment of the investigator renders the subject at high risk of treatment complication or reduces the probability of assessing clinical effect.
  • Other malignancies diagnosed within the last 5 years with the exception of Basal Cell Carcinoma of the skin.
  • Gastrointestinal disorders or abnormalities that may interfere with the absorption of genistein.
  • Patients unable to comply with the study protocol and follow-up schedule for any psychological, familial, sociological or geographical reason.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01628471

Contacts
Contact: Luc Daigneault, PhD 450- 629-2200 ext 227 ldaigneault@scimega.com
Contact: Patrick Colin, B.Pharm PhD 450-482 3530 pcolin@videotron.ca

Locations
Canada, Quebec
Hôpital Notre Dame du CHUM Recruiting
Montreal, Quebec, Canada, H2L 4M1
Contact: Normand Blais, MD, MSc, FRCP(C)    (514) 890-8000 ext 25381    n.blais@umontreal.ca   
Principal Investigator: Normand Blais, MD, FRCP(C)         
Sponsors and Collaborators
Uman Pharma
DSM Nutritional Products, Inc.
MDEIE Ministry, Québec Government
INRS-Institut Armand Frappier , Université du Québec
Investigators
Principal Investigator: Normand Blais, MD, FRCP(C) Hôpital Notre Dame du CHUM
  More Information

Additional Information:
No publications provided

Responsible Party: Uman Pharma
ClinicalTrials.gov Identifier: NCT01628471     History of Changes
Other Study ID Numbers: UMAN-10-01
Study First Received: May 9, 2012
Last Updated: January 17, 2013
Health Authority: Canada: Health Canada

Keywords provided by Uman Pharma:
Phase I b : advanced solid malignancy
Phase II a: stage III b or IV, Non Small Cell Lung Cancer

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Bronchial Neoplasms
Carcinoma, Bronchogenic
Lung Diseases
Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Decitabine
Genistein
Anticarcinogenic Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Estrogens
Estrogens, Non-Steroidal
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Phytoestrogens
Protective Agents
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014