A Phase II, International Open Label Trial of Minnelide™ in Patients With Refractory Pancreatic Cancer

Inclusion Criteria:

1. Willing and able to provide written informed consent.
2. Ability to comply with the protocol.
3. Aged ≥ 18 years.
4. Histologically or cytologically confirmed metastatic pancreatic adenocarcinoma that has progressed on one or more chemotherapy regimens.
5. Karnofsky performance status ≥ 70%.
6. At least one lesion that can be measured accurately at baseline as ≥10mm in the longest diameter (except lymph nodes which must have a short axis ≥15mm) with CT/MRI and which is suitable for repeated measurements per RECIST v1.1
7. Adequate haematological and end-organ function, as per the local institutions reference ranges, within 72 hrs prior to day 1 of cycle 1 of treatment defined by the following:
8. Life expectancy ≥ 12 weeks.
9. Negative pregnancy test within 14 days of day 1 cycle 1 for female patients of childbearing potential.
10. Tumour sites amenable to repeated biopsies.
11. Willingness to undergo paired tumour biopsies during the trial.
12. Agreement to use adequate contraception from 2 weeks before the start of treatment with Minnelide and until 90 days after completion of treatment.

Exclusion Criteria:

1. Patients with known or suspected brain metastasis
2. Significant cardiovascular disease such as New York Heart Associate Class III/IV, cardiac failure, myocardial infarction within 6 months prior to enrolment, unstable arrhythmia, or evidence of ischemia on ECG.
3. Baseline QTc exceeding 450msec (470msec for females) and / or patients receiving class 1A or class III anti-arrhythmic agents.
4. Known HIV, Hepatitis A, B or C infection.
5. Malignancies other than pancreatic cancer ≤5 years prior to Minnelide 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 localised prostate cancer treated with curative intent and absence of PSA relapse or incidental prostate cancer (Gleason score ≤3 +4 and PSA \<10ng/L undergoing active surveillance and treatment naïve).
6. Severe infections ≤ 4 weeks prior to enrolment in the study as well as active, uncontrolled bacterial, viral or fungal infections requiring systemic treatment.
7. Major surgical procedure ≤ 2 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
8. 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 Minnelide™ (6 weeks for nitrosoureas or Mitomycin C).
9. 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 Minnelide.
10. 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 Minnelide, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
11. Female patients who are pregnant or nursing.