Colon Cancer, Colorectal Cancer, Rectal Cancer
Conditions
Keywords
Genistein, soy supplements, phytoestrogens, colon cancer, rectal cancer, colorectal cancer, metastatic, stage IV, FOLFOX, FOLFOX-Avastin, Chemotherapy
Brief 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.
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)
Interventions
DRUGGenistein
Genistein combined with FOLFOX or FOLFOX-Avastin
Sponsors
DSM Nutritional Products, Inc.
Sofya Pintova
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events | up to 6 months | Number of adverse events to assess tolerability of genistein treatment. Evaluation of side effects conducted every 14 days before each chemotherapy/genistein cycle. |
| Percent Change in Tumor Size | end of Cycle 6 | Percent change in tumor size after cycle 6. Each cycle is 21 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate RECIST Criteria | up to 50 months | 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. |
| Number of Participants With Best Overall Response Rate (ORR) | up to 50 months | 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. |
| Response Rate RECIST Criteria | end of Cycle 6 | 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. |
| Percent of Patients With Progression Free Survival (PFS) at 6 Months and 12 Months | 6 month and 12 month | 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. |
| Overall Survival (OS) | up to 50 months | Overall Survival - Number of months still living since baseline |
| Progression Free Survival (PFS) | up to 50 months | 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. |
| Number of Participants With an Overall Response Rate (ORR) | up to 50 months | Number of participants with an ORR - the portion of patients with a tumor size reduction of a predefined amount for a minimum time period |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Genistein Genistein combined with FOLFOX or FOLFOX-Avastin Genistein 60mg/day orally for 7 days every 2 weeks. Genistein administered beginning 4 days prior to FOLFOX or FOLFOX-Avastin and continuing the 3 days of chemotherapy. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Genistein |
|---|---|
| Age, Continuous | 61 years |
| BRAF V600F Mutated | 0 Participants |
| BRAF V600F Unknown | 2 Participants |
| BRAF V600F WT | 11 Participants |
| ECOG 0 | 8 Participants |
| ECOG 1 | 5 Participants |
| KRAS/NRAS Mutated | 6 Participants |
| KRAS/NRAS Unknown | 2 Participants |
| KRAS/NRAS Wild Type (WT) | 5 Participants |
| Number of Metastatic Sites 1 | 8 Participants |
| Number of Metastatic Sites 2 | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 9 Participants |
| Tumor Location Left Colon | 10 Participants |
| Tumor Location Right Colon | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 13 / 13 | 13 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
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.
Time frame: up to 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Genistein | Number of Adverse Events | Grade 1 | 250 events |
| Genistein | Number of Adverse Events | Grade 2 | 119 events |
| Genistein | Number of Adverse Events | Grade 3 | 24 events |
| Genistein | Number of Adverse Events | Grade 4 | 0 events |
Primary
Percent Change in Tumor Size
Percent change in tumor size after cycle 6. Each cycle is 21 days.
Time frame: end of Cycle 6
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Genistein | Percent Change in Tumor Size | -43.0 Percent change |
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.
Time frame: up to 50 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Genistein | Best Overall Response Rate RECIST Criteria | Not evaluable | 2 Participants |
| Genistein | Best Overall Response Rate RECIST Criteria | PR | 6 Participants |
| Genistein | Best Overall Response Rate RECIST Criteria | SD | 3 Participants |
| Genistein | Best Overall Response Rate RECIST Criteria | PD | 2 Participants |
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
Time frame: up to 50 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Genistein | Number of Participants With an Overall Response Rate (ORR) | 6 Participants |
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.
Time frame: up to 50 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Genistein | Number of Participants With Best Overall Response Rate (ORR) | 8 Participants |
Secondary
Overall Survival (OS)
Overall Survival - Number of months still living since baseline
Time frame: up to 50 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Genistein | Overall Survival (OS) | 36.5 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.
Time frame: 6 month and 12 month
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Genistein | Percent of Patients With Progression Free Survival (PFS) at 6 Months and 12 Months | 6 months | 69 percentage of participants |
| Genistein | Percent of Patients With Progression Free Survival (PFS) at 6 Months and 12 Months | 12 months | 38 percentage of participants |
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.
Time frame: up to 50 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Genistein | Progression Free Survival (PFS) | 11.5 months |
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.
Time frame: end of Cycle 6
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Genistein | Response Rate RECIST Criteria | Not evaluable | 2 Participants |
| Genistein | Response Rate RECIST Criteria | SD | 1 Participants |
| Genistein | Response Rate RECIST Criteria | PD | 2 Participants |
| Genistein | Response Rate RECIST Criteria | PR | 8 Participants |