The researchers are doing this study to test the combination of radiation therapy (RT) and low dose chemotherapy in people with metastatic pancreatic cancer that has a homologous recombination deficiency (HRD) and has spread to the liver. The researchers will try to find the highest safe and effective dose of individualized dose-painted RT that can be given to the liver when combined with standard low dose chemotherapy. The conformal dose painted RT treatment plan will include higher doses of radiation to the areas of the liver where tumors can be seen, and a lower dose to the entire liver. The study will also look at blood samples from participants to learn why some people may respond to study treatment (whole liver RT in combination with low dose chemotherapy) better than others.

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the pancreas metastatic to the liver (liver metastases confirmed pathologically or radiographic liver lesions most consistent with metastases in a patient with pathologically proven pancreatic adenocarcinoma)
• Germline or biallelic somatic pathogenic mutations in the core HR genes including BRCA1, BRCA2, PALB2 and ATM genes are required for dose escalating cohort. Pathogenic germline or biallelic somatic alterations in other HR genes including (BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, RTEL1) are allowed in the expansion cohort. Confirmation of the required mutations can be from MSK IMPACT or any other approved germline genetic testing for eligibility purposes.
• ≥1 liver lesion(s) measurable on a contrast-enhanced liver CT, MRI or PET/CT performed within 6 weeks prior to study entry. Any tumor location within the liver is allowed
• At least 1 liver metastasis measuring ≤ 7 cm
• Extrahepatic disease outside the liver is permitted if the hepatic disease is judged to be life-limiting (1-2 sites of disease are allowed, including lung and non-regional nodes, up to and including 5 individual lesions)
• Age ≥18
• ECOG 0-2
• Any prior chemotherapy therapy is allowed including prior treatment with platinum containing chemotherapy and irrespective of response to prior therapy
• Prior treatment with FDA-approved or investigational biologics or novel molecularly targeted therapies, including oral or IV formulations, are permitted. Patients must be off prior targeted therapy for at least 14 days or 4 half-lives prior to the initiation of the study treatment
• Use of an effective means of contraception in men and women of child-bearing potential
• Adequate organ and marrow function within 14 days prior to study entry, defined as:
• Absolute neutrophil count (ANC)>1000/mm3
• Hemoglobin >9 gm/dl (Note: The use of transfusion or other intervention to achieve Hgb > 9.0 g/dl is acceptable.)
• Platelets >100,000/mm3
• Serum creatinine <1.5 mg/dl OR creatinine clearance of >50 cc/min
• Total bilirubin < 1.8 mg/dL
• Prothrombin time/INR < 1.7
• Albumin ≥ 28 g/L
• AST and ALT < 3 times ULN
• ALP < 2.5 times ULN

Exclusion Criteria:

• Prior invasive malignancy, except non-melanoma skin cancer, unless disease free for a minimum of 3 years

• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.

• History of underlying liver disease, including but not limited to cirrhosis, hepatitis or hemochromatosis

• History of major liver resection

• Variants of unknown significance (VUS) in core or non-core HR genes will be excluded

• Severe, active co-morbidity, defined as follows:

  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  • Transmural myocardial infarction within the last 6 months
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration

• Clinical ascites.

• Single right kidney. (A single left kidney is allowed)

• Absolute contraindication to cisplatin including severe hypersensitivity

• Pregnancy, nursing women, or women of childbearing potential, and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.