Radiation Therapy (RT) and Chemotherapy for the Treatment of Pancreatic Cancer With Homologous Recombination Deficiency That Has Spread to the Liver

• ClinicalTrials.gov Identifier: NCT05182112
• Recruitment Status: Recruiting
• First Posted: January 10, 2022
• Last Update Posted: December 9, 2022
• Sponsor: Memorial Sloan Kettering Cancer Center
• Information provided by (Responsible Party): Memorial Sloan Kettering Cancer Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Pancreatic Cancer	Radiation: Whole liver irradiation (WLI); Drug: Gemcitabine and Cisplatin	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: This is a phase I rolling 6 design dose escalation study.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Study of Precision CRT for Liver-Dominant Metastatic Pancreatic Cancer With Homologous Recombination Deficiency (PreCISeRT)
• Actual Study Start Date: December 20, 2021
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Radiation Therapy (RT) and Chemotherapy; Upon enrollment in the study, patients will undergo radiation simulation. Protocol therapy will start upon completion of RT planning (1-2 weeks). Chemoradiation will be initiated 1-2 weeks later depending on RT planning and consist of whole liver irradiation (WLI).

Radiation: Whole liver irradiation (WLI); Whole liver irradiation (WLI) to a total dose 1800cGy in 10 fractions will be given over 2 weeks with simultaneously integrated boost (SIB) to deliver focal doses of 3600cGy (dose level 1) and 4800cGy (dose level 2) to select gross lesions. SIBl dose assignment will be according to the dose escalation scheme, with all patients in dose level 1 receiving boost of 3600cGy to select lesions and those in dose level 2 receiving boosts of 4800cGy to select lesions. At least one lesion will be selected for dose escalation.; Drug: Gemcitabine and Cisplatin; Patients will start cisplatin 10 mg/m2 and gemcitabine 600 mg/m2 intravenously q2 weeks for 1 cycle while undergoing simulation and radiation treatment planning procedures. After completion of CRT, adjuvant cisplatin 25 mg/m2 and gemcitabine 600 mg/m2 q2 weeks will be continued until progression or unacceptable toxicity.

Outcome Measures

Primary Outcome Measures :

1. determine the maximum tolerated dose of focal simultaneously integrated boost (SIB) [ Time Frame: 1 year ]
   we will use a rolling 6 dose-escalation design which allows for accrual of two to six patients concurrently onto a dose level (hence tends to shorten the study conduct timeline) based on the number of patients currently enrolled and evaluable, the number experiencing dose-limiting toxicity (DLT), and the number still at risk of developing a DLT.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Marsha Reyngold, MD, PhD; 631-623-4267; reyngolm@mskcc.org

Contact: Eileen O'Reilly, MD; 646-888-4182

Locations

United States, New Jersey

Memorial Sloan Kettering Basking Ridge (All Protocol Activities); Recruiting

Basking Ridge, New Jersey, United States, 07920

Contact: Marsha Reyngold, MD, PhD 631-623-4267

Memorial Sloan Kettering Monmouth (All Protocol Activities); Recruiting

Middletown, New Jersey, United States, 07748

Contact: Marsha Reyngold, MD, PhD 631-623-4267

Memorial Sloan Kettering Bergen (All Protocol Activities); Recruiting

Montvale, New Jersey, United States, 07645

Contact: Marsha Reyngold, MD, PhD 631-623-4267

United States, New York

Memorial Sloan Kettering Suffolk - Commack (All Protocol Activities); Recruiting

Commack, New York, United States, 11725

Contact: Marsha Reyngold, MD, PhD 631-623-4267

Memorial Sloan Kettering Westchester (All Protocol Activities); Recruiting

Harrison, New York, United States, 10604

Contact: Marsha Reyngold, MD, PhD 631-623-4267

Memorial Sloan Kettering Cancer Center (All protocol activities); Recruiting

New York, New York, United States, 10065

Contact: Marsha Reyngold, MD, PhD 631-623-4267

Memorial Sloan Kettering Nassau (All Protocol Activities); Recruiting

Rockville Centre, New York, United States, 11553

Contact: Marsha Reyngold, MD, PhD 631-623-4267

Sponsors and Collaborators

Memorial Sloan Kettering Cancer Center

Investigators

• Principal Investigator: Marsha Reyngold, MD, PhD; Memorial Sloan Kettering Cancer Center

More Information

Additional Information:

Memorial Sloan Kettering Cancer Center 

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT05182112
• Other Study ID Numbers: 21-443
• First Posted: January 10, 2022
• Last Update Posted: December 9, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: 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.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Memorial Sloan Kettering Cancer Center:

Metastatic Pancreatic Cancer; Homologous Recombination Deficiency; Radiation Therapy (RT); 21-443

Additional relevant MeSH terms:

Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Gemcitabine; Antineoplastic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs