Docetaxel With or Without Ascorbic Acid in Treating Patients With Metastatic Prostate Cancer

PRIMARY OBJECTIVES:

I. To compare the proportion of metastatic prostate cancer patients with a prostate specific
antigen (PSA) decline of >= 50% over 8 cycles of docetaxel with ascorbic acid (Arm A) versus
docetaxel with placebo (Arm B).

II. To compare the proportion of adverse events (fatigue, nausea, bone pain, and anorexia)
experienced by metastatic prostate cancer patients receiving either docetaxel with ascorbic
acid (Arm A) versus docetaxel with placebo (Arm B).

SECONDARY OBJECTIVES:

I. To assess radiographic progression free survival (rPFS) in patients with metastatic
prostate cancer and compare between treatment arms.

II. To assess the proportion of high grade serious adverse events (fatigue, nausea, bone
pain, and anorexia) in patients with metastatic prostate cancer and compare between treatment
arms during 8 cycles of treatment.

III. To assess the proportion of high grade serious adverse events (all types) in patients
with metastatic prostate cancer and compare between treatment arms during 8 cycles of
treatment.

IV. To assess changes in quality of life measures as assessed by the Functional Assessment of
Cancer Therapy-Prostate (FACT-P) questionnaire.

V. To assess the proportion of metastatic prostate cancer patients requiring docetaxel dose
reductions and compare between treatment arms during 8 cycles of treatment.

TERTIARY OBJECTIVES:

I. To determine whether ascorbic acid alters docetaxel exposure and compare between treatment
arms.

II. To determine peak and trough ascorbic acid levels. III. As a pharmacodynamic measure of
oxidant injury in vivo, measure F2-isoprostanes.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive docetaxel intravenously (IV) over 60 minutes on day 1 and ascorbic
acid IV thrice weekly. Treatment repeats every 21 days for 8 courses in the absence of
disease progression or unacceptable toxicity.

ARM B: Patients receive docetaxel IV over 60 minutes on day 1 and placebo IV over 60 minutes
thrice weekly. Treatment repeats every 21 days for 8 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 6
months.

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),
hepatitis B, or hepatitis C infection