- 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.
-To determine the single agent antitumor activity (disease control rate) of the
anti-superenhancer agent Minnelide in participants with advanced, previously treated ASCP
- Age >= 18 years
- Histologically confirmed ASCP
- Participants with metastatic or locally advanced unresectable disease and progression on
at least 1 prior treatment regimen
- 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
- All participants will receive Minnelide at 2 mg/day PO on Days 1-21 of a 28 day cycle.
- 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.
- INCLUSION CRITERIA:
- Histological or cytological diagnosis of ASCP as confirmed by NIH Laboratory of
Pathology. ASCP will be defined as >= 30% malignant squamous component in background
of typical PDA.
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 diagnosis of
- 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,
- 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
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
- 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
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
- 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
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
- 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