Trial of Ascorbic Acid (AA) + Nanoparticle Paclitaxel Protein Bound + Cisplatin + Gemcitabine (AA NABPLAGEM) (AA NABPLAGEM)
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|ClinicalTrials.gov Identifier: NCT03410030|
Recruitment Status : Completed
First Posted : January 25, 2018
Last Update Posted : April 18, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Pancreatic Cancer Pancreas Cancer Pancreatic Adenocarcinoma Resectable Pancreatic Ductal Adenocarcinoma Pancreas Metastases||Drug: Ascorbic Acid Drug: Paclitaxel protein-bound Drug: Cisplatin Drug: Gemcitabine||Phase 1 Phase 2|
Pancreatic cancer continues to be a very lethal disease. It was estimated that in 2016, 53,070 Americans would be diagnosed with pancreatic ductal adenocarcinoma (PDA), and 41,780 would die from the disease. This makes pancreatic cancer the third leading cause of death from cancer in the US.
PDA is the twelfth most common cancer in the world with 338,000 new cases diagnosed in 2012. It is estimated that worldwide there will be > 300,000 deaths from pancreatic cancer. Furthermore unfortunately PDA is projected to be the second leading cause of death from cancer in the US by 2030.
Detection of pancreatic cancer has notoriously been very late in the disease and therefore the 5-year survival rate is only 8%, which is actually a slight improvement over the last few years. Right now the only potential cure for pancreatic cancer is surgical resection (if the disease is caught early). However only about 20% of PDA patients are eligible for potentially curable resection and unfortunately most (> 80%) have recurrence of their cancer within 2 years of resection, and those recurrences are almost universally fatal.
Recently it has been shown that there are regimens that actually improve survival for patients with advanced stage IV PDA. Conroy and colleagues have developed the Folfirinox regimen, which in a large randomized trial improved survival over gemcitabine as a single agent. Von Hoff and colleagues developed the nanoparticle albumin (nab) associated paclitaxel plus gemcitabine regimen which improved survival over single agent gemcitabine. Even more recently Jameson and colleagues have presented a combined regimen of nab-paclitaxel + gemcitabine + cisplatin in a small 24 patient phase Ib/II trial which showed a response rate of 71% with 2 patients having complete response, a 1-year survival of 65% and a median survival of 16+ months.
While there have been multiple investigators and investigations into the use of ascorbic acid for patients with cancer (see ClinTrials.gov), its use has generally not been found to be of help for patients particularly when given orally - e.g. 10 grams daily.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||27 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase IB/II Trial of High Dose Ascorbic Acid (AA) + Nanoparticle Paclitaxel Protein Bound + Cisplatin + Gemcitabine (AA NABPLAGEM) in Patients Who Have No Prior Therapy for Their Metastatic Pancreatic Cancer|
|Actual Study Start Date :||December 15, 2017|
|Actual Primary Completion Date :||September 14, 2021|
|Actual Study Completion Date :||January 10, 2022|
Experimental: Ascorbic Acid
Some human studies of high-dose IV vitamin C in patients with cancer have shown improved quality of life, as well as improvements in physical, mental, and emotional functions, symptoms of fatigue, nausea and vomiting, pain, and appetite loss. Intravenous high-dose ascorbic acid has caused very few side effects in clinical trials
Drug: Ascorbic Acid
Drug: Paclitaxel protein-bound
- Phase IB: Recommended Phase II dose (to give ≥ 20 mM) of ascorbic acid for Phase II [ Time Frame: approximately 63 days ]To determine the maximum tolerated dose (MTD) of high dose ascorbic acid (AA) with triple therapy of nanoparticle paclitaxel protein bound+ cisplatin + gemcitabine (NABPLAGEM) in patients with advanced stage IV metastatic pancreatic cancer
- Phase II: Disease control rate (CR+PR+SD x18 weeks) [ Time Frame: approximately 63 days ]To determine the preliminary efficacy (Disease control rate of CR+ PR+SD X 18 weeks) of the combination of high dose ascorbic acid (AA) at MTD with triple therapy of nanoparticle albumin- bound paclitaxel + cisplatin + gemcitabine (NABPLAGEM) in patients with advanced stage IV metastatic pancreatic cancer.
- Incidence of toxicities [ Time Frame: approximately 63 days ]Lab testing will be completed to evaluate standard of care labs for subject safety
- Percent of patients who normalize their CA19-9 [ Time Frame: approximately 63 days ]Lab testing will be completed to evaluate normalization of CA19-19
- overall survival [ Time Frame: approximately 12 weeks from last study treatment ]Telephone followup will be conducted every 12 weeks from the last dose of treatment to determine survival status
- Progression free [ Time Frame: approximately 12 weeks from last study treatment ]Telephone followup will be conducted every 12 weeks from the last dose of treatment to determine status of disease progression
- Changes in patient's self-reported quality of life [ Time Frame: approximately 63 days ]Changes in patient's self-reported quality of life will be determined by administering the MD Anderson Symptom Inventory (MDASI-GI)
- Changes in patient's self-reported pain levels [ Time Frame: approximately 63 days ]Changes in patient's self-reported pain levels will be determined by administering the Brief Pain Inventory (BPI)
- Tumor texture on radiologic scans [ Time Frame: approximately 63 days ]Imaging will be completed to evaluate tumor texture on radiologic scans as a non-invasive imaging biomarker for response, biologic, pathologic and outcome measures
- Correlation between peak plasma concentration of ascorbic acid and response to treatment [ Time Frame: approximately 63 days ]Lab testing will be completed to evaluate the correlation between peak plasma concentration of ascorbic acid and response to treatment
- Potential tumor biomarkers [ Time Frame: approximately 63 days ]Tumor biopsy testing will be completed to evaluate potential biomarkers in the tumor including tumor immune cell infiltration, stromal activation, stem cell enumeration, metabolic profiles, whole exome and whole genome CN, ChIP-seq/ATAQ seq, IHC and PCR assays on immune cell populations, CAFs, stem cell content (CD133, Aldh) and Musashi
- Potential blood biomarkers [ Time Frame: approximately 63 days ]Lab testing will be completed to evaluate potential biomarkers in the blood samples. Test may include CTCs/circCSC enumeration, Single CTC/circCSC transcription profiling, immune profiling [CD4+CD8+ T cells, MDSC (IDO-1+HLR-DR-/lowCD33+CD11b+CD14+), Immunosuppressive plasmocytes (CD19+CD138+IgA+IL-10+PD-L1+), Th17 (CD3+gdTCR+IL-17A+), Treg (CD4+Foxp3+), Hypo-responsive NK cells (CD3-CD56+KIR-NKG2A-), cfDNA, GPC1+ exosomes.
- Changes in circulating tumor stem cells [ Time Frame: approximately 63 days ]Lab testing will be completed to evaluate changes in numbers of circulating tumor stem cells and macrophage lineage changes
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, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Patients must meet the following criteria to be included in the trial:
- Be willing and able to provide written informed consent/assent for the trial.
- Be ≥ 18 years of age on day of signing informed consent.
- Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma (with measurable disease according to RECIST 1.1 criteria).
- Have a performance status of 0 or 1 on the ECOG performance scale.
- Demonstrate adequate organ function as defined below in table 4. All screening labs should be performed within 14 days of treatment initiation.
- Female participants of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving first dose of study medication.
- Female participants of childbearing potential must be willing to use adequate method of contraception (as outlined in section 4.4.2) for the duration of the trial.
- Male participants must agree to use adequate contraception (as outlined in section 4.4.2) for the duration of the trial.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.
Patients must not meet any of the following criteria in order to be eligible for the trial:
- Patients must have received no previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease. Prior treatments in the adjuvant setting with gemcitabine and/or 5-FU or gemcitabine administered as a radiation sensitizer are allowed, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present.
- Palliative surgery and/or radiation treatment less than 4 weeks prior to initiation of study treatment.
- Exposure to any investigational agent within 4 weeks prior to initiation of study treatment.
- Patients who need constant use of finger stick blood glucose monitoring for tight contro l of their diabetes being the ascorbic acid causes false low readings of glucose via that technology (Vasudevan and Hirsch 2014) 39
- Any person with a G6PD deficiency
- History of renal oxalate stones (if type of stone is unknown, need to assess urine oxalates level if >60mg/dL, then patient is not eligible for the study)
- Patient is taking acetaminophen at any dose, or any medication that contains acetaminophen within 72 hours of first dose of ascorbic acid.
- Hypersensitivity to any of the agents proposed for treatment.
- Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients 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 at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
- Has an active infection requiring systemic therapy.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through one week from the last dose of trial treatment.
- Patients with evidence of iron overload, defined as a transferrin saturation > 45 percent AND serum ferritin > 200 ng/mL (males) or >150 ng/mL (females).
- Current, serious, clinically significant cardiac arrhythmias as determined by the investigator, or patient receiving a digitalis derivative.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03410030
|United States, Arizona|
|HonorHealth Research Institute|
|Scottsdale, Arizona, United States, 85258|
|Principal Investigator:||Gayle S Jameson, RN, MSN, ACNP-BC, AOCN||HonorHealth Research Institute|
|Responsible Party:||HonorHealth Research Institute|
|Other Study ID Numbers:||
SU2C HRI NPG-002
|First Posted:||January 25, 2018 Key Record Dates|
|Last Update Posted:||April 18, 2023|
|Last Verified:||April 2023|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
If the study site is a 'covered site' under the definitions of the Health Insurance Portability and Accounting Act (HIPAA), the Investigator will ensure that the patient consents to the use of data by HonorHealth and its designees for the purposes of regulatory submissions, study publications, and drug approval.
SU2C will be notified of any outputs of the research such as guidelines, publications, presentation, changes in service delivery etc. prior to external submission or presentation. In any oral or written report or poster presentation of Results or otherwise relating to the Research, the support of CRUK, SU2C and the Lustgarten foundation will be acknowledged, displaying the relevant logs where possible. Any publications resulting from research funded in whole or in part by the Grant must be cited as required per signed confidentiality agreements.
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
|Time Frame:||to be determined|
The Investigator and any other study personnel involved in this study shall not disclose, or use for any purposes (other than for the performance of this study), any data, records, or other information (hereinafter collectively "information") disclosed to the Investigator or other study personnel. Such information shall remain the confidential and proprietary property of HonorHealth, and shall be disclosed only to the Investigator or other designated study personnel.
The obligation of non-disclosure shall not apply to the following:
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
|Product Manufactured in and Exported from the U.S.:||Yes|
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Endocrine System Diseases
Antineoplastic Agents, Phytogenic
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs