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

Brief summary public domain (ClinicalTrials.gov)

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.

Detailed description public domain (ClinicalTrials.gov)

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.

Intervention public domain (ClinicalTrials.gov)

Drug: Minnelide. Administered orally (2 mg) once daily for 21 days of 28-day cycles for 12 cycles.

Intervention public domain (ClinicalTrials.gov)

Diagnostic_Test: ECG. Screening and end of treatment visit.

Intervention public domain (ClinicalTrials.gov)

Diagnostic_Test: CT/MRI. Screening. Subsequent cycles Day 1 (≤3days) and Day 15 (±2 days) (every other cycle). End of treatment visit.

Intervention public domain (ClinicalTrials.gov)

Procedure: Tumor Biopsy. Optional. Baseline Cycle 1, Day 1 and Cycle 1, Day 15. End of treatment visit or progressive disease.

Arm public domain (ClinicalTrials.gov)

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

Primary outcome public domain (ClinicalTrials.gov)

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. Time frame: 16 weeks.

Secondary outcome public domain (ClinicalTrials.gov)

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). Time frame: Non-serious adverse events related to Minnelide that occur from start of treatment to 30 days after last treatment.

Secondary outcome public domain (ClinicalTrials.gov)

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). Time frame: Serious adverse events related to Minnelide that occur from start of treatment to 30 days after last treatment.

Secondary outcome public domain (ClinicalTrials.gov)

Progression Free Survival (PFS). Time frame: start of treatment to time of progression or death, a median of 1.76 months.

Secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (OS). Time frame: time from the start of treatment until death, a median of 4.91 months.

Secondary outcome public domain (ClinicalTrials.gov)

Objective Response Rate (ORR). Time frame: From start of treatment until radiological progression response or off study; the median is approximately 6 weeks.

Eligibility public domain (ClinicalTrials.gov)

* 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 …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 16 participants (actual).

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

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 [16 weeks]. Number, Proportion of participants (95% Confidence Interval). Complete Response: Arm 1, Cohort 1, Minnelide in Advanced Adenosquamous Carcinoma of the Pancreas (ASCP) (n=12): 0 (0 to 0). Partial Response: Arm 1, Cohort 1, Minnelide in Advanced Adenosquamous Carcinoma of the Pancreas (ASCP) (n=12): 0 (0 to 0). Stable Disease: Arm 1, Cohort 1, Minnelide in Advanced Adenosquamous Carcinoma of the Pancreas (ASCP) (n=12): .0083 (0.002 to 0.385).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

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 related to Minnelide that occur from start of treatment to 30 days after last treatment]. Count Of Participants, Participants. Abdominal pain: Grade 2 (n=12): 2; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Anemia: Grade 2 (n=12): 6; Grade 3 (n=12): 5; Grade 4 (n=12): 1; Grade 5 (n=12): 0. Anorexia: Grade 2 (n=12): 3; Grade 3 (n=12): 2; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Ascites: Grade 2 (n=12): 1; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Bloating: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Blood bilirubin increased: Grade 2 (n=12): 1; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Chills: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Creatinine increased: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Dehydration: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Diarrhea: Grade 2 (n=12): 2; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Encephalopathy: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 1; Grade 5 (n=12): 0. Enterocolitis infectious: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Eye disorders - Other, specify - corneal abrasion of the right eye: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Fall: Grade 2 (n=12): 3; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Fatigue: Grade 2 (n=12): 3; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Hiccups: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Hypercalcemia: Grade 2 (n=12): 1; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Hypoalbuminemia: Grade 2 (n=12): 4; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Hypoglycemia: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Hypokalemia: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Hyponatremia: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Hypophosphatemia: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Hypotension: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Malaise: Grade 2 (n=12): 2; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Nausea: Grade 2 (n=12): 5; Grade 3 (n=12): 3; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Neutrophil count decreased: Grade 2 (n=12): 2; Grade 3 (n=12): 2; Grade 4 (n=12): 1; Grade 5 (n=12): 0. Oropharyngeal pain: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Pain: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Platelet count decreased: Grade 2 (n=12): 3; Grade 3 (n=12): 2; Grade 4 (n=12): 3; Grade 5 (n=

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

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 related to Minnelide that occur from start of treatment to 30 days after last treatment]. Count Of Participants, Participants. Abdominal pain: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Anemia: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Dehydration: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Dyspnea: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Encephalopathy: Grade 2 (n=12): 0; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 1. Enterocolitis: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Nausea: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Nervous system disorders - Other specify - balance difficulty: Grade 2 (n=12): 1; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Stroke: Grade 2 (n=12): 0; Grade 3 (n=12): 0; Grade 4 (n=12): 0; Grade 5 (n=12): 1. Thromboembolic event: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Upper gastrointestinal hemorrhage: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0. Urinary tract infection: Grade 2 (n=12): 0; Grade 3 (n=12): 1; Grade 4 (n=12): 0; Grade 5 (n=12): 0.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Progression Free Survival (PFS) [start of treatment to time of progression or death, a median of 1.76 months]. Median, Months (95% Confidence Interval). Arm 1, Cohort 1, Minnelide in Advanced Adenosquamous Carcinoma of the Pancreas (ASCP) (n=12): 1.76 (0.90 to 2.62).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (OS) [time from the start of treatment until death, a median of 4.91 months]. Median, Months (95% Confidence Interval). Arm 1, Cohort 1, Minnelide in Advanced Adenosquamous Carcinoma of the Pancreas (ASCP) (n=12): 4.91 (1.96 to 7.85).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Objective Response Rate (ORR) [From start of treatment until radiological progression response or off study; the median is approximately 6 weeks]. Number, percentage of participants. Complete Response: Arm 1, Cohort 1, Minnelide in Advanced Adenosquamous Carcinoma of the Pancreas (ASCP) (n=12): 0. Partial Response: Arm 1, Cohort 1, Minnelide in Advanced Adenosquamous Carcinoma of the Pancreas (ASCP) (n=12): 0.