Pancreas Cancer, Pancreas Metastases, Pancreatic Adenocarcinoma Resectable, Pancreatic Cancer, Pancreatic Ductal Adenocarcinoma
Conditions
Brief summary
The purpose of this study is to see if a treatment regimen with a combination of paclitaxel protein bound (also known as nab-paclitaxel), gemcitabine, and cisplatin when given with high dose Ascorbic Acid will be safe and effective in individuals with untreated metastatic pancreatic cancer.
Detailed description
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.
Interventions
DRUGHigh Dose Ascorbic Acid 25 g/m^2
2x per week IV infusion Normal Saline on days Day 1, 3, 8, 10, 15, and 17 of each 21-day cycle
DRUGNanoparticle Paclitaxel protein bound 125mg/m^2
30 minute IV infusions on days 1 and 8 repeated every 21 days
DRUGCisplatin 25mg/m^2
Via 500mL of Normal Saline over 60 minute IV infusion on days 1 and 8 repeated every 21 days
DRUGGemcitabine 1000mg/m^2
Via 500mL of Normal Saline over 30 minute IV infusion on days 1 and 8 repeated every 21 days
DRUGHigh Dose Ascorbic Acid 37.5 g/m^2
2x per week IV infusion Normal Saline on days Day 1, 3, 8, 10, 15, and 17 of each 21-day cycle
DRUGHigh Dose Ascorbic Acid 56.25 g/m^2
2x per week IV infusion Normal Saline on days Day 1, 3, 8, 10, 15, and 17 of each 21-day cycle
DRUGHigh Dose Ascorbic Acid 75 g/m^2
2x per week IV infusion Normal Saline on days Day 1, 3, 8, 10, 15, and 17 of each 21-day cycle
Sponsors
HonorHealth Research Institute
Stand Up To Cancer
Cancer Research UK
Lustgarten Foundation
Translational Genomics Research Institute
Princeton University
Salk Institute for Biological Studies
Cold Spring Harbor Laboratory
Barts Cancer Institute
University of Arizona
Imaging Endpoints
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase IB: 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: 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Dose Received [Identifying Recommended Maximum Tolerated Dose (MTD)] | From enrollment through end of treatment, up to 40 weeks | 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, the total dose received of ascorbic acid (g/m\^2) by participants was measured. |
| Duration of Dose in Days [Identifying Recommended Maximum Tolerated Dose (MTD)] | From enrollment through end of treatment, up to 40 weeks | 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, the duration of ascorbic acid dose in days is reported. |
| Duration of Dose in Weeks [Identifying Recommended Maximum Tolerated Dose (MTD)] | From enrollment through end of treatment, up to 40 weeks | 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, the duration of ascorbic acid dose in weeks is reported. |
| Disease Control Rate (CR+PR+SD at 18 Weeks) | 18 weeks | Preliminary efficacy as measured by disease control rate (DCR), defined as the percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD) at 18 weeks according to RECIST v1.1. CR = disappearance of all target lesions; PR = at least 30% decrease in sum of the longest diameters for target lesions, SD = insufficient change to qualify for PR or progressive disease \[defined as at least 20% increase in sum of the longest diameters for target lesions\]. |
| Best Overall Response | From enrollment through end of treatment, up to 36 weeks | Best overall response according to RECIST v1.1. Complete response (CR) = disappearance of all target lesions; Partial response (PD) = at least 30% decrease in sum of the longest diameters for target lesions; Stable disease (SD) = insufficient change to qualify for PR or PD; Progressive disease (PD) = at least 20% increase in sum of the longest diameters for target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Toxicities | From enrollment through 30 days after the end of treatment, up to 40 weeks | Incidence of adverse events reported according to National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
| Normalization of Tumor Markers by AA Treatment Group | From enrollment through study completion, up to 40 weeks | The percentage of patients who had elevated levels of tumor marker CA 19-9 (or CA-125/CEA if not expressors of CA 19-9) and had their levels normalize. Elevated levels were defined as any value \>35 U/mL for CA 19-9, \>35 U/mL for CA-125, and \>3 ng/mL for CEA. Normalization was defined as any patient who had elevated tumor marker values at baseline and decreased to CA 19-9 value of 0.0-35 U/mL, CA-125 value of 0.0-35 U/mL, or CEA value of 0.0-3 ng/mL during treatment. |
| Overall Survival | Approximately 12 weeks from last study treatment, assessed up to 3 years | Telephone follow-up conducted every 12 weeks from the last dose of treatment to determine survival status. |
| Progression-free Survival | Approximately 12 weeks from last study treatment, assessed up to 3 years | Telephone follow-up conducted every 12 weeks from the last dose of treatment to determine status of disease progression. |
| Quality of Life: MD Anderson's Symptom Inventory-GI (MDASI-GI) | From Cycle 1 to end of treatment, up to 40 weeks | Changes in patient's self-reported quality of life as determined by administering the MD Anderson Symptom Inventory (MDASI-GI). This questionnaire asks patients to rank the severity of symptoms using a 0-10 scale (0 = not present to 10 = as bad as you can imagine) and averages the responses of 18 questions to produce an MDASI-GI score on a 0-10 scale. MDASI-GI scores measured at the start of Cycle 1 and at the end of treatment (EOT) are reported here. |
| Quality of Life: Brief Pain Inventory (BPI) - Pain Intensity (PI) | From start of Cycle 1 to end of treatment, up to 40 weeks | Changes in patient's self-reported pain levels determined by administering the Brief Pain Inventory (BPI) - Pain Intensity (PI) assessment. This questionnaire asks about pain intensity using a 0-10 scale (0 = not present to 10 = as bad as you can imagine) and averages the responses of 4 questions to output a BPI-PI score on a 0-10 scale. BPI-PI scores measured at the start of Cycle 1 and at the end of treatment (EOT) are reported here. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORGayle S Jameson, RN, MSN, ACNP-BC, AOCN
HonorHealth Research Institute
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous Age | 63.9 years |
| Albumin g/dL | 3.1 g/dL |
| Baseline CA 19-9 Elevated | 6 Participants |
| Baseline CA 19-9 Normal | 3 Participants |
| Body Surface Area | 1.7 (m^2) |
| ECOG Score ECOG Score 0 | 1 Participants |
| ECOG Score ECOG Score 1 | 4 Participants |
| Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported | 0 Participants |
| History of Prior Treatment Adjuvant & Neoadjuvant | 1 Participants |
| History of Prior Treatment No Prior Treatment | 16 Participants |
| Neutrophil to Lymphocyte Ratio (NLR) High (> 5) | 5 Participants |
| Neutrophil to Lymphocyte Ratio (NLR) Low (≤ 5) | 6 Participants |
| Neutrophil to Lymphocyte Ratio (NLR) | 4.8 calculated ratio |
| Primary Site of Tumor Body of Pancreas | 3 Participants |
| Primary Site of Tumor Head of Pancreas | 9 Participants |
| Primary Site of Tumor Neck of Pancreas | 1 Participants |
| Primary Site of Tumor Tail of Pancreas | 5 Participants |
| Race (NIH/OMB) Race American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Race Asian | 0 Participants |
| Race (NIH/OMB) Race Black or African American | 0 Participants |
| Race (NIH/OMB) Race More than one race | 0 Participants |
| Race (NIH/OMB) Race Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Race Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Race White | 7 Participants |
| Region of Enrollment United States | 6 Participants |
| Sex: Female, Male Gender Female | 12 Participants |
| Sex: Female, Male Gender Male | 2 Participants |
| Sites of Metastatic Disease Liver, Ascites | 3 Participants |
| Sites of Metastatic Disease Liver & Lung | 1 Participants |
| Sites of Metastatic Disease Liver & Lymph Nodes | 1 Participants |
| Sites of Metastatic Disease Lung | 2 Participants |
| Sites of Metastatic Disease Lymph Node | 1 Participants |
| Sites of Metastatic Disease Other | 0 Participants |
| Time Since Diagnosis | 0.2 years STANDARD_DEVIATION 0.5 |
| Tumor Resection No Resection | 15 Participants |
| Tumor Resection Whipple Procedure | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 4 / 4 | 6 / 7 |
| other Total, other adverse events | 6 / 6 | 4 / 4 | 7 / 7 |
| serious Total, serious adverse events | 0 / 6 | 0 / 4 | 2 / 7 |
Outcome results
None listed