Clinical trial NCT03621644: Stereotactic MRI-guided On-table Adaptive Radiation Therapy (SMART) for Locally Advanced Pancreatic Cancer
Official title: Prospective Phase II Study of Stereotactic Magnetic Resonance Imaging (MRI) Guided On-table Adaptive Radiation Therapy (SMART) for Patients With Borderline or Inoperable Locally Advanced Pancreatic Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Pancreatic Cancer
Keywords: Pancreatic Cancer
Radiation Therapy
SBRT
Lead sponsor: Viewray Inc.
Sponsor class: INDUSTRY
First posted: 2018-08-08
Enrollment: 133
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: High-dose magnetic resonance imaging (MRI) guided hypofractionated radiation therapy delivered using daily adaptive dose planning has been shown in a retrospective study to result in improved overall survival, relative to patients receiving lower radiation doses, in patients with locally advanced pancreatic cancer, without increasing the rate of serious gastrointestinal toxicity.

The goal of the proposed trial is to investigative in a controlled, prospective manner the robustness of this outcome, and to track quality of life over a 5-year trial period.

Detailed description: Prior stereotactic body radiotherapy (SBRT) experiences for treatment of locally advanced pancreatic cancer entailed either single-fraction or multi-fraction approaches delivering 33 Gray (Gy) in 5 fractions. Excellent tolerance and tumor control has been demonstrated, but median survival remained approximately 14 months. This highlights the strengths and limitations of SBRT to current radiation doses for pancreatic cancer. A prior Washington University institutional study and retrospective review has shown the safety of delivering 67.5 Gy in 15 fractions for inoperable pancreatic cancer using a strict 'isotoxicity' approach of limiting the gastrointestinal (GI) organs at risk (stomach, duodenum, small bowel and large bowel) to 45 Gy to 0.5 cm3 or less. This regimen resulted in no grade 3 or higher GI toxicities, and only one death in the 19 patients with a median follow-up of 15 months. This is significantly improved from prior experiences, where approximately 15 months represents the median survival for most studies of inoperable pancreatic cancer.

A recent retrospective analysis of 42 locally advanced pancreatic cancer patients treated by magnetic resonance imaging (MRI) guided radiation therapy at four institutions (University of California, Los Angeles, University of Wisconsin, Vrije Universiteit Medical Center (VUmc), Amsterdam, and Washington University, St. Louis) demonstrated that high-dose stereotactic body radiotherapy (SBRT) or hypofractionated radiation therapy delivered using daily ADAPTIVE dose planning on an MRI-guided radiotherapy system (MRIdian, ViewRay Inc.) has the potential to further improve overall survival. A control group of 19 patients treated to more conventional radiation doses without frequent dose adaptation showed a median survival of 14.8 months, while patients treated to high radiation doses (n=23, maximum biologically equivalent dose at alpha/beta = 10 Gy, or BED10 of \> 90 Gy) under daily or almost daily adaptive re-planning had an estimated median survival of 27.8 months (p=0.005). Interestingly, increased radiation dose delivery using daily dose adaptation was correlated with less grade 3 toxicity (0% in the high dose group vs 15.8% in patients treated to lower radiation doses without dose adaptation).

The compelling data of this retrospective study prompted the development of this current prospective clinical trial designed to assess the primary objective of grade 3 or greater GI toxicity at 90 days for patients with borderline resectable or inoperable locally advanced pancreatic cancer treated with MRI-guided on-table adaptive radiation therapy and soft tissue tracking with radiation beam gating to 50 Gy in 5 fractions. Secondary objectives include assessment of (1) overall survival at 2 years, (2) distant progression free survival at 6 months, and (3) changes in patient-reported quality of life (QOL) from pre-treatment to 3 and 12 months post-treatment.

Eligibility criteria: Inclusion Criteria:

1. Histologically or cytologically confirmed locally advanced adenocarcinoma of the pancreas that is considered unresectable or borderline resectable on institutional standardized criteria of unresectability or medical inoperability. Patients with and without regional adenopathy are eligible as long as lymph nodes are adjacent to primary tumor.
2. Greater than or equal to 3 months of systemic chemotherapy
3. At least 18 years of age.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
5. Normal bone marrow and organ function as defined below:

   1. Absolute neutrophil count ≥ 500/mcL (microliters)
   2. Platelets ≥ 50,000/mcL
   3. Hemoglobin ≥ 8.0 g/dL (deciliters)
   4. Total bilirubin ≤ 1.5 x IULN
   5. Aspartate Aminotransferase AST(SGOT) / Alanine Aminotransferase ALT(SGPT) ≤ 3.0 x Institutional Upper Limit of Normal (IULN)
6. Women of childbearing 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. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
7. Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

1. Distant metastatic disease as assessed by staging positron emission tomography / computed tomography (PET/CT) or CT of the chest and abdomen within 6 weeks of starting radiation therapy
2. Carbohydrate antigen (CA19.9) \> 500 U/ml.
3. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
4. Currently receiving any other investigational agents.
5. Major surgery within 4 weeks prior to first day of treatment.
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
7. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
8. Medical/psychological contraindication to magnetic resonance imaging (MRI).

Primary outcomes:
measure: Gastrointestinal toxicity assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5
timeFrame: 90 days
Secondary outcomes:
measure: Overall survival
timeFrame: 2 years
measure: Distant progression-free survival
timeFrame: 6 months
measure: Patient-reported quality of life (QOL)
timeFrame: 3 and 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Orlando
country: United States
facility: Orlando Health
state: Florida
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health Sciences
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock
state: New Hampshire
city: New York
country: United States
facility: Cornell University
state: New York
city: Portland
country: United States
facility: Providence Portland Cancer Center
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Madison
country: United States
facility: University of Wisconisin
state: Wisconsin
city: Tel Aviv
country: Israel
facility: Assuta Medical Center
Study officials:
affiliation: Henry Ford Health System
name: Parag J Parikh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MD Anderson
name: Percy Lee, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Daniel Low, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Miami Cancer Institute
name: Michael Chuong, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rudra S, Jiang N, Rosenberg SA, Olsen JR, Roach MC, Wan L, Portelance L, Mellon EA, Bruynzeel A, Lagerwaard F, Bassetti MF, Parikh PJ, Lee PP. Using adaptive magnetic resonance image-guided radiation therapy for treatment of inoperable pancreatic cancer. Cancer Med. 2019 May;8(5):2123-2132. doi: 10.1002/cam4.2100. Epub 2019 Apr 1.