Photoradiation With Verteporfin to Facilitate Immunologic Activity of Pembrolizumab in Unresectable, Locally Advance or Metastatic Pancreatic Cancer

Photodynamic Priming to Facilitate Immunologic Activity of Anti-PD1 in Patients With Pancreatic Cancer

This phase II trial tests how well photoradiation with verteporfin and pembrolizumab plus standard of care chemotherapy works in treating patients with pancreatic cancer that cannot be removed by surgery (unresectable), that has spread to nearby tissue or lymph nodes (locally advanced) or to other places in the body (metastatic). Photoradiation uses light activated drugs, such as verteporfin, that become active when exposed to light. These activated drugs may kill tumor cells. Vertoporfin may also increase tumor response to immunotherapy. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX), work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Photoradiation with verteporfin and pembrolizumab plus standard of care chemotherapy may kill more tumor cells in patients with unresectable, locally advanced or metastatic pancreatic cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Stage II Pancreatic Cancer AJCC v8; Stage III Pancreatic Cancer AJCC v8; Stage IV Pancreatic Cancer AJCC v8; Metastatic Pancreatic Adenocarcinoma; Locally Advanced Pancreatic Adenocarcinoma; Unresectable Pancreatic Adenocarcinoma
• Intervention / Treatment: Other: Questionnaire Administration; Biological: Pembrolizumab; Procedure: Biospecimen Collection; Procedure: Biopsy; Drug: Fluorouracil; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Irinotecan; Procedure: Magnetic Resonance Imaging; Procedure: Lymph Node Biopsy; Drug: Verteporfin; Procedure: Computed Tomography; Procedure: Endoscopic Ultrasound; Drug: Photodynamic Therapy; Procedure: Positron Emission Tomography

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate overall response rate (ORR) per immune-mediated Response Evaluation Criteria in Solid Tumors (iRECIST) criteria in patients with unresectable pancreatic ductal adenocarcinoma (PDAC) who have failed first line treatment treated with the combination photodynamic priming (PDP) and pembrolizumab.

SECONDARY OBJECTIVES:

I. To evaluate duration of response (DOR) per iRECIST criteria in patients treated with the combination of PDP and pembrolizumab.

II. To evaluate progression-free survival (PFS) per iRECIST criteria in patients treated with the combination of PDP and pembrolizumab.

III. To evaluate overall survival (OS) in patients treated with the combination of PDP and pembrolizumab.

IV. To evaluate toxicity profile per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 as assessed by treating clinicians of the combination of PDP and pembrolizumab.

OTHER OBJECTIVES:

I. To evaluate the local and systemic immune response by evaluation of tumor directed cytotoxic lymphocytes within the primary and metastatic tumor sites using endoscopic ultrasound (EUS) guided fine needle aspiration before and after PDP.

II. To evaluate the biomarkers generated by the lymphocyte cytotoxicity assays using harvested lymphocytes from these sites.

III. To evaluate systemically circulating tumor directed cytotoxic lymphocyte sub-populations before and after PDP.

IV. To evaluate quality of life using Quality of Life Questionnaire-Pancreatic Cancer 26 (QLQ PAN26), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).

OUTLINE:

Patients receive verteporfin intravenously (IV) and undergo a biopsy and intratumoral photoradiation over 60-90 minutes using EUS or computed tomography (CT) guidance on day 0. Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 6 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care oxaliplatin IV over 2-6 hours, leucovorin IV over 15 minutes - 2 hours, irinotecan IV over 90 minutes, and fluorouracil IV on days 3, 15 and 29 of cycle 1 only, then on days 1, 15, and 29 of remaining cycles. Cycles repeat every 42 days for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients may optionally undergo lymph node biopsy on day 2 or 3 of cycle 1. Additionally, patients undergo blood sample collection, CT, positron emission tomography (PET)/CT and optional PET/magnetic resonance imaging (MRI) on study.

