Superenhancer Inhibitor Minnelide in Advanced Refractory Adenosquamous Carcinoma of the Pancreas (ASCP)

Study Overview
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Brief Summary
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Background: Pancreatic cancer is one of the most lethal types of cancer. ASCP is a highly aggressive type of pancreatic cancer. It is very rare. Researchers want to see if a drug called Minnelide can be used to treat ASCP. Objective: To see if Minnelide is an effective treatment for ASCP. Eligibility: Adults ages 18 and older with ASCP whose cancer did not respond to previous treatments. Design: Participants will be screened with: Medical history Physical exam Blood and urine samples Evaluation of ability to do daily activities Electrocardiogram to test heart function Body and/or brain scans. For these, participants will lie in a machine that takes pictures of the body. They may have a contrast agent injected into a vein. Tumor sample. If one is not available, participants will have a tumor biopsy. The biopsy will be taken with a small needle put through the skin into the tumor. Treatment will be given in 28-day cycles, for up to 12 cycles. There is a 7-day resting period between cycles. Participants will take Minnelide by mouth every day for 21 days of each cycle. They will keep a medicine diary. Participants will have at least 1 study visit every cycle. They will review their medicine diary. They will repeat some screening tests. Participants may have optional tumor biopsies. Some participants may need to take birth control during the study and for up to 6 months after treatment. Participants will have an end-of-treatment visit 4 weeks after they stop taking the study drug. They will repeat some screening tests.

Detailed Description
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Background: Adenosquamous carcinoma of the pancreas (ASCP) is a highly aggressive variant of pancreatic ductal adenocarcinoma (PDA), the most common type of pancreas cancer. ASCP is estimated to account for 0.5-4% of the 55,000 people who are diagnosed with pancreatic cancer in the U.S. each year, making it a very rare tumor type. No prospective clinical trials specific to ASCP have ever been performed. Preclinical data in ASCP models indicate that an activated superenhancer network drives epigenetic changes which cause the prognostically unfavorable squamous differentiation. Genomic analysis of ASCP tumors identifies frequent amplification of MYC. Minnelide is a small molecule anti-superenhancer drug that inhibits MYC. The recommended dose of Minnelide has previously been established through clinical testing for other indications. Primary Objective: -To determine the single agent antitumor activity (disease control rate) of the anti-superenhancer agent Minnelide in participants with advanced, previously treated ASCP Eligibility: Age >= 18 years Histologically confirmed ASCP or high suspicion for ASCP based on histologic analysis for squamous markers Participants with metastatic or locally advanced unresectable disease and progression on at least 1 prior treatment regimen Design: This is a phase II single cohort clinical trial with one arm. The number of evaluable participants needed for the primary endpoint is 25; maximum accrual set at 55 participants (accounting for screen failures and inevaluable participants). iNITIALparticipants will receive Minnelide at 2 mg/day PO on Days 1-21 of a 28 day cycle. Later participants will receive a higher dose of 2.5 mg/day PO on the same schedule. Treatment will be continued for up to 12 cycles (1 year) in the absence of disease progression or unacceptable toxicity. Treatment response will be assessed by imaging every 2 cycles (8 weeks). Optional tumor biopsies will be requested mid-cycle 1 and at time of progression. A disease control rate of >= 40% in this highly refractory population would constitute a positive study. Up to 12 participants will treated be initially. If 3 of the 12 participants have a response, then up to 13 additional participants will be entered to determine the true response rate.

Official Title
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A Phase II Trial of the Superenhancer Inhibitor Minnelide in Advanced Refractory Adenosquamous Carcinoma of the Pancreas (ASCP)

Conditions
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Adenosquamous Carcinoma of the Pancreas

Intervention / Treatment
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* Drug: Minnelide


