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

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

Background:

Pancreatic cancer is one of the most lethal types of cancer. American Society for Clinical Pathology (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.

Study Overview

• Status: Completed
• Conditions: Adenosquamous Carcinoma of the Pancreas
• Intervention / Treatment: Drug: Minnelide; Diagnostic test: ECG; Diagnostic test: CT/MRI; Procedure: Tumor Biopsy

Detailed Description

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 United States (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).
• initial participants will receive Minnelide at 2 mg/day by mouth (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 be treated 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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Histological or cytological diagnosis of adenosquamous carcinoma of the pancreas (ASCP) or high suspicion for ASCP as confirmed by National Institutes of Health (NIH) Laboratory of Pathology. ASCP will be defined as >=30% malignant squamous component in background of typical pancreatic ductal adenocarcinoma (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 criterion, 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 Response Evaluation Criteria in Solid Tumors (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, gastrointestinal (GI) upset.
• Age >18 years.
• Eastern Cooperative Oncology Group (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 (Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl) >= 45 mL/min for participant with creatinine levels >1.5 x institutional upper limit of normal (ULN)

• total bilirubin <= 1.5 x ULN OR direct bilirubin <= ULN for participants with total bilirubin levels >1.5 x ULN
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (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-hydroxytryptamine 3 (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 hepatitis B virus (HBV) or hepatitis C virus (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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm 1, Cohort 1, Minnelide in Advanced Adenosquamous Carcinoma of the Pancreas (ASCP); Minnelide 2mg Days 1-21 of 28-day cycle (x12)

Drug: Minnelide; Administered orally (2 mg) once daily for 21 days of 28-day cycles for 12 cycles.; Other Names: 14-O-phosphonooxymethyltriptolide-disodium-salt and Minnelide-001; Diagnostic test: ECG; Screening and end of treatment visit.; Other Names: Electrocardiogram; Diagnostic test: CT/MRI; Screening. Subsequent cycles Day 1 (≤3days) and Day 15 (±2 days) (every other cycle). End of treatment visit.; Other Names: Computed tomography/Magnetic resonance imaging; Procedure: Tumor Biopsy; Optional. Baseline Cycle 1, Day 1 and Cycle 1, Day 15. End of treatment visit or progressive disease.; Other Names: Tumor Bx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Evaluable Participants Who Experience Clinical Benefit (Disease Control Rate = Complete Response (CR)+Partial Response (PR)+Stable Disease x16 Weeks) Reported Along With a 95% Confidence Interval	To determine the single agent antitumor activity (disease control rate = CR + PR + stable disease x16 weeks) of the anti-superenhancer agent Minnelide in participants with advanced, previously treated adenosquamous carcinoma of the pancreas (ASCP) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters while on study. Progressive Disease is least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study.	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experience a Non-serious Grade 2 or Higher Toxicity, by Grade and Type of Toxicity Assessed by the Common Terminology Criteria for Adverse Events (CTCAE)	Non-serious adverse events of Minnelide were assessed by the Common Terminology Criteria for Adverse Events (CTCAE). A non-serious adverse event is any untoward medical occurrence. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse events.	Non-serious adverse events related to Minnelide that occur from start of treatment to 30 days after last treatment
Number of Participants Who Experience a Serious Grade 2 or Higher Toxicity, by Grade and Type of Toxicity Assessed by the Common Terminology Criteria for Adverse Events (CTCAE)	Serious adverse events of Minnelite were assessed by the Common Terminology Criteria for Adverse Events (CTCAE). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse events.	Serious adverse events related to Minnelide that occur from start of treatment to 30 days after last treatment
Progression Free Survival (PFS)	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. PFS will be determined using the Kaplan-Meier method and reported along with a 95% confidence interval for the median. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Progressive Disease is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.	start of treatment to time of progression or death, a median of 1.76 months
Overall Survival (OS)	OS is defined as the length of time from the start of treatment until death. OS will be determined by using the Kaplan-Meier method and reported along with a 95% confidence interval for the median.	time from the start of treatment until death, a median of 4.91 months
Objective Response Rate (ORR)	Objective response rate (ORR) will be calculated as the percentage of participants with Complete Response (CR) or Partial Response (PR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST)1.1 criteria. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.	From start of treatment until radiological progression response or off study; the median is approximately 6 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Adverse Events were monitored/assessed from the first study intervention, Study Day 1 of Cycle 1 through 30 days after the study agent (s) was/were administered

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Anish Thomas, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Skorupan N, Ahmad MI, Steinberg SM, Trepel JB, Cridebring D, Han H, Von Hoff DD, Alewine C. A phase II trial of the super-enhancer inhibitor Minnelide in advanced refractory adenosquamous carcinoma of the pancreas. Future Oncol. 2022 Jun;18(20):2475-2481. doi: 10.2217/fon-2021-1609. Epub 2022 May 10.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2022
• Primary Completion (Actual): March 30, 2025
• Study Completion (Actual): March 30, 2025

Study Registration Dates

• First Submitted: May 20, 2021
• First Submitted That Met QC Criteria: May 20, 2021
• First Posted (Actual): May 21, 2021

Study Record Updates

• Last Update Posted (Estimated): October 7, 2025
• Last Update Submitted That Met QC Criteria: September 17, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Pancreatic Ductal Adenocarcinoma; MYC; epigenetic changes; triptolide; HSP70
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Neoplasms, Complex and Mixed; Carcinoma; Pancreatic Neoplasms; Carcinoma, Adenosquamous; Diagnostic Techniques and Procedures; Diagnosis; Tomography; Diagnostic Imaging; Diagnostic Techniques, Cardiovascular; Radiography; Heart Function Tests; Electrodiagnosis; Image Interpretation, Computer-Assisted; Radiographic Image Enhancement; Image Enhancement; Photography; Tomography, X-Ray; 14-O-phosphonooxymethyltriptolide disodium salt; Magnetic Resonance Imaging; Electrocardiography; Tomography, X-Ray Computed
• Other Study ID Numbers: 10000254; 000254-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely. Genomic data is available once genomic data is uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data is made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No