After completion of study treatment, patients are followed up at 30 and 90 days and every 3 months to progression then every 6 months for up to 3 years after registration.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
      • Contact: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
      • Principal Investigator: Vinay Chandrasekhara, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years
• Primary tumor histologically or cytologically confirmed (previously biopsied) meta-static, unresectable, or locally advanced pancreatic ductal adenocarcinoma (PDAC), including malignant transformation of a mucinous tumor [intraductal papillary-mucinous neoplasm (IPMN) or mucinous cystic neoplasm (MCN)]
• Measurable disease as defined by iRECIST. NOTE: Tumor lesions in previously irradiated area are considered measurable if previous evidence of progression has been found in these lesions
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Hemoglobin ≥ 9.0 g/dL (obtained ≤ 15 days prior to registration)
• White blood cell (WBC) ≥ 2500/mm^3 (obtained ≤ 15 days prior to registration)
• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained ≤ 15 days prior to registration)
• Platelet count ≥ 100,000/mm^3 (obtained ≤ 15 days prior to registration)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 15 days prior to registration)
• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN ( ≥ 5 x ULN for patients with liver involvement) (obtained ≤ 15 days prior to registration)
• Prothrombin time (PT) / international normalized ratio (INR) / activated partial thromboplastin time (aPTT) ≤ x ULN (obtained ≤ 15 days prior to registration) OR if patient is receiving anticoagulant therapy then INR or aPTT is within target range of therapy
• Creatinine ≤ 1.5 x ULN (obtained ≤ 15 days prior to registration) OR calculated creatinine clearance ≥ 50 ml/min using the Cockcroft-Gault formula
• Negative pregnancy test done ≤ 8 days prior to registration, for persons of childbearing potential only
• Provide written informed consent
• Ability to complete questionnaire(s) by themselves or with assistance
• Willingness to provide mandatory blood specimens for correlative research
• Willingness to provide mandatory tissue specimens for correlative research
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

Exclusion Criteria:

• Any of the following because this study involves an investigational agent, the genotoxic, mutagenic, and teratogenic effects of which on the developing fetus and newborn are unknown:

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception
• Histology or cytology of pancreatic tumor other than adenocarcinoma
• History of immunodeficiency illness or immune suppressive medication including systemic steroid therapy or any other form of immunosuppressive therapy ≤ 7 days prior to registration

• Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment.

  • EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 3 months since completion of prior treatment
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• Known history of human immunodeficiency virus (HIV) infection

• Concurrent active hepatitis B (defined as hepatitis B surface antigen [HBsAg] positive and/or detectable hepatitis B virus [HBV] deoxyribonucleic acid [DNA]) and hepatitis C virus (defined as anti-hepatitis C virus [HCV] antibody [Ab] positive and detectable HCV ribonucleic acid [RNA]) infection

  • EXCEPTIONS:

    • For patients with evidence of hepatitis B virus (HBV) infection (HBsAg positive), patients must have completed at least 4 weeks of HBV antiviral therapy and the HBV viral load must be undetectable at the time of registration
    • Patients with a history of hepatitis C virus (HCV) are eligible if they have an undetectable HCV viral load. Patients must have completed curative anti-viral treatment ≥ 4 weeks prior to registration
    • NOTE: Patients without symptoms or prior history do not require testing prior to registration
• History of unstable angina, new onset angina ≤ 3 months prior to registration, myocardial infarction ≤ 6 months prior to registration, or current congestive heart failure New York Heart Association class III or higher

• Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection
  • Current diagnosis or previous history of immune-related (non-infectious) pneumonitis or interstitial lung disease that requires or required steroids
  • Active autoimmune disease that has required systemic treatment ≤ 2 years prior to registration (i.e., with the use of disease-modifying agents, cortico-steroids, or immunosuppressive drugs) NOTE: Replacement therapy (thyroxine, insulin, or physiologic corticosteroid replacement therapy) is allowed
  • Any condition requiring systemic treatment with either corticosteroids ( > 10 mg daily prednisone equivalents) or other immunosuppressive medications. NOTE: Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Or psychiatric illness/social situations that would limit compliance with study requirements

• Other active concurrent malignancy

  • EXCEPTIONS: Non-melanotic skin cancer, carcinoma-in-situ of the cervix, papillary thyroid cancer, or other in situ cancer that has undergone potentially curative therapy
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (verteportin, photoradiation, pembrolizumab); Patients receive verteporfin IV and undergo a biopsy and intratumoral photoradiation over 60-90 minutes using EUS or CT guidance on day 0. Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 6 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care oxaliplatin IV over 2-6 hours, leucovorin IV over 15 minutes - 2 hours, irinotecan IV over 90 minutes, and fluorouracil IV on days 3, 15 and 29 of cycle 1 only, then on days 1, 15, and 29 of remaining cycles. Cycles repeat every 42 days for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients may optionally undergo lymph node biopsy on day 2 or 3 of cycle 1. Additionally, patients undergo blood sample collection, CT, PET/CT and optional PET/MRI on study.