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Histological or cytological diagnosis of ASCP or high suspicion for ASCP as confirmed by NIH Laboratory of Pathology. ASCP will be defined as >=30% malignant squamous component in background of typical PDA. If malignant squamous component is identified in the sample, but the pathologist is unable to determine whether it is >= 30%, then the participant will be considered to have high suspicion for ASCP. Note: To meet this criteria, participant must be able to submit a suitable archival tumor specimen (primary or metastatic site) for review or currently have tumor in a location deemed low risk for core biopsy so that suitable tissue can be acquired for confirmation of diagnosis. Note that cytopathology specimens are not considered suitable for definitive diagnosis of ASCP but can be used to determine high suspicion for ASCP. Participants with metastatic, recurrent or locally advanced unresectable disease and progression or intolerance to at least 1 prior systemic treatment regimen in the advanced disease setting. Disease measurable by RECIST 1.1 criteria. Progressive disease as evidenced by increasing tumor size on radiologic assessment, increasing serum tumor marker (on last 2 measurements taken at least 1 week apart), increasing ascites, and/or worsening tumor-related symptoms such as weight loss, pain, GI upset. Age >18 years. ECOG performance status <2 (Karnofsky >60%). Be willing and able to provide written informed consent for the trial. Participants must have adequate organ and marrow function as defined below: absolute neutrophil count (ANC) >= 1,500/microL platelets >= 100,000/microL hemoglobin >= 9.0 g/dL or >= 5.6 mmol/La* Creatinine <= 1.5 x ULN OR measured or calculated *bcreatinine clearance (GFR can also be used in place of creatinine or CrCl) >= 45 mL/min for participant with creatinine levels >1.5 x institutional ULN total bilirubin <= 1.5 x ULN OR direct bilirubin <= ULN for participants with total bilirubin levels >1.5 x ULN AST (SGOT) and ALT (SGPT) <= 2.5 x ULN (<= 5 x ULN for participants with liver metastases) International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT): <= 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR = glomerular filtration rate; ULN=upper limit of normal. *a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. *b Creatinine clearance (CrCl) should be calculated per institutional standard. Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies. -The effects of Minnelide on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months (women) and 3 months (men) after the last dose of trial treatment. Male participants must also refrain from donating sperm during this period. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. EXCLUSION CRITERIA: Has uncontrolled vomiting or medical condition which inhibits oral ingestion or digestion because the study treatment is administered orally. Pregnant and/or women who are breast feeding are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Minnelide. Is currently participating and receiving trial therapy, or has participated in a trial of an investigational agent/therapy or used an investigational device within 3 weeks of the first planned treatment on this study. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1/Day 1 Requires use of ondansetron or another prohibited medication. Note that other 5-HT3 inhibitors are NOT prohibited. Has received major surgery within the last 4 weeks, minor endoscopic procedure such as biliary stenting within the last 2 weeks, or percutaneous procedure such as hepatic biopsy or celiac plexus block within 24 hours of planned treatment start date. Note: participant must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate if: a) follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression at >= 4 weeks since treatment, AND b) participant has stability of baseline neurologic symptoms without receiving immunosuppressive-doses of systemic corticosteroid (physiologic replacement doses are permitted) x7 days or increases in other supportive medications that treat neurologic symptoms such as antiepileptics x14 days. Participants with carcinomatous meningitis are excluded regardless of clinical stability. Has an active infection requiring systemic therapy. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Has known uncontrolled or poorly controlled human immunodeficiency virus (HIV) infection. HIV is considered uncontrolled or poorly controlled if an HIV-infected individual is not taking highly active anti-retroviral therapy or has a detectable viral load within the previous 6 months. Has active HBV or HCV or is currently under treatment for HBV or HCV. Active HBV or HCV does not include previously cleared HBV or HCV or successfully cured HBV or HCV through treatment Has received a live vaccine within 30 days of planned start of trial therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist (Registered Trademark)) are live attenuated vaccines, and are not allowed. -History of allergic reactions attributed to compounds of similar chemical or biologic composition to Minnelide

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Minnelide<br>Minnelide 2mg Days 1-21 of 28 day cycle (x12) | Drug: Minnelide<br>* Administered orally (2 mg) once daily for 21 days of 28-day cycles for 12 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| disease control rate | To determine the single agent antitumor activity (disease control rate = CR+PR+stable x16 weeks) of the anti-superenhancer agent Minnelide in participants with advanced, previously treated ASCP | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety and tolerability of Minnelide | AEs and SAEs of Minnelite | duration of treatment | 
| progression free survival (PFS) | frequency and grade of AEs and SAEs | start of treatment to 30 days after last treatment | 
| Overall Survival (OS) | The length of time from the start of treatment that patients diagnosed with the disease are still alive. | through 1 year after last Minnelide treatment in the last subject who completes treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic Ductal Adenocarcinoma, epigenetic changes, MYC, triptolide, HSP70