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Pembrolizumab with or without Defactinib before and after Surgery for the Treatment of Resectable Stage I-IIB Pancreatic Ductal Adenocarcinoma

Trial Status: Active

This phase II trial studies how well pembrolizumab with or without defactinib works before and after surgery for the treatment of stage I-IIB pancreatic ductal adenocarcinoma that can be removed by surgery (resectable). 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. Defactinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This study is being done to test the effectiveness (anti-tumor activity), safety, and ability to increase the body's immune system to fight pancreatic cancer by combining standard chemotherapy before and after surgery, with pembrolizumab, with and without defactinib.

Inclusion Criteria

  • INITIAL ENROLLMENT (PRE NEO-ADJUVANT CHEMOTHERAPY): Has histologically confirmed diagnosis of pancreatic ductal adenocarcinoma will be enrolled in this study
  • INITIAL ENROLLMENT (PRE NEO-ADJUVANT CHEMOTHERAPY): Has resectable disease at the time of diagnosis
  • INITIAL ENROLLMENT (PRE NEO-ADJUVANT CHEMOTHERAPY): Has received no systemic therapy for pancreatic ductal adenocarcinoma (PDAC) (prior symptomatic treatments such as pain medicines are acceptable)
  • INITIAL ENROLLMENT (PRE NEO-ADJUVANT CHEMOTHERAPY): Has stage =< IIb disease at time of diagnosis and trial enrollment
  • INITIAL ENROLLMENT (PRE NEO-ADJUVANT CHEMOTHERAPY): Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization
  • INITIAL ENROLLMENT (PRE NEO-ADJUVANT CHEMOTHERAPY): Has CA 19-9 > 200 in setting of a total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN. This criteria only applies at the time of initial pre study enrollment evaluation
  • INITIAL ENROLLMENT (PRE NEO-ADJUVANT CHEMOTHERAPY): A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of any study treatment and refrain from donating sperm during this period
  • INITIAL ENROLLMENT (PRE NEO-ADJUVANT CHEMOTHERAPY): A female participant is eligible to participate if she is not pregnant (in the case of a positive human chorionic gonadotropin [HCG] test, a transvaginal ultrasound must be used to confirm lack of pregnancy), not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of any study treatment
  • INITIAL ENROLLMENT (PRE NEO-ADJUVANT CHEMOTHERAPY): The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
  • NEOADJUVANT THERAPY (PRE-NEOADJUVANT THERAPY): Absolute neutrophil count (ANC) >= 1000/uL (within 3 days prior to the start of study treatment)
  • NEOADJUVANT THERAPY (PRE-NEOADJUVANT THERAPY): Platelets >= 80,000/uL (within 3 days prior to the start of study treatment)
  • NEOADJUVANT THERAPY (PRE-NEOADJUVANT THERAPY): Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 3 days prior to the start of study treatment) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
  • NEOADJUVANT THERAPY (PRE-NEOADJUVANT THERAPY): Creatinine =< 1.5 x ULN OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (within 3 days prior to the start of study treatment) * Creatinine clearance (CrCl) should be calculated per institutional standard
  • NEOADJUVANT THERAPY (PRE-NEOADJUVANT THERAPY): Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (within 3 days prior to the start of study treatment) (except subjects with Gilbert syndrome, who may enroll as long as total bilirubin < 3.0 mg/dL)
  • NEOADJUVANT THERAPY (PRE-NEOADJUVANT THERAPY): Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x ULN (within 3 days prior to the start of study treatment)
  • ADJUVANT IMMOTHERAPY (POST-SURGERY): Absolute neutrophil count (ANC) >= 1,000/uL (within 3 days of dosing with investigational agent[s])
  • ADJUVANT IMMOTHERAPY (POST-SURGERY): Platelets >= 80,000/uL (within 3 days of dosing with investigational agent[s])
  • ADJUVANT IMMOTHERAPY (POST-SURGERY): Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 3 days of dosing with investigational agent[s]) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
  • ADJUVANT IMMOTHERAPY (POST-SURGERY): Creatinine =< 1.5 x ULN OR measured or calculated craetinine clearance (GFR can also be used in place of CrCl) >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (within 3 days of dosing with investigational agent[s]) * Creatinine clearance (CrCl) should be calculated per institutional standard
  • ADJUVANT IMMOTHERAPY (POST-SURGERY): Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (except subjects with Gilbert syndrome, who may enroll as long as total bilirubin < 3.0 mg/dL) (within 3 days of dosing with investigational agent[s])
  • ADJUVANT IMMOTHERAPY (POST-SURGERY): AST (SGOT) and ALT (SGPT) =< 3.0 x ULN (within 3 days of dosing with investigational agent[s])

