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Entinostat and the FOLFOX Chemotherapy Regimen in Treating Patients with Metastatic Pancreatic Cancer

Trial Status: Approved

This phase Ib trial studies the best dose of entinostat when given together with the standard of care FOLFOX chemotherapy regimen in treating patients with pancreatic cancer that has spread to other places in the body (metastatic). Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in the FOLFOX chemotherapy regimen, such as oxaliplatin, leucovorin calcium, and fluorouracil, 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. Giving the standard FOLFOX regimen together with entinostat may work better in treating patients with pancreatic cancer compared to the FOLFOX regimen alone.

Inclusion Criteria

  • Willing and able to provide written informed consent
  • Ability to comply with the protocol
  • Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma that has progressed after first-line gemcitabine + nab-paclitaxel-based chemotherapy
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
  • At least one lesion that can be measured accurately at baseline as >= 10 mm in the longest diameter (except lymph nodes which must have a short axis >= 15 mm) with CT/magnetic resonance imaging (MRI) and which is suitable for repeated measurements per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 cells / mm^3) (within 72 hours [hrs] prior to day 1 of cycle 1 of treatment)
  • Platelet count >= 150 x 10^9/L (>= 150,000 cells/mm^3) (within 72 hrs prior to day 1 of cycle 1 of treatment)
  • Hemoglobin (Hb) >= 9 g/dl (>= 9 mg/L) (within 72 hrs prior to day 1 of cycle 1 of treatment)
  • International normalized ratio (INR) =< 1.5 x upper limit of normal (ULN) (within 72 hrs prior to day 1 of cycle 1 of treatment)
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (within 72 hrs prior to day 1 of cycle 1 of treatment)
  • Bilirubin =< 1.5 x ULN (within 72 hrs prior to day 1 of cycle 1 of treatment)
  • Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 x ULN (or =< 5 x ULN in the presence of liver metastasis) (within 72 hrs prior to day 1 of cycle 1 of treatment)
  • Creatinine =< 1.5 x ULN or calculated creatinine clearance >= 50 ml/min calculated as per local institution standards (within 72 hrs prior to day 1 of cycle 1 of treatment)
  • Negative serum or urine pregnancy test within 14 days of day 1 cycle 1 for female subjects of childbearing potential. Female subjects of childbearing potential as well as male subjects must agree to use effective contraception during the study and for 120 days after the last of entinostat. Non-childbearing potential is defined as: * >= 45 years of age and has not had menses for > 2 years * Amenorrhoeic for < 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation * Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure otherwise the subject must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last dose of study drug
  • Tumor sites amenable to repeated biopsies
  • Willingness to undergo paired tumor biopsies during the trial

Exclusion Criteria

  • Subjects with known or suspected brain metastasis
  • Significant cardiovascular disease such as New York Heart Association class III/IV, cardiac failure, myocardial infarction within 6 months prior to enrollment, unstable arrhythmia, or evidence of ischemia on electrocardiography (ECG)
  • Baseline corrected QT interval (QTc) exceeding 450 msec (470 msec for females) and / or subjects receiving class 1A or class III anti-arrhythmic agents
  • Known human immunodeficiency virus (HIV) or active hepatitis A, B or C infection (with positive viral polymerase chain reaction [PCR])
  • Malignancies other than pancreatic cancer =< 5 years prior to entinostat and FOLFOX cycle 1 day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcomes (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score =< 3 + 4 and PSA < 10 ng/L undergoing active surveillance and treatment naive)
  • Severe infections =< 4 weeks prior to enrollment in the study as well as active, uncontrolled bacterial, viral or fungal infections requiring systemic treatment
  • Major surgical procedure =< 2 weeks prior to enrollment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis
  • Treatment with chemotherapy or other investigational agents within 28 days (or at least 5 x the half-life of the drug) prior to day 1 cycle 1 of entinostat and FOLFOX (6 weeks for nitrosoureas or mitomycin C)
  • Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational medicinal product (IMP) within =< 5 x the half-life of the IMP prior to day 1 cycle 1 of entinostat and FOLFOX
  • Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of entinostat or FOLFOX, may affect the interpretation of the results, render the subject at high risk from treatment complications or interferes with obtaining informed consent
  • Female subjects who are pregnant or nursing
  • Pre-existing neuropathy >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2
  • Previous treatment with platinum agents
  • Allergy to benzamide or inactive components of entinostat
  • Any contraindication to oral agents or significant nausea and vomiting, malabsorption or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption

Pennsylvania

Philadelphia
University of Pennsylvania / Abramson Cancer Center
Status: APPROVED
Contact: Thomas Benjamin Karasic
Phone: 215-614-1858

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of the combination of entinostat and oxaliplatin, leucovorin calcium, and fluorouracil (FOLFOX).

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of the entinostat and FOLFOX combination.

II. To evaluate the efficacy of entinostat and FOLFOX based on progression-free survival (PFS) at 6 months and overall response rate (ORR).

TERTIARY/EXPLORATORY OBJECTIVES:

I. To explore potential biomarkers that may help predict response to entinostat and FOLFOX including tumor immune cell infiltration and changes in circulating tumor cell biology.

II. Textural analysis of computed tomography (CT) scans including tumor density.

III. To assess the efficacy of entinostat and FOLFOX as measured by tumor size and volume changes.

IV. To assess the pharmacodynamic effect of entinostat and FOLFOX on tumor markers such as CA19.9 or other tumor marker levels (% subjects with >= 20% decrease).

OUTLINE: This is a dose-escalation study of entinostat.

Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on days 1 and 15. Patients also receive entinostat orally (PO) on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 18 months from the start of study.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
University of Pennsylvania / Abramson Cancer Center

Principal Investigator
Thomas Benjamin Karasic

  • Primary ID UPCC 19218
  • Secondary IDs NCI-2019-04231
  • Clinicaltrials.gov ID NCT03760614