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

A Randomized Phase 2 Trial of Ascorbic Acid in Combination With Docetaxel in Men With Metastatic Prostate Cancer

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.

Study Overview

• Status: Terminated
• Conditions: Metastatic Prostate Carcinoma; Stage IV Prostate Cancer; Hormone-Resistant Prostate Cancer
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Other: Pharmacological Study; Drug: Docetaxel; Other: Placebo; Dietary supplement: Ascorbic Acid

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20016
      • Sibley Memorial Hospital
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • Anne Arundel Health System, Research Institute
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland Seidman Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Pharmacological Study; Correlative studies; Drug: Docetaxel; Given IV; Other Names: Taxotere; RP56976; Taxotere Injection Concentrate; Dietary supplement: Ascorbic Acid; Given IV; Other Names: Vitamin C; 2-(1,2-dihydroxyethyl)-4,5-dihydroxy-furan-3-one; Asorbicap; C Vitamin; C-Long; Ce-Vi-Sol; Cecon; Cenolate; Cetane; Cevalin; L-Ascorbic Acid; VIT C; Vitamin-C
Placebo Comparator: 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Pharmacological Study; Correlative studies; Drug: Docetaxel; Given IV; Other Names: Taxotere; RP56976; Taxotere Injection Concentrate; Other: Placebo; Given IV; Other Names: placebo therapy; PLCB; sham therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	up to 24 weeks
Number of Participants With Adverse Events	Number of participants experiencing fatigue, nausea, bone pain, and anorexia as defined by CTCAE 4.0	Up to 30 days after the last dose of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 24 weeks
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	Up to 30 days after last dose of study drug
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	Up to 24 weeks
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.	Up to course 6 of therapy (18 weeks)
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	Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 24 weeks
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.	Up to course 6 (18 weeks)
Peak and Trough Ascorbic Acid Levels		Up to 24 weeks

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Channing Paller, MD, Johns Hopkins University/Sidney Kimmel Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2016
• Primary Completion (Actual): July 31, 2021
• Study Completion (Actual): October 14, 2021

Study Registration Dates

• First Submitted: August 4, 2015
• First Submitted That Met QC Criteria: August 4, 2015
• First Posted (Estimated): August 6, 2015

Study Record Updates

• Last Update Posted (Actual): June 7, 2023
• Last Update Submitted That Met QC Criteria: June 5, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Micronutrients; Antioxidants; Docetaxel; Vitamins; Ascorbic Acid
• Other Study ID Numbers: J15106 (Other Identifier: Johns Hopkins University/Sidney Kimmel Cancer Center); P30CA006973 (U.S. NIH Grant/Contract); NCI-2015-01169 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); IRB00070691 (Other Identifier: JHM IRB)