Other: Questionnaire Administration; Ancillary studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; BCD-201; Pembrolizumab Biosimilar BCD-201; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Drug: Fluorouracil; Given IV; Other Names: 5-Fluracil; Fluracil; 5 Fluorouracil; 5 Fluorouracilum; 5 FU; 5-Fluoro-2,4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; 5-Fu; 5FU; AccuSite; Carac; Fluoro Uracil; Fluouracil; Flurablastin; Fluracedyl; Fluril; Fluroblastin; Ribofluor; Ro 2-9757; Ro-2-9757; Drug: Leucovorin; Given IV; Other Names: Folinic acid; Drug: Oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; Ai Heng; Aiheng; Diaminocyclohexane Oxalatoplatinum; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; Drug: Irinotecan; Given IV; Procedure: Magnetic Resonance Imaging; Undergo PET/MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Lymph Node Biopsy; Undergo lymph node biopsy; Other Names: Biopsy of Lymph Node; Drug: Verteporfin; Given IV; Other Names: Visudyne; Benzoporphyrin Derivative Monoacid Ring A; BPD-MA; Procedure: Computed Tomography; Undergo CT or PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Endoscopic Ultrasound; Undergo EUS; Other Names: endosonography; EUS; Drug: Photodynamic Therapy; Undergo intratumoral photoradiation; Other Names: PDT; Photoradiation Therapy; Procedure: Positron Emission Tomography; Undergo PET/CT and PET/MRI; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; PT; Positron emission tomography (procedure)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	ORR will be defined as the proportion of patients who achieve complete response (CR) or partial response (PR) per immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) during protocol treatment among evaluable patients.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response (DOR)	DOR will be defined as the time from the date of first documented CR or PR to the date of first documented disease progression per iRECIST or death due to all causes, whichever occurs first.	Up to 5 years
Progression-free survival (PFS)	PFS will be defined as the time from the date of registration to the date of first documented disease progression per iRECIST or death due to all causes, whichever occurs first.	Up to 5 years
Overall survival (OS)	OS will be defined as the time from the date of registration to the date of death due to all causes, whichever occurs first.	Up to 5 years
Incidence of adverse events (AEs)	AEs will be graded using the Common Terminology Criteria for Adverse Events version 5.0. AEs and the maximum grade for each type of AE will be summarized for each patient. Frequency tables will be reviewed to determine patterns.	Up to 90 days after last dose of study drug (treatment cycles are usually 29 days)

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Vinay Chandrasekhara, M.D., Mayo Clinic in Rochester

Study record dates

Study Major Dates

• Study Start (Estimated): May 5, 2024
• Primary Completion (Estimated): July 4, 2029
• Study Completion (Estimated): July 4, 2029

Study Registration Dates

• First Submitted: April 19, 2024
• First Submitted That Met QC Criteria: April 19, 2024
• First Posted (Actual): April 24, 2024

Study Record Updates

• Last Update Posted (Actual): April 24, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Adenocarcinoma; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Photosensitizing Agents; Dermatologic Agents; Micronutrients; Vitamins; Immune Checkpoint Inhibitors; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Verteporfin; Fluorouracil; Oxaliplatin; Pembrolizumab; Leucovorin; Irinotecan
• Other Study ID Numbers: MC230404 (Other Identifier: Mayo Clinic); P30CA015083 (U.S. NIH Grant/Contract); P01CA084203 (U.S. NIH Grant/Contract); NCI-2024-03078 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 23-009036 (Other Identifier: Mayo Clinic Institutional Review Board)

Drug and device information, study documents

• 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