Hormone-Resistant Prostate Cancer, Metastatic Prostate Carcinoma, Stage IV Prostate Cancer
Conditions
Brief summary
This randomized phase II trial studies how well docetaxel works when given with or without ascorbic acid in treating patients with prostate cancer that has spread to other places in the body. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ascorbic acid (vitamin C) is a water-soluble vitamin that may help inhibit the growth of cancer cells. It is not yet known whether docetaxel works better when given with or without ascorbic acid in treating prostate cancer.
Interventions
DIETARY_SUPPLEMENTAscorbic Acid
Given IV
DRUGDocetaxel
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
OTHERPlacebo
Given IV
OTHERQuality-of-Life Assessment
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have metastatic castration-resistant prostate cancer (prostate cancer progressing despite castrate levels of testosterone \[\< 50 ng/dL\] using standard measures of progression defined by Prostate Cancer Working Group 2), are chemo-naïve for metastatic castration-resistant prostate cancer (mCRPC); patients must have symptomatic disease or visceral metastases or otherwise be eligible for docetaxel treatment per investigator judgment (e.g. for progression on imaging or rapidly rising PSA despite 2nd line hormonal treatment); * Note: Six cycles of prior docetaxel are allowed in hormone-sensitive disease, per Eastern Cooperative Oncology Group (ECOG) 3805 data and have been off of docetaxel for at least 12 months * Have a pathological diagnosis of prostate carcinoma * Patients may be receiving continuous hormonal ablation with surgical or medical castration with baseline testosterone \< 50 ng/dL * Patient may be receiving bone targeted agents * Have evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and/or Prostate Cancer Working Group 2 (PCWG2) criteria * Have ECOG performance status 0-1 * Have an estimated life expectancy \> 4 months * Absolute neutrophil count \>= 1500/mm\^3 * Platelets \>= 100,000/mm\^3 * Hemoglobin \>= 9 g/dL * Total bilirubin =\< 1.0 upper limit of normal (ULN) * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN * Creatinine =\< 1.6 mg/dl (for patients with \> 1.6 mg/dl, calculated or measured creatinine clearance must be \>= 55 mL/minute \[Cockcroft-Gault\]) * Men of reproductive potential and those who are surgically sterilized (i.e., postvasectomy) must agree to practice effective barrier contraception that has an expected failure rate of \< 1% during and for 30 days after discontinuation of study treatment * If condoms are used as a barrier contraceptive, a spermicidal agent should be added to ensure that pregnancy does not occur * Have the ability to understand, and have given written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
Exclusion criteria
* Have had known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for CNS involvement for at least one week prior to trial treatment; patients with primary brain tumors are not eligible; however, as patients are completing abiraterone therapy, they will be allowed to continue up to 10 mg/day of prednisone * Have had prior chemotherapy for metastatic disease in castration-resistant prostate cancer (prior chemotherapy for hormone-sensitive disease, more than twelve months prior to registration, is acceptable) * Have had had surgery within four weeks of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement * Have had palliative radiation or biological cancer therapy within 2 weeks prior to the first dose of study drug * Have received other investigational drugs within 28 days prior to enrollment * Is expected to require any other form of systemic or localized antineoplastic therapy while on study * Patients who require frequent (several times a day) monitoring of their blood glucose or patients who have recently been hospitalized for glucose control * Are being treated with anticoagulation therapy (aspirin and nonsteroidal anti-inflammatory drugs \[NSAIDS\] are allowed) * The subject requires concomitant treatment with the following inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4): * Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin * Antifungals: itraconzaole, ketoconazole, voriconazole, fluconazole, posaconazole * Antidepressants: nefazodone * Antidiuretic: conivaptan * Anti-retrovirals: delaviridine or protease inhibitors (ritonavir, indinavir, lopinavir/ritonavir, saquinavir, nelfinavir) or cobicistat-boosted antiretrovirals * Gastrointestinal (GI): cimetidine, aprepitant * Hepatitis C: boceprevir, telaprevir * Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or pummelos, star fruit, exotic citrus fruits, or grapefruit hybrids * Have uncontrolled intercurrent illness, including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Has glucose-6-phosphate dehydrogenase (G6PD) deficiency * Have end stage renal disease * Has history of calcium oxalate stones * Has history of iron overload * Have a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) * Have a know active uncontrolled hepatitis B, or hepatitis C infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Up to 30 days after the last dose of study drug | Number of participants experiencing fatigue, nausea, bone pain, and anorexia as defined by CTCAE 4.0 |
| Number of Participates With a Decline in Prostate-specific Antigen From Their Baseline Measurement | up to 24 weeks | prostate-specific antigen decline will be defined as ≥ 50% from baseline measurement |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Serious Adverse Events | Up to 30 days after last dose of study drug | Number of serious adverse events of all types as defined by Common Terminology Criteria for Adverse Events 4.0. A serious adverse event is an undesirable sign, symptom, or medical condition that: * Results in death * Is life threatening * Requires inpatient hospitalization or causes prolongation of existing hospitalization for \>24 hours * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Is an important medical event |
| Number of Participates Experiencing Serious Adverse Events (SAE) | Up to 24 weeks | Number of serious adverse events defined as grade 3 or higher (fatigue, nausea, bone pain, and anorexia) in participates as defined by CTCAE 4.0 |
| Average Number of Times Docetaxel Had Dose Reductions | Up to 24 weeks | The number of dose reductions and total number of completed cycles will be summarized by study arm. |
| Change in Quality of Life (QoL) as Measured by the FACT-P Questionnaire | Up to course 6 of therapy (18 weeks) | The (FACT-P) is made up of 39 question, with the total score ranging between 0 and 156 with 0 being the best and 156 as the worst. |
| Radiographic Progression Free Survival (rPFS) | Up to 3 years | To determine the rPFS of participates that receive at least one dose of ascorbic acid compared to those who received placebo |
Other
| Measure | Time frame | Description |
|---|---|---|
| F2-isoprostanes, a Pharmacodynamic Measure of Oxidant Injury in Vivo | Up to course 6 (18 weeks) | Correlative analyses will assess the association between ascorbic acid and lipid peroxidation (F2-isoprostanes) in the two study arms, globally, and over time. Comparisons of ascorbic acid and F2-isoprostanes by study arm at cycle 1, cycle 2, cycle 4 and cycle 6, accounting for baseline measures obtained from the same patient, will be made by taking differences between post baseline and baseline values and comparing these differences between arms of the study with t-tests. Regression will also be used to assess the association between F2-isoprostane and ascorbic acid at cycle 4 and at cycle 6. |
| Effect of Ascorbic Acid on Docetaxel Exposure | Up to 24 weeks | To determine whether ascorbic acid alters docetaxel exposure and compare between treatment arms, pharmacokinetics samples will be collected prior to, during, and after ascorbic acid and docetaxel infusions. |
| Peak and Trough Ascorbic Acid Levels | Up to 24 weeks | — |
Countries
United States
Participant flow
Pre-assignment details
12 subjects were Screen fails
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Docetaxel, Ascorbic Acid) Patients receive docetaxel IV on day 1 and ascorbic acid IV twice weekly. The first ascorbic acid treatment will be given on day 1 (same day as docetaxel). Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.
Ascorbic Acid: Given IV
Docetaxel: Given IV
Laboratory Biomarker Analysis: Correlative studies
Pharmacological Study: Correlative studies
Quality-of-Life Assessment: Ancillary studies | 34 |
| Arm B (Docetaxel, Placebo) Patients receive docetaxel IV on day 1 and placebo IV twice weekly.The first placebo treatment will be given on day 1 (same day as docetaxel). Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.
Docetaxel: Given IV
Laboratory Biomarker Analysis: Correlative studies
Pharmacological Study: Correlative studies
Placebo: Given IV
Quality-of-Life Assessment: Ancillary studies | 16 |
| Total | 50 |
Baseline characteristics
| Characteristic | Arm A (Docetaxel, Ascorbic Acid) | Total | Arm B (Docetaxel, Placebo) |
|---|---|---|---|
| Age, Continuous | 70 years | 70 years | 69 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 47 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 37 Participants | 10 Participants |
| Region of Enrollment United States | 34 Participants | 50 Participants | 16 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 34 Participants | 50 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 16 |
| other Total, other adverse events | 34 / 34 | 16 / 16 |
| serious Total, serious adverse events | 8 / 34 | 3 / 16 |
Outcome results
Primary
Number of Participants With Adverse Events
Number of participants experiencing fatigue, nausea, bone pain, and anorexia as defined by CTCAE 4.0
Time frame: Up to 30 days after the last dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Docetaxel, Ascorbic Acid) | Number of Participants With Adverse Events | bone pain | 2 Participants |
| Arm A (Docetaxel, Ascorbic Acid) | Number of Participants With Adverse Events | nausea | 17 Participants |
| Arm A (Docetaxel, Ascorbic Acid) | Number of Participants With Adverse Events | anorexia | 12 Participants |
| Arm A (Docetaxel, Ascorbic Acid) | Number of Participants With Adverse Events | fatigue | 25 Participants |
| Arm B (Docetaxel, Placebo) | Number of Participants With Adverse Events | anorexia | 2 Participants |
| Arm B (Docetaxel, Placebo) | Number of Participants With Adverse Events | nausea | 6 Participants |
| Arm B (Docetaxel, Placebo) | Number of Participants With Adverse Events | bone pain | 2 Participants |
| Arm B (Docetaxel, Placebo) | Number of Participants With Adverse Events | fatigue | 11 Participants |
Primary
Number of Participates With a Decline in Prostate-specific Antigen From Their Baseline Measurement
prostate-specific antigen decline will be defined as ≥ 50% from baseline measurement
Time frame: up to 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Docetaxel, Ascorbic Acid) | Number of Participates With a Decline in Prostate-specific Antigen From Their Baseline Measurement | 13 Participants |
| Arm B (Docetaxel, Placebo) | Number of Participates With a Decline in Prostate-specific Antigen From Their Baseline Measurement | 5 Participants |
Secondary
Average Number of Times Docetaxel Had Dose Reductions
The number of dose reductions and total number of completed cycles will be summarized by study arm.
Time frame: Up to 24 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A (Docetaxel, Ascorbic Acid) | Average Number of Times Docetaxel Had Dose Reductions | 7 dose reductions |
| Arm B (Docetaxel, Placebo) | Average Number of Times Docetaxel Had Dose Reductions | 9 dose reductions |
Secondary
Change in Quality of Life (QoL) as Measured by the FACT-P Questionnaire
The (FACT-P) is made up of 39 question, with the total score ranging between 0 and 156 with 0 being the best and 156 as the worst.
Time frame: Up to course 6 of therapy (18 weeks)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A (Docetaxel, Ascorbic Acid) | Change in Quality of Life (QoL) as Measured by the FACT-P Questionnaire | 116.4580 score on a scale |
| Arm B (Docetaxel, Placebo) | Change in Quality of Life (QoL) as Measured by the FACT-P Questionnaire | 113.9834 score on a scale |
Secondary
Number of Participates Experiencing Serious Adverse Events (SAE)
Number of serious adverse events defined as grade 3 or higher (fatigue, nausea, bone pain, and anorexia) in participates as defined by CTCAE 4.0
Time frame: Up to 24 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Docetaxel, Ascorbic Acid) | Number of Participates Experiencing Serious Adverse Events (SAE) | fatigue | 0 Participants |
| Arm A (Docetaxel, Ascorbic Acid) | Number of Participates Experiencing Serious Adverse Events (SAE) | nausea | 0 Participants |
| Arm A (Docetaxel, Ascorbic Acid) | Number of Participates Experiencing Serious Adverse Events (SAE) | bone pain | 0 Participants |
| Arm A (Docetaxel, Ascorbic Acid) | Number of Participates Experiencing Serious Adverse Events (SAE) | anorexia | 1 Participants |
| Arm B (Docetaxel, Placebo) | Number of Participates Experiencing Serious Adverse Events (SAE) | anorexia | 0 Participants |
| Arm B (Docetaxel, Placebo) | Number of Participates Experiencing Serious Adverse Events (SAE) | fatigue | 0 Participants |
| Arm B (Docetaxel, Placebo) | Number of Participates Experiencing Serious Adverse Events (SAE) | bone pain | 0 Participants |
| Arm B (Docetaxel, Placebo) | Number of Participates Experiencing Serious Adverse Events (SAE) | nausea | 0 Participants |
Secondary
Number of Serious Adverse Events
Number of serious adverse events of all types as defined by Common Terminology Criteria for Adverse Events 4.0. A serious adverse event is an undesirable sign, symptom, or medical condition that: * Results in death * Is life threatening * Requires inpatient hospitalization or causes prolongation of existing hospitalization for \>24 hours * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Is an important medical event
Time frame: Up to 30 days after last dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Docetaxel, Ascorbic Acid) | Number of Serious Adverse Events | grade 2 | 4 events |
| Arm A (Docetaxel, Ascorbic Acid) | Number of Serious Adverse Events | grade 4 | 3 events |
| Arm A (Docetaxel, Ascorbic Acid) | Number of Serious Adverse Events | grade 3 | 18 events |
| Arm A (Docetaxel, Ascorbic Acid) | Number of Serious Adverse Events | grade 5 | 0 events |
| Arm A (Docetaxel, Ascorbic Acid) | Number of Serious Adverse Events | grade 1 | 0 events |
| Arm B (Docetaxel, Placebo) | Number of Serious Adverse Events | grade 5 | 0 events |
| Arm B (Docetaxel, Placebo) | Number of Serious Adverse Events | grade 1 | 0 events |
| Arm B (Docetaxel, Placebo) | Number of Serious Adverse Events | grade 2 | 0 events |
| Arm B (Docetaxel, Placebo) | Number of Serious Adverse Events | grade 3 | 6 events |
| Arm B (Docetaxel, Placebo) | Number of Serious Adverse Events | grade 4 | 0 events |
Secondary
Radiographic Progression Free Survival (rPFS)
To determine the rPFS of participates that receive at least one dose of ascorbic acid compared to those who received placebo
Time frame: Up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Docetaxel, Ascorbic Acid) | Radiographic Progression Free Survival (rPFS) | 10.12 months |
| Arm B (Docetaxel, Placebo) | Radiographic Progression Free Survival (rPFS) | 9.97 months |
Other Pre-specified
Effect of Ascorbic Acid on Docetaxel Exposure
To determine whether ascorbic acid alters docetaxel exposure and compare between treatment arms, pharmacokinetics samples will be collected prior to, during, and after ascorbic acid and docetaxel infusions.
Time frame: Up to 24 weeks
Other Pre-specified
F2-isoprostanes, a Pharmacodynamic Measure of Oxidant Injury in Vivo
Correlative analyses will assess the association between ascorbic acid and lipid peroxidation (F2-isoprostanes) in the two study arms, globally, and over time. Comparisons of ascorbic acid and F2-isoprostanes by study arm at cycle 1, cycle 2, cycle 4 and cycle 6, accounting for baseline measures obtained from the same patient, will be made by taking differences between post baseline and baseline values and comparing these differences between arms of the study with t-tests. Regression will also be used to assess the association between F2-isoprostane and ascorbic acid at cycle 4 and at cycle 6.
Time frame: Up to course 6 (18 weeks)
Other Pre-specified
Peak and Trough Ascorbic Acid Levels
Time frame: Up to 24 weeks