Pancreatic Cancer
Conditions
Keywords
high risk stage IIb or III adenocarcinoma of the pancreas
Brief summary
The primary goal of the research study is to determine whether treating pancreatic cancer patients with hydroxychloroquine in combination with gemcitabine before surgery is safe. The secondary goal is to determine if this new treatment regimen can effectively treat pancreatic cancer. This study will test the safety and efficacy of this combination in two parts, or phases.
Detailed description
This is a phase I/II trial designed to assess the safety, tolerability and efficacy of neoadjuvant oral hydroxychloroquine (Plaquenil®) in combination with FDR gemcitabine in subjects with high risk IIb or III adenocarcinoma of the pancreas. Eligible subjects will be administered hydroxychloroquine orally once or twice daily (depending on dose) in combination with FDR gemcitabine (on days 1 and 15) for 31 days prior to surgical resection. Dose escalations of hydroxychloroquine will proceed using Storer's Up-and-Down algorithm D. Subjects will be monitored for side effects and tolerability of the drug. Pre- and post-treatment PET scans will be the primary means to assess response to therapy. Resected tumors will also be assessed for evidence of inhibition of autophagy as well as histopathologic response and margin negative resection and number of positive lymph nodes.
Interventions
DRUGHydroxychloroquine
Oral dosing daily starting at 48 hours before first dose of gemcitabine (starting on Day -2) and for a total of 31 days (ending on Day 29), prior to surgical resection. Capsules are available in 200 mg strengths. Daily doses are 200, 400, 600, 800, 1000, or 1200 mg, and will be administered BID for doses above 200 mg.
DRUGGemcitabine
Intravenous administration on Days 1 and 15, with the infusion given at the fixed dose rate of 10mg/m2/min (e.g. 150 min for a 1500 mg/m2 dose).
Sponsors
National Institutes of Health (NIH)
Amer Zureikat
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with biopsy-proven adenocarcinoma of the pancreas * staged by IIb or greater by by EUS, or tumor greater than 2.6 cm on EUS or pancreatic protocol helical CT scan demonstrating venous involvement * Karnofsky performance status \>/= 70. * No active second malignancy except for basal cell carcinoma of the skin * Normal renal, hepatic, and hematologic function at the time of enrollment as evidenced by: * Serum creatinine level ≤1.5 the upper limits of normal * Serum total bilirubin level ≤1.5 X ULN * White blood cell count \>/= 3.5x109/ml per ml and platelet count ≥ 100x109 per ml * Age \>18 years. * For subjects with obstructive jaundice, the biliary tract must be drained with a temporary plastic or a short permanent metallic biliary stent. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Subjects deemed surgically unresectable or subjects unwilling to undergo surgical resection. * Subjects who have received chemotherapy within 12 months prior to study entry. * Prior use of radiotherapy or investigational agents for pancreatic cancer. * Any evidence of metastasis to distant organs (liver, lung, peritoneum). * Symptomatic or endoscopic evidence of gastric outlet obstruction * Concurrent malignancies with evidence of active or measurable disease except basal cell carcinoma of the skin * Inability to adhere to study and/or follow-up procedures * History of allergic reactions or hypersensitivity to the study drugs (hydroxychloroquine, gemcitabine). * Other concurrent experimental therapy. * The effects of HCQ, and gemcitabine on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. All females of childbearing potential must have a blood test or urine study within two weeks prior to registration to rule out pregnancy. Should a woman become pregnant while participating in this study, she should inform her treating physician immediately. If a man impregnates a woman while participating in this study, he should inform his treating physician immediately as well. * Because patients with immune deficiency are at increased risk of lethal infections when treated with bone marrow-suppressive therapy, HIV-positive patients are excluded from the study. For patients receiving combination anti-retroviral therapy, the potential impact of pharmacokinetic interactions with HCQ and gemcitabine is unknown. Appropriate studies may be undertaken in patients with HIV and those receiving combination anti-retroviral therapy in the future. * Due to the risk of disease exacerbation, patients with porphyria are ineligible. * Patients with psoriasis are ineligible unless the disease is well controlled and they are under the care of a specialist who agrees to monitor the patient for exacerbations. * Patients requiring the use of enzyme-inducing anti-epileptic medication that includes: phenytoin, carbamazepine, phenobarbital, primidone or oxcarbazepine are excluded. * Patients with previously documented macular degeneration or diabetic retinopathy are excluded. * Baseline EKG with QTc \>470 msec (including subjects on medication). Subjects with ventricular pacemaker for whom QT interval is not measurable will be eligible on a case-by-case basis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants That Experienced a Dose Limiting Toxicity (DLT) | Up to 31 days | Number of Participants at each dose level of HCQ that experienced a Dose Limiting Toxicity (DLT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 35 months | Median number of months of overall survival for participants receiving study treatment. |
| Disease-free Survival (DFS) by Response to HCQ Treatment | Up to 30 months | Median number of months of disease-free survival in participants who did and did not experience response to HCQ treatment. Patients who had \>51 % increase in their LC3-II staining were classified as having a response to HCQ. |
| Overall Survival (OS) by p53 Mutant Status | Up to 35 months | — |
| Overall Survival (OS) by Response to HCQ Treatment | Up to 35 months | Median number of months of overall survival in participants who did and did not experience response to HCQ treatment. Patients who had \>51 % increase in their LC3-II staining were classified as having a response to HCQ. |
| Disease-free Survival (DFS) | Up to 30 months | Median number of months of disease-free survival for participants receiving study treatment. |
| Disease-free Survival (DFS) by CA 19-9 Response | Up to 30 months | Median number of months of disease-free survival for participants who experienced Ca 19-9 (surrogate biomarker) response (either an increase or decrease in Ca 19-9), or no Ca 19-9 response. Per participant increases in Ca 19-9 ranged from \>0 to 225%. Per participant decreases in Ca 19-9 ranged from \>0 to 100%. |
| Overall Survival (OS) by CA 19-9 Response | Up to 35 months | Median number of months of overall survival for participants who experienced Ca 19-9 (surrogate biomarker) response (either an increase or decrease in Ca 19-9), or, no Ca 19-9 response. Per participant increases in Ca 19-9 ranged from \>0 to 225%. Per participant decreases in Ca 19-9 ranged from \>0 to 100%. |
| Disease-free Survival by p53 Genetic Status | Up to 35 months | — |
| R0 Resection Rate | Up to 30 months | Number of participants that underwent a resection with microscopically margin-negative resection in which no gross or microscopic tumor remains in the primary tumor bed (24) / number of that completed treatment (31) |
Countries
United States
Participant flow
Pre-assignment details
35 enrolled 2 participants withdrew prior to treatment 1 participants removed from protocol after the first dose of gemcitabine due to cerebrovascular accident unrelated to study drug 1 patient removed from protocol due to allergic rash likely related to gemcitabine 31 participants remained to receive gemcitabine + HCQ treatment
Participants by arm
| Arm | Count |
|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (≤1200 mg/Day) Participants wtih pancreatic adenocarcinoma treated with two doses of fixed dose gemcitabine (1500 mg/m\^2) administered (study days 3 and 17) in combination with oral HCQ (maximum dose of 1200 mg/day) taken for 31 consecutive days until the day of surgery. | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Preoperative Gemcitabine (1500 mg/m^2) + HCQ (≤1200 mg/Day) |
|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 10 |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 34 / 35 |
| serious Total, serious adverse events | 4 / 35 |
Outcome results
Primary
Number of Participants That Experienced a Dose Limiting Toxicity (DLT)
Number of Participants at each dose level of HCQ that experienced a Dose Limiting Toxicity (DLT).
Time frame: Up to 31 days
Population: Observed for dose-limiting toxicities or treatment delays attributed to HCQ to determine the maximum tolerated dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Number of Participants That Experienced a Dose Limiting Toxicity (DLT) | 0 participants |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (400 mg/Day) | Number of Participants That Experienced a Dose Limiting Toxicity (DLT) | 0 participants |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (600 mg/Day) | Number of Participants That Experienced a Dose Limiting Toxicity (DLT) | 0 participants |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (800 mg/Day) | Number of Participants That Experienced a Dose Limiting Toxicity (DLT) | 0 participants |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (1000 mg/Day) | Number of Participants That Experienced a Dose Limiting Toxicity (DLT) | 0 participants |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (1200 mg/Day) | Number of Participants That Experienced a Dose Limiting Toxicity (DLT) | 0 participants |
Secondary
Disease-free Survival by p53 Genetic Status
Time frame: Up to 35 months
Population: Participants that completed more than 80 % of the intended dose of HCQ.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Disease-free Survival by p53 Genetic Status | p53 WT | 21.4 months |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Disease-free Survival by p53 Genetic Status | p53 Mutant | 11.8 months |
Secondary
Disease-free Survival (DFS)
Median number of months of disease-free survival for participants receiving study treatment.
Time frame: Up to 30 months
Population: Participants that completed more than 80 % of the intended dose of HCQ.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Disease-free Survival (DFS) | 11.97 months |
Secondary
Disease-free Survival (DFS) by CA 19-9 Response
Median number of months of disease-free survival for participants who experienced Ca 19-9 (surrogate biomarker) response (either an increase or decrease in Ca 19-9), or no Ca 19-9 response. Per participant increases in Ca 19-9 ranged from \>0 to 225%. Per participant decreases in Ca 19-9 ranged from \>0 to 100%.
Time frame: Up to 30 months
Population: Analysis population included a total of 26 participants who received study treatment, who experienced either an increase or decrease in Ca 19-9, or no Ca 19-9 surrogate biomarker response.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Disease-free Survival (DFS) by CA 19-9 Response | Ca 19-9 Response | 21.4 months |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Disease-free Survival (DFS) by CA 19-9 Response | No Ca 19-9 Response | 6.9 months |
Secondary
Disease-free Survival (DFS) by Response to HCQ Treatment
Median number of months of disease-free survival in participants who did and did not experience response to HCQ treatment. Patients who had \>51 % increase in their LC3-II staining were classified as having a response to HCQ.
Time frame: Up to 30 months
Population: Subset of participants that completed more than 80% of the intended dose of HCQ treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Disease-free Survival (DFS) by Response to HCQ Treatment | No response to HQC treatment | 6.9 months |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Disease-free Survival (DFS) by Response to HCQ Treatment | Response to HQC treatment | 15.03 months |
Secondary
Overall Survival (OS)
Median number of months of overall survival for participants receiving study treatment.
Time frame: Up to 35 months
Population: Participants that completed more than 80% of the intended dose of HCQ.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Overall Survival (OS) | 34.83 months |
Secondary
Overall Survival (OS) by CA 19-9 Response
Median number of months of overall survival for participants who experienced Ca 19-9 (surrogate biomarker) response (either an increase or decrease in Ca 19-9), or, no Ca 19-9 response. Per participant increases in Ca 19-9 ranged from \>0 to 225%. Per participant decreases in Ca 19-9 ranged from \>0 to 100%.
Time frame: Up to 35 months
Population: Analysis population included participants who received study treatment, who experienced either an increase or decrease in Ca 19-9, or no Ca 19-9 surrogate biomarker response
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Overall Survival (OS) by CA 19-9 Response | Ca 19-9 Response (increase or decrease) | 34.8 months |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Overall Survival (OS) by CA 19-9 Response | No Ca 19-9 Response | 8.8 months |
Secondary
Overall Survival (OS) by p53 Mutant Status
Time frame: Up to 35 months
Population: Participants that completed more than 80 % of the intended dose of HCQ.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Overall Survival (OS) by p53 Mutant Status | p53 WT | NA months |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Overall Survival (OS) by p53 Mutant Status | p53 Mutant | 26.1 months |
Secondary
Overall Survival (OS) by Response to HCQ Treatment
Median number of months of overall survival in participants who did and did not experience response to HCQ treatment. Patients who had \>51 % increase in their LC3-II staining were classified as having a response to HCQ.
Time frame: Up to 35 months
Population: Subset of participants that completed more than 80 % of the intended dose of HCQ.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Overall Survival (OS) by Response to HCQ Treatment | Response to HQC treatment | 34.83 months |
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | Overall Survival (OS) by Response to HCQ Treatment | No response to HQC treatment | 10.83 months |
Secondary
R0 Resection Rate
Number of participants that underwent a resection with microscopically margin-negative resection in which no gross or microscopic tumor remains in the primary tumor bed (24) / number of that completed treatment (31)
Time frame: Up to 30 months
Population: Participants that completed more than 80 % of the intended dose of HCQ.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Preoperative Gemcitabine (1500 mg/m^2) + HCQ (200 mg/Day) | R0 Resection Rate | 77 percentage of participants |