A Phase IIa Clinical Trial of First-Line Cyclical Gemcitabine, Cisplatin, and Durvalumab Alternating With Pemigatinib for Advanced Biliary Tract Cancers With FGFR2 Alterations
This phase II trial tests how well giving gemcitabine, cisplatin and durvalumab alternating with pemigatinib for the treatment of biliary tract cancer with FGFR2 alterations that cannot be removed by surgery (unresectable), that has spread to nearby tissue or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill cancer cells. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pemigatinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal FGFR protein that signals cancer cells to multiply. This may help keep cancer cells from growing and may kill them. Giving gemcitabine, cisplatin and durvalumab alternating with pemigatinib may work well for the treatment of unresectable, locally advanced or metastatic biliary tract cancer with FGFR2 alterations.
• Adults 18 years of age or older with histologically or cytologically confirmed unresectable locally advanced or metastatic carcinoma of the biliary tract, including intrahepatic and extrahepatic cholangiocarcinoma, gallbladder, and ampulla of Vater, at the time of diagnosis
• Patients must have tumors classified as having FGFR2 gene fusion/rearrangements or other gain-of function alterations involved in FGFR as detected by any analytically validated, Clinical Laboratory Improvement Act (CLIA)-certified molecular testing, including commercial tests (Foundation Medicine, Caris, Tempus, Guardant360, and others) or other platforms of next generation sequencing. Gene rearrangements are structural variants that can include inversions, translocations, duplications, and truncations. In addition, all patients will have tumor specimens sent and stored centrally
• Patients are permitted to have received one 21-day or 28-day cycle of either gemcitabine/cisplatin or gemcitabine/cisplatin with immunotherapy (either durvalumab or pembrolizumab) prior to inclusion in trial, and this will count as the first cycle in the schematic
• One or more measurable lesions per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients with ECOG performance status of 2 may be considered on a case-by-case basis by Principal Investigator
• Life expectancy of greater than 4 months
• Ability to understand and participate voluntarily, sign informed consent, and follow the study treatment plan and scheduled visits
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1500/mm3)
‣ Note: Patients must not have required a blood transfusion or growth factor support ≤ 14 days before sample collection
• Platelets ≥ 75 × 109/L
‣ Note: Patients must not have required a blood transfusion or growth factor support ≤ 14 days before sample collection
• Hemoglobin ≥ 90 g/L (9 g/dL)
‣ Note: Patients must not have required a blood transfusion or growth factor support ≤ 14 days before sample collection
• Prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (APTT) are all ≤ 1.5 × upper limits of normal (ULN), with the exception of patients taking blood thinners with coagulation factor elevation associated with these drugs
• Serum bilirubin ≤ 1.5 × ULN (≤ 5 × ULN if the tumor involves the liver), unless associated with patient's primary cancer and/or metastases and with Principal Investigator's approval; biliary drains and stents are acceptable
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are ≤ 3 × ULN (if with liver metastases, AST and ALT ≤ 5 × ULN), unless associated with patient's primary cancer and/or metastases and with Principal Investigator's approval; biliary drains and stents are acceptable
• Creatinine clearance ≥ 50 mL/min (calculated according to Cockcroft-Gault formula)
• Patients with an inherited cancer syndrome or a medical/family history suggestive of an inherited cancer syndrome are eligible
• Recovery from adverse events of previous systemic anti-cancer therapies to baseline or grade 1, except for:
‣ alopecia
⁃ stable neuropathy of ≤ grade 2 due to prior cancer therapy
• Able to swallow and retain oral medication
• Patients who are human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements:
‣ They must be stable on their anti-retroviral regimen with evidence of at least two undetectable viral loads within the past 6 months on the same regimen; the most recent undetectable viral load must be within the past 12 weeks.
⁃ They must have a CD4 count of greater than 250 cells/mcL over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count \< 200 cells/mcL over the past 2 years, unless it was deemed related to the cancer and/or chemotherapy induced bone marrow suppression.
⁃ For patients who have received chemotherapy in the previous one month, a CD4 count \< 250 cells/mcL during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy.
⁃ They must have an undetectable viral load and a CD4 count ≥ 250 cells/mcL within 7 days of enrollment.
⁃ They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months. HIV-infected patients will be monitored every 12 weeks for viral load and CD4 counts
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of hepatitis B surface antigen \[HbsAg\]) are eligible
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)