Overview
The purpose of this Phase I study is to determine the recommended phase 2 dose (RP2D) and safety profile of NBTXR3 activated by radiation therapy for the treatment of patients with pancreatic cancer that has spread to nearby tissues or lymph nodes (locally advanced) or may be able to be removed by surgery (borderline-resectable). NBTXR3 is a drug that when activated by radiation therapy, may cause targeted destruction of cancer cells. Radiation therapy uses high energy to kill cancer cells and shrink tumors. Giving NBTXR3 followed by radiation therapy may work better to treat locally advanced or borderline-resectable pancreatic cancer compared to radiation therapy alone.
Description
PRIMARY OBJECTIVE:
I. To determine the recommended phase II dose (RP2D) of hafnium oxide nanoparticles NBTXR3 (NBTXR3) activated by radiation therapy (RT) (hereafter referred to R3/RT).
SECONDARY OBJECTIVES:
I. To evaluate the anti-tumor response of R3/RT. II. To evaluate the safety and feasibility of R3/RT. III. To evaluate time-to-event outcomes.
EXPLORATORY OBJECTIVES:
I. To evaluate the body kinetic profile of intratumorally injected NBTXR3. II. To evaluate time to event outcomes for subjects with clinical staging of locally advanced, unresectable disease.
III. To evaluate resectability conversion rates. IV. To evaluate surgical outcomes in subjects who undergo surgery after radiation therapy.
V. To associate radiomic measurements with outcomes. VI. To evaluate biomarkers of response in subjects treated with R3/RT.
OUTLINE: This is a dose-escalation study of NBTXR3.
Patients receive NBTXR3 intratumorally (IT) on day 1. Patients then undergo 15 fractions of intensity modulated radiation therapy (IMRT) between days 15-43 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 1 month and then every 3 months for up to 1 year.
Eligibility
Inclusion Criteria:
- Signed informed consent form (ICF) indicating that participant understands the purpose of, and procedures required for, the study and is willing to participate in the study
- Biopsy proven ductal adenocarcinoma of the pancreas as defined by the following:
- Borderline resectable pancreatic adenocarcinoma (BRPC) has no aortic involvement with at least ONE of the following features:
- Superior mesenteric vein (SMV) or portal vein (PV) with a tumor interface of >= 180 degrees OR short segment occlusion amenable to reconstruction
- Superior mesenteric artery (SMA) or celiac axis (CA) with a tumor interface of < 180 degrees
- Any degree of hepatic artery interface this is amenable to reconstruction
- Locally advanced pancreatic adenocarcinoma (LAPC) has at least ONE of the following features:
- Occlusion of the SMV or PV that is not amenable to reconstruction
- Tumor interface of the SMA or CA >= 180 degrees
- Involvement of the hepatic artery that is not amenable to reconstruction
- Aortic involvement
- Has had a 4-month course (+/- 2-months) of chemotherapy for PDAC without radiographic evidence of metastatic disease. Following chemotherapy regimens are allowed:
- Gemcitabine/nab-paclitaxel
- Gemcitabine/capecitabine
- Gemcitabine/cisplatin
- Gemcitabine
- Leucovorin calcium, fluorouracil and oxaliplatin (FOLFOX)
- Fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX)
- Amenable to undergo the endoscopic ultrasound guided injection of NBTXR3 as per investigator or treating physician
- Has a target lesion in the pancreas that is identifiable on cross sectional imaging by repeated measurements (via Response Evaluation Criteria for Solid Tumors [RECIST v1.1]) at the same anatomical location
- Nodal disease only is not allowed
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Hemoglobin >= 8.0 g/dL (at screening)
- Absolute neutrophil count (ANC) >= 1,500/mm^3 (at screening)
- Platelet count >= 100,000/mm^3 (at screening)
- Creatinine =< 1.5 x upper limit of normal (ULN) (at screening)
- Total bilirubin =< 2.0 mg/dL (at screening)
- Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) (at screening)
- Negative pregnancy test =< 7 days prior to NBTXR3 injection in all females of child-bearing potential
- If participant has a history of prior duodenal or biliar plastic stent, it should be replaced with a metal stent >= 1 weeks prior to study day 1
Exclusion Criteria:
- Prior radiation therapy to the upper abdomen
- Prior surgical resection of pancreatic tumor
- Diagnosis other than pancreatic ductal adenocarcinoma. All other histologic types (i.e., adenosquamous, cystadenocarcinoma, etc.) are not eligible to participate on this study
- LAPC or BRPC with radiographic evidence of metastasis at screening
- Receiving any approved or investigational anti-neoplastic agent other than the chemotherapies specified in this protocol (i.e., chemotherapies listed above)
- Known uncontrolled (grade >= 2) or active gastric or duodenal ulcer disease within 30 days of enrollment
- Known contraindication to iodine-based or gadolinium-based intravenous (IV) contrast
- Active malignancy, in addition to pancreatic cancer, with the exception of basal cell carcinoma of the skin definitively treated and relapse free within at least 1 year since diagnosis
- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes, second or third degree atrioventricular heart block without a permanent pacemaker in place)
- Class III or IV congestive heart failure as defined by the New York Heart Association functional classification system < 6 months prior to screening
- Known active, uncontrolled (high viral load) human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection
- Patients who have been vaccinated for hepatitis B and do not have a history of infection are eligible
- Female patients who are pregnant or breastfeeding
- Women of child-bearing potential and their male partners who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period. Acceptable methods of contraception are those that, alone or in combination, result in a failure rate of < 1% per year when used consistently and correctly
- Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments