Clinical trial NCT01978184: Randomized Phase II Trial of Pre-Operative Gemcitabine and Nab Paclitacel With or With Out Hydroxychloroquine
Official title: Randomized Phase II Trial of Pre-Operative Gemcitabine and Nab Paclitacel With or With Out Hydroxychloroquine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pancreatic Cancer
Keywords: Pancreatic Cancer, resectable adenocarcinoma of the pancreas
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2013-11-07
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized phase II trial that will examine the ability of the hydroxychloroquine to improve the clinical activity of a pre-operative regimen of gemcitabine and nab-paclitaxel in subjects with potentially resectable adenocarcinoma of the pancreas. Eligible subjects will receive 2 cycles of gemcitabine and nab-paclitaxel (day 1, 8, 15) with or without hydrocychloroquine followed by surgical resection. Primary endpoint will be histologic response as graded by Evans criteria. Secondary endpoints will be CA19-9 response and PET response. Pre and post treatment tissue biopsies will be obtained to assess for levels of autophagy in tumor, liver and peripheral blood.


Eligibility criteria: Inclusion Criteria:

* Subjects with biopsy-proven potentially resectable or borderline adenocarcinoma of the pancreas as determined by National Comprehensive Cancer Network (NCCN) criteria
* Karnofsky performance status of 70-100%
* No active second malignancy except for basal cell carcinoma of the skin
* Patient has adequate biological parameters as demonstrated by the following blood counts at screening
* Absolute neutrophil count (ANC) ≥1.5 × 109/L;
* Platelet count ≥100,000/mm3 (100 × 109/L);
* Hemoglobin (Hgb) ≥9 g/dL.
* Patient has the following blood chemistry levels at Baseline
* aspartate aminotransferase (AST) (SGOT), Alanine transaminase (SGPT) ≤2.5 × upper limit of normal range (ULN)
* Total bilirubin ≤ULN
* Serum Creatinine ≤ 1.5mg/dl OR calculated creatinine clearance ≥ 50 for those patients with creatinine greater than 1.5
* Prothrombin time (PT)within normal limits (WNL). If patient is on warfarin for prophylactic clot presentation for indwelling catheter, Partial PT/PTT may be +/- 15 %
* thromboplastin time (PTT) WNL. If patient on warfarin for prophylactic clot presentation for indwelling catheter, PT/PTT may be +/- 15 %
* Age \>18 years.
* Patient must be able to swallow enteral medications with no requirement for a feeding tube. Patient's must not have intractable nausea or vomiting which prohibits the patient from oral medications
* 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 randomization.
* Prior use of radiotherapy or investigational agents for pancreatic cancer.
* Any evidence of metastasis to distant organs (liver, lung, peritoneum).
* Symptomatic evidence of gastric outlet obstruction
* Inability to adhere to study and/or follow-up procedures
* History of allergic reactions or hypersensitivity to the study drugs (hydroxychloroquine, gemcitabine, abraxane).
* 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 randomization to rule out pregnancy.
* 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 electrocardiogram (EKG) with corrected QT interval (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.
* Patient with a history of interstitial lung disease, history of slowly progressive dyspnea, sarcoidosis, silicosis, idiopathic pulmonary fibrosis or pulmonary hypersensitivity pneumonitis
* Patient with known active infection with HIV, Hepatitis B or Hepatitis C
* Patients requiring use of warfarin for therapeutic purposes.

Primary outcomes:
measure: Evans Grade Histopathologic Response
timeFrame: Up to 4 years
measure: Age at Diagnosis
timeFrame: Baseline - At the time of diagnosis, prior to treatment
measure: CT Tumor Size
timeFrame: Baseline - At the time of diagnosis, prior to treatment
measure: Cancer Diagnosis Stage
timeFrame: Baseline - At the time of diagnosis, prior to treatment
measure: Type of Surgical Procedure (Operation)
timeFrame: At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy)
measure: Robotic Resection Surgery
timeFrame: At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy)
measure: Age-Adjusted Charlson Comorbidity Index
timeFrame: Prior to treatment
Secondary outcomes:
measure: Carbohydrate Antigen 19-9 (CA19-9) Response
timeFrame: Prior to treatment (average 73.3 +/- 9.9 days prior to surgery)
measure: Carbohydrate Antigen 19-9 (CA19-9) Response
timeFrame: After treatment (50-67 days post treatment/surgery)
measure: Positive Lymph Node Involvement
timeFrame: At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy)
measure: Rate of R0 Resection
timeFrame: At the time of surgery (≥2 weeks and ≤6 weeks post chemotherapy)
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Hillman Cancer Center
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh CancerCenters
name: Herbert Zeh, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Miller-Ocuin JL, Liang X, Boone BA, Doerfler WR, Singhi AD, Tang D, Kang R, Lotze MT, Zeh HJ 3rd. DNA released from neutrophil extracellular traps (NETs) activates pancreatic stellate cells and enhances pancreatic tumor growth. Oncoimmunology. 2019 Jun 11;8(9):e1605822. doi: 10.1080/2162402X.2019.1605822. eCollection 2019.
citation: Boone BA, Murthy P, Miller-Ocuin J, Doerfler WR, Ellis JT, Liang X, Ross MA, Wallace CT, Sperry JL, Lotze MT, Neal MD, Zeh HJ 3rd. Chloroquine reduces hypercoagulability in pancreatic cancer through inhibition of neutrophil extracellular traps. BMC Cancer. 2018 Jun 22;18(1):678. doi: 10.1186/s12885-018-4584-2.