Patient case: 56-year-old female with basal cell carcinoma; genetic feature: PTCH1

Clinical trial: Preoperative Pilot Study to Assess Safety and Immunological Effect of Pembrolizumab (Keytruda®) in Combination With Paricalcitol With or Without Chemotherapy in Patients With Resectable Pancreatic Cancer

Summary: The goal of this clinical research is to learn about the safety and tolerability of Keytruda® (pembrolizumab) in combination with paricalcitol, with or without standard chemotherapy in patients who have resectable pancreatic cancer. In this study, standard chemotherapy is the combination of Gemzar® (gemcitabine) and Abraxane® (nab-paclitaxel).
  Researchers also want to learn if giving the study drugs before surgery may help to control the disease. The safety of this drug combination will also be studied.

Detailed description: Study Groups:
  If you are found to be eligible to take part in this study, you will be assigned to 1 of 2 study groups based on when you joined the study. This is done because no one knows if one group is better, the same, or worse than the other.
  -  If you are in Group 1, you will receive pembrolizumab and paricalcitol.
  -  If you are in Group 2, you will receive pembrolizumab, paricalcitol, and standard chemotherapy.
  The first 3 participants will be enrolled in Group 1. After that, participants will be enrolled into groups in an alternating pattern or as decided by the study doctor until 15 patients total are enrolled per arm. Both you and the study doctor will know to which group you have been assigned.
  Study Drug Administration:
  All participants will receive pembrolizumab by vein over about 30 minutes on Days 1 and 22, and paricalcitol by vein over about 15 minutes on Days 1, 8, 15, 22, 29, and 36.
  If you are in Group 2, you will also receive gemcitabine by vein over about 30 minutes and nab-paclitaxel by vein over about 30-40 minutes, on Days 1, 8, and 15.
  Length of Treatment:
  You may be able to receive the study drugs for up to 36 days. You will no longer be able to receive treatment if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  Study Visits:
  On Days 1 and 22:
  -  You will have a physical exam.
  -  Blood (about 7-8 tablespoons) will be drawn for routine and biomarker testing.
  On Days 8, 15, 29, and 36, blood (about 3 tablespoons) will be drawn for routine tests.
  End-of-Treatment Visit:
  Within 1 week after you complete treatment:
  -  You will have a physical exam.
  -  You will have an MRI or CT scan.
  -  Blood (about 6-7 tablespoons) will be drawn for routine and biomarker testing.
  After treatment, your doctor will decide if you are eligible for surgery. If you are eligible for surgery, you will sign a separate consent document that will describe the surgery procedures and its risks in detail.
  If you are eligible for surgery, a sample of the tumor that is removed during surgery will be collected and used for research tests to study specific proteins that may be on the surface of the tumor. These tests may help better understand cancer and why it did or did not respond to the study drugs.
  Follow Up:
  About 30 days after either surgery or your last dose of drugs (if you did not have surgery):
  -  You will have a physical exam.
  -  Blood (about 2 tablespoons) will be drawn for routine and biomarker testing.
  Follow-Up:
  Every 4 months for the first year after your follow-up visit, and then every 6 months for the next 2 years, you will have standard of care imaging and blood draws. The results will be reviewed by the study staff. Your participation in this study will be over after all data has been collected.
  However, if you start a new anti-cancer treatment or the disease gets worse during follow-up, you will be called every 12 weeks to learn how you are doing. These calls will continue until you withdraw from the study or the study ends.
  This is an investigational study. Pembrolizumab is FDA approved and commercially available for the treatment of melanoma and non-small cell lung cancer. Paricalcitol is FDA approved and commercially available for preventing hyperparathyroidism (a type of hormonal disorder). Gemcitabine and nab-paclitaxel are FDA approved and commercially available for the treatment of many cancers, including pancreatic cancer.
  It is considered investigational to use the combination of pembrolizumab and paricalcitol, by itself or in combination with standard chemotherapy, to treat pancreatic cancer. The study doctor can explain how the study drugs are designed to work.
  Up to 30 participants will take part in this study. All will be enrolled at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Be willing and able to provide written informed consent for the trial.
  2. Patients must have potentially resectable pancreatic carcinoma and have agreed to undergo surgical resection at MD Anderson Cancer Center if operable. They will have undergone staging (physical examination, contrast enhanced CT or MRI (if CT contraindicated) to determine resectability.
  3. Patients with ECOG performance status 0-1 are eligible.
  4. There will be no upper age restriction. Patients less than 18 years of age are excluded from the protocol because carcinoma of the pancreas is rarely seen in the pediatric population.
  5. Have histologically or cytologically confirmed diagnosis of pancreatic carcinoma
  6. Have no known metastases.
  7. Previous systemic chemotherapy or radiation for pancreatic cancer is not allowed.
  8. In subjects requiring biliary decompression, biliary stent or drainage using percutaneous transhepatic cholangiogram (PTC) are allowed.
  9. Patients must have no fever or evidence of infection or other coexisting medical condition that would preclude administration of study drugs. Patients with uncontrolled congestive heart failure, unstable angina and myocardial infarction within 3 months will be excluded
  10. Have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication, Pembrolizumab (Cycle 1, Day 1) (female subjects of childbearing potential). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  11. Be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication (male and female subjects of childbearing potential. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  12. #11 Cont'd. Acceptable methods of contraception are as follows: Single method (one of the following is acceptable): intrauterine device (IUD), vasectomy of a female subject's male partner, contraceptive rod implanted into the skin. Combination method (requires use of two of the following): diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), hormonal contraceptive: oral contraceptive pill (estrogen/ progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection. Abstinence is acceptable if this is the usual lifestyle and preferred contraception method for the subject.
  13. Demonstrate adequate organ function (as defined in Table 2: Adequate Organ Function Laboratory Tests in protocol). All screening laboratory tests should be performed within 7 days of treatment initiation.
  Exclusion Criteria:
  1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, herbal/complementary oral or IV medicine, or used an investigation device within 4 weeks of the first dose of treatment.
  2. Major cardiovascular or pulmonary comorbidity that precludes use of general anesthesia (NYHA [New York Heart Association] Class III and IV)
  3. Had prior systemic therapy for pancreatic cancer
  4. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the P.I. and Merck.
  6. Has a diagnosed additional malignancy within 5 years prior to first dose of study treatment with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers.
  7. Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by local site investigator and radiology review.
  8. Has a known history of, or any evidence of, interstitial lung disease or (non-infectious) pneumonitis that required steroids or there is current pneumonitis.
  9. Has an active infection requiring systemic therapy.
  10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator, including dialysis.
  11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
  13. Has received prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agents, or if the subject has previously participated in Merck Pembrolizumab clinical trials.
  14. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
  15. Has documented active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). In patients without a known history of hepatitis B or C, serologies should be obtained at screening.
  16. Has received a live vaccine within 30 days of planned start of study therapy (Cycle 1, Day 1). Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed
  17. Has laboratory evidence of hypercalcemia (>/=11mg/dl (in presence of normal albumin)) and/or hyperphosphatemia (>/= 5.5).

Relevance to patient case: not relevant