Exclusion Criteria

  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Receiving, or previously received, any chemotherapy, radiation therapy or investigational agent for pancreatic cancer
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has received prior therapy with FAK inhibitor
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization and allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has a known additional malignancy that is progressing or has required active treatment within the past 2 years or that is expected to require active treatment within two years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, low grade prostate cancer or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has known active metastasis, central nervous system (CNS) metastases and/or carcinomatous meningitis
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has active autoimmune disease that has required systemic treatment in the 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
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has an active infection requiring systemic therapy
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has a known history of human immunodeficiency virus (HIV)
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA] qualitative detection) infection. Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study: pembrolizumab and defactinib
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Received growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin, within 14 days of study drug administration. Use of such agents while on receiving study treatments is also prohibited. Use of agents during standard of care (SOC) therapies, as long as they are > 14 days from the administration of study therapies (pembrolizumab and defactinib) are allowed
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Is taking a medication that is a strong inhibitor or inducer of CYP3A4, CYP2C9, OATP1B1 or OATPIB3
  • INITIAL ENROLLMENT (PRE-NEOADJUVANT CHEMOTHERAPY): Has history of any organ transplant, including corneal transplants
  • NEOADJUVANT IMMUNOTHERAPY (POST-NEOADJUVANT CHEMOTHERAPY): Evidence of metastatic disease on pre-immunotherapy computed tomography (CT) or magnetic resonance imaging (MRI) imaging
  • NEOADJUVANT IMMUNOTHERAPY (POST-NEOADJUVANT CHEMOTHERAPY): Unable to complete at least 1 cycle of neoadjuvant standard of care chemotherapy with gemcitabine and nab-paclitaxel (patient should have minimum of 3 doses over two cycles)
  • NEOADJUVANT IMMUNOTHERAPY (POST-NEOADJUVANT CHEMOTHERAPY): Received growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug administration
  • NEOADJUVANT IMMUNOTHERAPY (POST-NEOADJUVANT CHEMOTHERAPY): Is taking a medication that is a strong inhibitor or inducer of CYP3A4, CYP2C9, OATP1B1 or OATPIB3
  • NEOADJUVANT IMMUNOTHERAPY (POST-NEOADJUVANT CHEMOTHERAPY): Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
  • NEOADJUVANT IMMUNOTHERAPY (POST-NEOADJUVANT CHEMOTHERAPY): Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
  • NEOADJUVANT IMMUNOTHERAPY (POST-NEOADJUVANT CHEMOTHERAPY): Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
  • ADJUVANT IMMUNOTHERAPY (POST-SURGERY): More than 90 days have elapsed since surgery (in the absence of adjuvant chemotherapy). The subject will be considered off treatment
  • ADJUVANT IMMUNOTHERAPY (POST-SURGERY): Subjects who were found to have unresectable or metastatic disease intraoperatively
  • ADJUVANT IMMUNOTHERAPY (POST-SURGERY): Subjects who develop disease recurrence in the adjuvant setting. These subjects will be monitored for the safety endpoint but will not continue to receive further immunotherapy and FAK inhibition or immunotherapy alone
  • ADJUVANT IMMUNOTHERAPY (POST-SURGERY): Are found to have an R2 resection following surgery
  • ADJUVANT IMMUNOTHERAPY (POST-SURGERY): Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
  • ADJUVANT IMMUNOTHERAPY (POST-SURGERY): Has severe hypersensitivity (≥Grade 3) to defactinib and/or any of its excipients
  • ADJUVANT IMMUNOTHERAPY (POST-SURGERY): Received growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days of study drug administration
  • ADJUVANT IMMUNOTHERAPY (POST-SURGERY): Is taking a medication that is a strong inhibitor or inducer of CYP3A4, CYP2C9, OATP1B1 or OATPIB3
  • ADJUVANT IMMUNOTHERAPY (POST-SURGERY): Subjects who are unable to receive second cycle of neoadjuvant immunotherapy due to treatment related toxicity from pembrolizumab or defactinib

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Lei Zheng
Phone: 410-955-8893

PRIMARY OBJECTIVES:

I. To assess changes in CD8 T cell intratumoral infiltration with pembrolizumab and defactinib or pembrolizumab alone, following neoadjuvant chemotherapy utilizing established multiplex immunohistochemistry (IHC).

II. To assess the pathologic complete response (pCR) rate of neoadjuvant pembrolizumab and focal adhesion kinase (FAK) inhibitor, defactinib or pembrolizumab alone following neoadjuvant chemotherapy.

SECONDARY OBJECTIVES:

I. To assess overall survival (OS).

II. To assess disease free survival (DFS).

III. To assess safety: the proportion of subjects experiencing at least one grade 3/4 non-lymphopenia adverse events (AE).

EXPLORATORY OBJECTIVES:

I. To assess immunogenic cell death (calreticulin IHC and signaling pathways following neoadjuvant chemotherapy/pre-immunotherapy and surgical biopsy specimens through immunohistochemistry and nanostring polymerase chain reaction (PCR) analysis.

II. To assess CD68/CD8 ratio via multiplex IHC.

III. To assess expression of programmed death-ligand (PD-L1) and programmed death (PD-1) via IHC.

IV. To assess immune signatures relevant to PD-L1/PD-1 activation and associated immunosuppressive pathways.

V. To assess pre- versus (vs.) post-treatment (pre-immunotherapy biopsy specimens and post-immunotherapy resected tumor specimens) intratumoral and peripheral blood T cell receptor (TCR) clonality.

VI. To assess changes of TAM (tumor associated macrophages), myeloid-derived suppressor cells (MDSC) and T-reg cells with pembrolizumab and defactinib or pembrolizumab alone, following neoadjuvant chemotherapy utilizing established multiplex IHC.

VII. To assess activity of pancreatic stellate cells via alpha-Smooth muscle actin (alphaSMA) and fibroblast activate protein (FAP) immunohistochemistry (IHC) with pembrolizumab and defactinib or pembrolizumab alone, following neoadjuvant chemotherapy.

VIII. To assess near pathologic complete response (CR) rate and grade 3 pathologic response rate.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and defactinib orally (PO) twice daily (BID) on days 1-21. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery between 10 to 25 days following the start of the second cycle of pembrolizumab. Following 4 cycles of standard of care chemotherapy, patients receive pembrolizumab IV on day 1 and defactinib PO BID on days 1-21. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery between 10 to 25 days following the start of the second cycle of pembrolizumab. Following 4 cycles of standard of care chemotherapy, patients receive pembrolizumab IV on day 1. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 90 days, and then every 12 weeks for up to 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Lei Zheng

  • Primary ID J18140
  • Secondary IDs NCI-2019-06307, CRMS-70184, IRB00182490
  • Clinicaltrials.gov ID NCT03727880