Proton w/FOLFIRINOX-Losartan for Pancreatic Cancer

• ClinicalTrials.gov Identifier: NCT01821729
• Recruitment Status: Unknown
• First Posted: April 1, 2013
• Results First Posted: September 17, 2019
• Last Update Posted: September 25, 2020
• Sponsor: Massachusetts General Hospital
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Theodore Sunki Hong, Massachusetts General Hospital

Tracking Information

• First Submitted Date: March 27, 2013
• First Posted Date: April 1, 2013
• Results First Submitted Date: August 27, 2019
• Results First Posted Date: September 17, 2019
• Last Update Posted Date: September 25, 2020
• Study Start Date: July 2013
• Actual Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 27, 2019)

Number of Participants With R0 Resection [ Time Frame: At the time of surgery (approximately 4 months after the start of treatment) ]

The number of participants that received treatment with proton radiation along with FOLFIRINOX-Losartan and then subsequently underwent attempted surgery and achieved R0 resection. R0 resection means that no cancer cells were seen microscopically at the resection margin.

Original Primary Outcome Measures (submitted: March 27, 2013)

Feasibility of combining FOLFIRINOX-Losartan [ Time Frame: 2 years ]

To determine the feasibility of the combination of FOLIRINIOX-Losartan in patients with locally advanced unresectable pancreas cancer determining the proportion free of radiographic progression at the time of restaging and consideration of proton therapy after induction chemotherapy

Current Secondary Outcome Measures (submitted: August 27, 2019)

• Progression-Free Survival [ Time Frame: From the start of treatment until death or progression, median duration of 17.5 months ]
  To determine the progression free survival of patients with locally advanced disease who receive FOLFIRINOX-Losartan and proton beam radiation therapy. Disease progression was assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Progressive disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesion, taking as reference the smal lest sum LD recorded since the treatment started or the appearance of one or more new lesions (new lesions must be > slice thickness).
• Overall Survival for FOLFIRINOX + Proton Beam Radiation [ Time Frame: 2 years ]
  To determine overall survival in patients treated with preoperative FOLFIRINOX and proton beam radiation therapy
• Overall Survival for FOLFIRINOX Without Proton Radiation [ Time Frame: 2 years ]
  To determine the overall survival of patients with locally advanced disease who receive FOLFIRINOX-Losartan without proton radiation (i.e. patients who demonstrate progression at restaging)
• Determine Toxicity FOLFIRINOX-Losartan [ Time Frame: 2 years ]
  To determine the toxicity of FOLFIRINOX-Losartan in patients with locally advanced pancreatic disease
• Determine Toxicity of FOLFIRINOX-Losartan and Proton Beam Radiation [ Time Frame: 2 years ]
  To determine the toxicity of FOLFIRINOX-Losartan and proton beam radiation in patients with locally advanced pancreatic cancer.
• Rate of Downstaging [ Time Frame: 2 years ]
  To determine the rate of downstaging to surgical resection of FOLFIRINOX-Losartan followed by proton radiation in patients with locally advanced pancreatic cancer
• Determine Correlation of Somatic Gene Mutations and Outcome [ Time Frame: 2 years ]
  To determine the correlation between a panel of somatic genetic mutations (SNaPSHOT) and outcome in locally advanced pancreatic cancer treated with FOLFIRINOX-Losartan +/- proton beam radiation/capecitabine
• Determine Correlation Between Circulating Biomarkers and Outcome [ Time Frame: 2 years ]
  To determine the correlation between circulating biomarkers of TGF-B1 downregulation, including circulating Collagen I levels, and outcome in locally advanced pancreatic cancer treated with FOLFIRINOX-Losartan +/- proton beam radiation/capecitabine.
• Describe Quality of Life, Symptom Burden and Mood [ Time Frame: 2 years ]
  Describe quality of life, symptom burden and mood in the study population
• To Measure Utilization of Health Services [ Time Frame: 2 years ]
  To measure utilization of health services (ER, hospital and ICU visits) in the study population

Original Secondary Outcome Measures (submitted: March 27, 2013)

