Phase II Trial of Paricalcitol and Hydroxychloroquine (PH) Combination With Gemcitabine and Nab-Paclitaxel in Advanced or Metastatic Pancreatic Cancer
Overview
- Phase
- Phase 2
- Intervention
- Gemcitabine
- Conditions
- Advanced Pancreatic Adenocarcinoma
- Sponsor
- Emory University
- Enrollment
- 10
- Locations
- 3
- Primary Endpoint
- Assessment of Tumor Response to Combination of Paricalcitol and Hydroxychloroquine With Common Front-line Therapy.
- Status
- Completed
- Last Updated
- 3 months ago
Overview
Brief Summary
This phase II trial investigates how well paricalcitol and hydroxychloroquine work when combined with gemcitabine and nab-paclitaxel in treating patients with pancreatic cancer that has spread to other places in the body (advanced or metastatic). Paricalcitol (a form of vitamin D) works by blocking a signal in the cancer cells that leads to growth and spreading of the tumor. Hydroxychloroquine (an autophagy inhibitor) enhances the activity of standard chemotherapy on cancer cells and prevent them to utilize energy to grow. Chemotherapy drugs, such as gemcitabine and nab-paclitaxel, 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. Giving paricalcitol and hydroxychloroquine together with standard chemotherapy (gemcitabine and nab-paclitaxel) may work better in treating patients with pancreatic cancer compared to either paricalcitol or hydroxychloroquine alone.
Detailed Description
PRIMARY OBJECTIVE: I. To evaluate the anti-tumor activity of the combination of paricalcitol plus hydroxychloroquine (PH) when added to gemcitabine and nab-paclitaxel treatment by assessing the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of the combination of paricalcitol plus hydroxychloroquine (PH) when added to gemcitabine and nab-paclitaxel treatment in patients with advanced pancreatic cancer. II. To evaluate the anti-tumor activity of the combination of paricalcitol plus hydroxychloroquine (PH) when added to gemcitabine and nab-paclitaxel treatment by assessing progression-free survival (PFS) and overall survival (OS). TERTIARY/EXPLORATORY OBJECTIVES: I. Evaluate the effects of PH on cancer-associated fibroblasts (CAF) and immune cells using mass cytometry (CyTOF) to characterize the presence and distribution of these cells. II. Multiplex immunohistochemistry (IHC) to evaluate these pathways including TGF-beta1, TGF-beta1 RII, SMAD4, LC3 in addition to markers of fibrosis (collagen) and tumor (cytokeratin). OUTLINE: Beginning day -14, patients receive paricalcitol intravenously (IV) three times weekly and hydroxychloroquine orally (PO) twice daily (BID). Patients also receive gemcitabine IV over 30 minutes and nab-paclitaxel IV over 30 minutes on days 1, 8, 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 28 days and every 12 weeks thereafter.
Investigators
Olatunji Alese
Principal Investigator
Emory University
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed advanced or metastatic adenocarcinoma of the pancreas (stage IV)
- •Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded as \>= 10 mm (\>= 1 cm) on computed tomography (CT) scan, magnetic resonance imaging (MRI)
- •Patients may have had prior neoadjuvant or adjuvant treatment for pancreatic cancer. The last dose of chemotherapy must have been 12 months prior to study entry. No prior systemic therapy for metastatic disease
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- •Hemoglobin \>= 9.0 g/dl (no transfusions allowed within 7 days of cycle 1 day 1 to meet entry criteria) (within 28 days of cycle 1 day 1)
- •Absolute neutrophil count (ANC) \>= 1,500/mcL (after at least 7 days without growth factor support or transfusion) (within 28 days of cycle 1 day 1)
- •Platelets \>= 100,000/mcL (no transfusions allowed within 7 days of cycle 1 day 1 to meet entry criteria) (within 28 days of cycle 1 day 1)
- •International normalized ratio (INR) =\< 1.5 (within 28 days of cycle 1 day 1)
- •Partial thromboplastin time (PTT) \< 1.5 x upper limits of normal (ULN) (within 28 days of cycle 1 day 1)
- •Total bilirubin =\< 1.5 times the institutional upper limit of normal (ULN) (within 28 days of cycle 1 day 1)
Exclusion Criteria
- •Prior chemotherapy or any other investigational agents for the treatment of metastatic pancreatic cancer
- •Concurrent use of any other anti-cancer therapy, including chemotherapy, targeted therapy, immunotherapy, or biological agents
- •History of use of HCQ (aminoquinolines) or paricalcitol in the 6 months prior to study entry
- •Pre-existing hypercalcemia, defined as baseline serum calcium (corrected for albumin) above the institutional upper limit of normal
- •After signing consent, vitamin D or calcium containing supplements must be stopped and no vitamin D or calcium supplements can be taken while the patient is enrolled to the study due to increased risk for hypercalcemia
- •Pre-existing, clinically significant peripheral neuropathy, defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher neurosensory or neuro-motor toxicity, regardless of etiology
- •Participants with uncontrolled brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
- •Current use of medications that prolong QT interval unless approved by principal investigator (PI) or substances that are strong inhibitors or inducers of CYP450 3A enzyme(s)- unless approved by PI
- •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
- •Patients with known G6PD deficiency, severe psoriasis, porphyria, macular degeneration or severe diabetic retinopathy are ineligible because of the potential for greater HCQ toxicity
Arms & Interventions
Treatment (paricalcitol, hydroxychloroquine, chemotherapy)
Beginning day -14, patients receive paricalcitol IV three times weekly and hydroxychloroquine PO BID. Patients also receive gemcitabine IV over 30 minutes and nab-paclitaxel IV over 30 minutes on days 1, 8, 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Gemcitabine
Treatment (paricalcitol, hydroxychloroquine, chemotherapy)
Beginning day -14, patients receive paricalcitol IV three times weekly and hydroxychloroquine PO BID. Patients also receive gemcitabine IV over 30 minutes and nab-paclitaxel IV over 30 minutes on days 1, 8, 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Hydroxychloroquine
Treatment (paricalcitol, hydroxychloroquine, chemotherapy)
Beginning day -14, patients receive paricalcitol IV three times weekly and hydroxychloroquine PO BID. Patients also receive gemcitabine IV over 30 minutes and nab-paclitaxel IV over 30 minutes on days 1, 8, 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Nab-paclitaxel
Treatment (paricalcitol, hydroxychloroquine, chemotherapy)
Beginning day -14, patients receive paricalcitol IV three times weekly and hydroxychloroquine PO BID. Patients also receive gemcitabine IV over 30 minutes and nab-paclitaxel IV over 30 minutes on days 1, 8, 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Paricalcitol
Outcomes
Primary Outcomes
Assessment of Tumor Response to Combination of Paricalcitol and Hydroxychloroquine With Common Front-line Therapy.
Time Frame: At 8 weeks
To evaluate the anti-tumor activity of the combination of paricalcitol plus hydroxychloroquine (PH) when added to gemcitabine and nab-paclitaxel treatment by assessing the Overall Response Rate (ORR) by RECIST 1.1. ORR is defined as the percentage of people in the trial who have partial response (PR) or complete response (CR). The Response rate will be estimated with Clopper-Pearson with a 90% exact confidence interval.
Secondary Outcomes
- Incidence of Adverse Events(1 year)
- Progression-free Survival(32.5 Months)
- Overall Survival(32.5 Months)