Clinical trial NCT03652428: Phase I Nab-Paclitaxel Plus Gemcitabine With Proton Therapy for Locally Advanced Pancreatic Cancer (LAPC)
Official title: Phase I Study of Concurrent Nab-Paclitaxel + Gemcitabine With Hypofractionated, Ablative Proton Therapy for Locally Advanced Pancreatic Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Locally Advanced Pancreatic Cancer
Keywords: LAPC
Nab-paclitaxel +Gemcitabine
Proton Therapy
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
First posted: 2018-08-29
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the maximum tolerated dose of the chemotherapy drugs nab-paclitaxel and gemcitabine when combined with hypofractionated ablative proton therapy for the treatment of locally advanced pancreatic cancer. You will receive proton therapy once a day (Monday - Friday) for 3 weeks. Participants will also receive chemotherapy on each Monday of those three weeks.

Detailed description: The investigators propose a phase I trial to determine the maximum tolerable dose (MTD) and the recommended dose for phase II (RP2D) of concurrent nab-paclitaxel + gemcitabine in combination with ablative IMPT delivered as a fixed dose of 67.5 Gy in 15 fractions daily fractions with 5 fractions per week. In contrast to prior pancreatic cancer studies of chemoradiotherapy which utilized photon RT to treat gross disease and elective lymph nodes (1,2) the proposed study is hypothesized to reduce toxicity risk by limiting highly conformal IMPT to the gross tumor volume. Furthermore, to increase the margin of safety in a manner similar to published data from MDACC (3), the high dose region will be limited to areas at least 5 mm from nearby GI structures (duodenum, small bowel, stomach, etc.). Regions within this area will be treated only to 37.5 Gy in 15 fractions. This dose limitation is also important given that paclitaxel, in addition to increasing systemic efficacy, is a known radiosensitizer (1).

Eligibility criteria: Inclusion Criteria:

1. Cytologic or histologic proof of adenocarcinoma of the pancreas.
2. Nonmetastatic pancreatic cancer. Metastatic disease includes spread to distant (non-regional) lymph nodes, organs, peritoneum and ascites.
3. Unequivocal radiographic findings contraindicating resection including, but not limited to, solid tumor contact with any of the following: 1) the SMA \>180º; 2) the celiac axis \>180º; 3) the first jejunal superior mesenteric artery (SMA) branch; 4) unreconstructible superior mesenteric vein (SMV)/portal vein due to tumor involvement or occclusion; 5) the most proximal draining jejunal branch into the SMV.
4. ECOG Performance Status 0 or 1.
5. Absolute neutrophil count ≥1,000/mm3
6. Platelet count ≥100,000/mm3
7. Creatinine ≤1.5 × upper limit of normal
8. Calculated creatinine clearance \>45 mL/min
9. Total bilirubin ≤2 mg/dL

Exclusion Criteria:

1. Patients with resectable or borderline resectable pancreatic cancer are ineligible.
2. No prior definitive resection of pancreatic cancer.
3. No prior radiation therapy to the abdomen that would overlap fields required in this study. Prior radiotherapy for other disease is allowed.
4. No prior chemotherapy except for FOLFIRINOX, Gem-Abrax, or Gem-Cap. A patient may be registered for the trial while undergoing chemotherapy.
5. Any grade 4 toxicity prior to start of chemoradiotherapy that may be due to induction chemotherapy.
6. Greater than 2 dose reductions during induction chemotherapy.
7. Chronic concomitant treatment with strong inhibitors of CYP3A4. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to the start of study treatment. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment.
8. Baseline Grade ≥ 2 neuropathy. Known Gilbert's disease or known homozygosity for UGAT1A1\*28 polymorphism.
9. Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 14 days of study entry if they are in childbearing years/premenopausal.
10. Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with gemcitabine and nab-paclitaxel.
11. Non-compliance with induction chemotherapy.

Primary outcomes:
measure: Maximum Tolerated Dose of Gemcitabine and nab-Paclitaxel in LAPC patients receiving proton therapy
timeFrame: Patients will be followed for 12 months after registration or until death, whichever occurs first.
Secondary outcomes:
measure: Primary Tumor Response in LAPC patients receiving proton therapy with concurrent Gemcitabine and nab-Paclitaxel
timeFrame: Patients will be followed for 12 months after registration or until death, whichever occurs first.
measure: Survival status (disease-free-survival vs. overall survival)
timeFrame: Patients will be followed for 12 months after registration or until death, whichever occurs first.
measure: Median Overall Survival of Patients
timeFrame: Patients will be followed for 12 months after registration or until death, whichever occurs first.
measure: R0 Resection
timeFrame: Patients will be followed for 12 months after registration or until death, whichever occurs first.
measure: Number of adverse events/toxicites reported during and following treatment of concurrent nab-paclitaxel + gemcitabine combined with hypofractionated ablative proton therapy
timeFrame: Patients will be followed for 12 months after registration or until death, whichever occurs first.
measure: Quality of life through and after treatment
timeFrame: Patients will be followed for 12 months after registration or until death, whichever occurs first.
Other outcomes:
Locations:
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Baltimore
country: United States
facility: University of Maryland Medical Center/Maryland Proton Treatment Center
state: Maryland
Study officials:
affiliation: University of Maryland/Maryland Proton Treatment Center
name: Jason Molitoris, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rich T, Harris J, Abrams R, Erickson B, Doherty M, Paradelo J, Small W Jr, Safran H, Wanebo HJ. Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12. Am J Clin Oncol. 2004 Feb;27(1):51-6. doi: 10.1097/01.coc.0000046300.88847.bf.
citation: Crane CH, Janjan NA, Evans DB, Wolff RA, Ballo MT, Milas L, Mason K, Charnsangavej C, Pisters PW, Lee JE, Lenzi R, Vauthey JN, Wong A, Phan T, Nguyen Q, Abbruzzese JL. Toxicity and efficacy of concurrent gemcitabine and radiotherapy for locally advanced pancreatic cancer. Int J Pancreatol. 2001;29(1):9-18. doi: 10.1385/IJGC:29:1:09.
citation: Krishnan S, Chadha AS, Suh Y, Chen HC, Rao A, Das P, Minsky BD, Mahmood U, Delclos ME, Sawakuchi GO, Beddar S, Katz MH, Fleming JB, Javle MM, Varadhachary GR, Wolff RA, Crane CH. Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation. Int J Radiat Oncol Biol Phys. 2016 Mar 15;94(4):755-65. doi: 10.1016/j.ijrobp.2015.12.003. Epub 2015 Dec 11.