• Progression-Free Survival [ Time Frame: 2 years ]
  To determine the progression free survival of patients with locally advanced disease who receive FOLFIRINOX-Losartan and proton beam radiation therapy
• Overall Survival for FOLFIRINOX + Proton Beam Radiation [ Time Frame: 2 years ]
  To determine overall survival in patients treated with preoperative FOLFIRINOX and proton beam radiation therapy
• Overall Survival for FOLFIRINOX Without Proton Radiation [ Time Frame: 2 years ]
  To determine the overall survival of patients with locally advanced disease who receive FOLFIRINOX-Losartan without proton radiation (i.e. patients who demonstrate progression at restaging)
• Determine Toxicity FOLFIRINOX-Losartan [ Time Frame: 2 years ]
  To determine the toxicity of FOLFIRINOX-Losartan in patients with locally advanced pancreatic disease
• Determine Toxicity of FOLFIRINOX-Losartan and Proton Beam Radiation [ Time Frame: 2 years ]
  To determine the toxicity of FOLFIRINOX-Losartan and proton beam radiation in patients with locally advanced pancreatic cancer.
• Rate of Downstaging [ Time Frame: 2 years ]
  To determine the rate of downstaging to surgical resection of FOLFIRINOX-Losartan followed by proton radiation in patients with locally advanced pancreatic cancer
• Determine correlation of Somatic Gene Mutations and Outcome [ Time Frame: 2 years ]
  To determine the correlation between a panel of somatic genetic mutations (SNaPSHOT) and outcome in locally advanced pancreatic cancer treated with FOLFIRINOX-Losartan +/- proton beam radiation/capecitabine
• Determine Correlation Between Circulating Biomarkers and Outcome [ Time Frame: 2 years ]
  To determine the correlation between circulating biomarkers of TGF-B1 downregulation, including circulating Collagen I levels, and outcome in locally advanced pancreatic cancer treated with FOLFIRINOX-Losartan +/- proton beam radiation/capecitabine.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Proton w/FOLFIRINOX-Losartan for Pancreatic Cancer
• Official Title: Phase II Feasibility Study of FOLFIRINOX-Losartan Followed by Accelerated Short Course Radiation Therapy With Capecitabine for Locally Advanced Pancreatic Cancer

Brief Summary

This is a Phase II clinical trial, which tests the safety and effectiveness of an investigational combination of drugs to learn whether the combination of drugs works in treating a specific cancer. "Investigational" means that the combination of drugs is being studied. It also means that the FDA has not yet approved it for your type of cancer. Proton beam radiation therapy is an FDA approved radiation delivery system.

Conventional radiation therapy uses photons to treat cancer before patients undergo surgery to remove the tumor. In this study we are using radiation with protons, which spares surrounding tissue and organs from radiation. Proton radiation delivers radiation to the area requiring radiation with no dose beyond the treatment area. This may reduce side effects that patients would normally experience with conventional radiation therapy.

Researchers in the laboratory have discovered pathways inside cancer cells which contribute to the growth and survival of tumors. The FOLFIRINOX chemotherapy regimen is a combination of the drugs 5-fluorouracil, leucovorin and oxaliplatin. These chemotherapy drugs, along with the chemotherapy drug capecitabine, work by blocking these pathways and thereby preventing tumor growth. Capecitabine is FDA approved to be used alone or with other drugs to treat other types of advanced cancer, but not pancreatic cancer. In past research studies, FOLFIRINOX followed by radiation therapy with capecitabine has been identified as the most effective and active chemotherapy for patients with cancer that is spreading, and this is why we are using it to treat your type of cancer.

Losartan is classified as an angiotensin-receptor blocker (ARB), and is FDA approved for use in people with high blood pressure. Recent studies in people with different types of cancer, including pancreatic cancer, have shown that combining chemotherapy drugs with an ARB can help reduce/stop tumor growth more effectively than chemotherapy alone. Losartan has been used in previous research studies, and information from those research studies suggests that this drug in combination with FOLFIRINOX and capecitabine may be better at treating your type of cancer.

In this research study, we seek to determine whether combining FOLFIRINOX with Losartan before proton radiation therapy will be more efficient at controlling the growth of or shrinking your tumor than just FOLFIRINOX alone.

Detailed Description

If you are willing to participate in this research study, you will be asked to undergo some screening tests and procedures to confirm that you are eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that you do not take part in the research study. If you have had some of these tests or procedures recently, they may or may not have to be repeated. These tests and procedures will include a medical history, routine physical exam, performance status, assessment of your tumor, routine blood tests, a blood sample to check your kidney function and a serum or urine pregnancy test if applicable. If these tests show that you are eligible to participate in the research study, you will begin the study treatment. If you do not meet the eligibility criteria, you will not be able to participate in this research study.

There are two phases to this study. Phase I involves FOLFIRINOX and Losartan. The treatment plant will begin with 8 cycles of FOLFIRINOX. Each cycle is 14 days, or 2 weeks long. FOLFIRINOX is comprised of four drugs: Oxaliplatin, irinotecan, fluorouracil and leucovorin. On Day 1 of each 14 day cycle, you will receive oxaliplatin via IV infusion over a period of 2 hours. Irinotecan will be administered via IV infusion on Day 1 of each cycle over a period of 90 minutes.

You will receive fluorouracil (5FU) on Day 1 of each cycle via IV infusion over a period of 2-4 minutes. You will then be fitted with an ambulatory infusion pump that will be delivered continuously over 46-48 hours.

In addition to these infusions, FOLFIRINOX will always be administered along with a two hours IV infusion of leucovorin, a drug composed of reduced folic acid, which helps enhance the effects of chemotherapy. You will be give leucovorin through a vein in your arm for 2 hours a day on Day 1 of each cycle.

You will also receive an injection of Neulasta after each FOLFIRINOX treatment. Neulasta is used to reduce the chance of infection from chemotherapy by boosting your white blood cell count. It will be administered 24-48 hours after your FOLFIRINOX infusion (on Day 3 or 4).

You will take one dose of Losartan by mouth every day during Phase I for all 8 cycles of FOLFIRINOX. If the dose of Losartan given to you during the first week does not give you any serious side effects, your dose will be increased once for the remainder of Phase I. We have provided a drug diary for you with instructions on how to take this tablet and what to do incase of any missed or vomited doses. We will monitor your response to treatment with a chest/abdominal CT after four cycles of FOLFIRINOX therapy (8 weeks).

Phase II involves Restaging/Proton Beam Radiation Therapy and Capecitabine. At this time your study doctor will assess for any progress in your cancer after the FOLFIRINOX + Losartan treatment again via CT scan. If your cancer has progressed, you will be removed from the study and continue with standard of care treatment. If it has not progressed, you will continue to the proton radiation therapy and capecitabine phase of the study.

During this phase you will receive proton beam radiation therapy at the Francis H. Burr Proton Therapy center for 1 week, Monday through Friday. Each visit is expected to take 30-45 minutes.

During the week of proton radiation therapy and for the week after, you will take capecitabine by mouth on Monday through Friday, for a total of ten days. You will be given a drug diary with instructions on how to take capecitabine and what to do in case of a missed or vomited dose.

You will receive the following tests and procedures at various time points during both portions of the study. These tests and procedures will include: routine blood tests, blood sample to check kidney function, CA19-9 and CEA blood tests, Chest CT/Abdominal-Pelvic CT, assessment for side effects, vital signs, performance status, routine physical exam and blood pressure monitoring.

After the final dose of study drug you will come into the clinic for follow-up visits for some assessments every 3 months until your cancer progresses. You will undergo the following tests: routine physical exam, vital signs, performance status, routine blood tests, assessment for side effects. In addition you are required to have a chest and abdominal/pelvic CT every 6 months for the first two years, and yearly for years 3-5. We would like to keep track of your medical condition for the rest of your life. We would like to do this by calling you on the telephone once a year to see how you are doing. Keeping in touch with you and checking on your condition every year helps us look at the long term effects of the research study.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pancreatic Cancer

Intervention

• Drug: FOLFIRINOX
  Oxaliplatin via IV on Day 1 over 2 hours; Irinotecan via IV on Day 1 over 90 minutes, 5FU via IV on Day 1 over 2-4 minutes
  Other Names:

  • 5-Fluorouracil
  • 5FU
  • Leucovorin
  • Oxaliplatin
• Drug: Losartan
  Taken orally every day during Phase I for all 8 cycles
• Radiation: Proton Beam Radiation
  30-45 minutes per day, daily Monday-Friday

Study Arms

Experimental: Experimental Arm

FOLFIRINOX, Losartan, Proton Beam Radiation Therapy

Interventions:

• Drug: FOLFIRINOX
• Drug: Losartan
• Radiation: Proton Beam Radiation

• Publications *: Murphy JE, Wo JY, Ryan DP, Clark JW, Jiang W, Yeap BY, Drapek LC, Ly L, Baglini CV, Blaszkowsky LS, Ferrone CR, Parikh AR, Weekes CD, Nipp RD, Kwak EL, Allen JN, Corcoran RB, Ting DT, Faris JE, Zhu AX, Goyal L, Berger DL, Qadan M, Lillemoe KD, Talele N, Jain RK, DeLaney TF, Duda DG, Boucher Y, Fernandez-Del Castillo C, Hong TS. Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. JAMA Oncol. 2019 Jul 1;5(7):1020-1027. doi: 10.1001/jamaoncol.2019.0892.

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: January 18, 2017): 50
• Original Estimated Enrollment (submitted: March 27, 2013): 32
• Estimated Study Completion Date: September 2021
• Actual Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Cytologic or histologic proof pancreatic ductal carcinoma
• Locally advanced, unresectable disease
• Life expectancy of at least 3 months

Exclusion Criteria:

• Evidence of metastatic disease
• Pregnant or breastfeeding
• Serious concomitant systemic disorders incompatible with the study
• Already treated on ACE or ARB therapy for hypertension or renal protection at the time of enrollment
• Baseline hypotension
• Prior chemotherapy, radiation therapy, or biologic therapy for treatment of pancreatic tumor
• Treatment for other invasive carcinomas within the last 5 years who are greater than 5% risk of recurrence at the time of eligibility screening (carcinoma in-situ and basal cell carcinoma/squamous cell carcinoma of the skin are allowed)
• Other serious uncontrolled medical conditions
• Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome
• Known, existing coagulopathy
• Prior systemic fluoropyrimidine therapy
• Participation in any investigational drug study within 4 weeks preceding the start of study treatment
• History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance or oral drug intake
• Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment
• Taking cimetidine
• Receiving other study agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-fluorouracil, irinotecan, oxaliplatin or losartan

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01821729
• Other Study ID Numbers: 13-051
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Theodore Sunki Hong, Massachusetts General Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Massachusetts General Hospital
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Theodore Hong, MD; Massachusetts General Hospital

• PRS Account: Massachusetts General Hospital
• Verification Date: September 2020