Inclusion Criteria:
1.
Part 1 enrollment complete
Biopsy-proven metastatic pancreatic adenocarcinoma with documented radiographic disease
progression on or after one or more systemic therapies. Chemotherapy given as part of prior
chemoradiation in the setting of non-metastatic pancreatic cancer does not count as a line
of therapy. Chemotherapy given for at least 4 months as adjuvant after complete response is
considered as a first line therapy.
Part 2 actively enrolling
Biopsy-proven metastatic pancreatic adenocarcinoma on or after two prior lines of systemic
therapy. Chemotherapy given as part of prior chemo- radiation in the setting of
non-metastatic pancreatic cancer does not count as a line of therapy unless metastases
develop within 6 months of completing the chemosensitization. Chemotherapy given for at
least 4 months as adjuvant after a CR to any therapy (e.g. surgery and radiation therapy)
is also considered as a first line therapy. Of the two prior lines, patients should have
received a gemcitabine-based regimen for a prior line and a 5-FU based regimen as a prior
line of therapy. Investigational therapies as part of a prior line regimen are permitted.
2. Subjects have received two (2) and not more than two (2) previous systemic regimens for
the treatment of pancreatic adenocarcinoma
3. Subject must be eligible to receive one or more of the Physician Choice options.
4. Radiographically measurable disease of at least one site by CT scan (or MRI, if allergic
to CT contrast media). Imaging results must be obtained within the 14-day window prior to
randomization
5. Subjects must have completed any investigational cancer therapy at least 30 days prior
to first dose.
6. Subjects must have completed any other cancer therapy at least 14 days prior to first
dose and recovered from major side effects of prior therapies or procedures.
7. ≥18 years of age.
8. ECOG PS ≤2.
9. Adequate organ function defined as follows (lab results must be obtained within the
7-day window prior to randomization):
1. All laboratory parameters ≤ Grade 2 NCI Common Terminology Criteria for Adverse Events
(CTCAE) criteria.
2. In addition:
i. Hematologic: Platelets ≥ 100 x 109 g/dL; Absolute Neutrophil Count ≥ 1.5 x 109/L
(without platelet transfusion or growth factors within the 7 days prior to the screening
laboratory assessment).
ii. Hepatic: transaminase /alanine transaminase ≤ 2.5 x upper limit of normal (ULN); total
or conjugated bilirubin ≤ 1.5 x ULN, alkaline phosphatase (ALP) < 2.5 x ULN.
iii. Renal: serum creatinine ≤1.5 x ULN and creatinine clearance ≥ 60 mL/min as calculated
by the Cockroft-Gault method.
iv. Coagulation: International normalized ratio (INR) ≤ 1.2 within 28 days of starting
study.
v. Albumin: ≥ 3.0 g/dL.
vi. Weight: No more than a 5% change from Screening to Randomization (must be at least 1
week apart).
10. All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before
baseline, with the exception of alopecia and neurotoxicity (CTCAE Grade 1 or 2 permitted).
11. Able and willing to provide written informed consent to participate in this study.
12. Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow up.
13. Subjects must be able to swallow whole capsules.
14. Female subjects must either be of non-reproductive potential, not breast-feeding or
must have a negative urine or serum pregnancy test within 28 days of study treatment,
confirmed prior to treatment on Day 1.
15. Subjects of fertile potential who engage in heterosexual intercourse with partners of
childbearing potential must attest to the use of highly effective contraception while
enrolled in the study and for at least 6 months following the last dose of study drug.
Highly effective birth control methods include the following (the subject should choose 2
to be used with their partner):
1. Oral, injectable, or implanted hormonal contraceptives.
2. Condom with a spermicidal foam, gel, film, cream, or suppository.
3. Occlusive cap (diaphragm or cervical/vault cap) with a spermicidal foam, gel, film,
cream, or suppository.
Or any one of the following:
1. Intrauterine device.
2. Intrauterine system (for example, progestin-releasing coil).
3. Vasectomized male (as determined by the investigator).
4. Tubal ligation/sterilization (female).
Exclusion criteria for Parts 1 and 2 are as follows:
1. Any screening laboratory, ECG, or other findings that, in the opinion of the
investigator, medical monitor or the sponsor, indicate an unacceptable risk for the
subject's participation in the study.
2. History or evidence of any clinically significant disorder, condition, or disease
that, in the opinion of the investigator or medical monitor would pose a risk to the
subject's safety or interfere with the study evaluations, procedures, or completion.
Examples include intercurrent illness such as active uncontrolled infection, active or
chronic bleeding event within 28 days of baseline, uncontrolled cardiac arrhythmia, or
psychiatric illness/social situation that would limit compliance with study
requirements.
3. History of a concurrent or second malignancy, except for adequately treated localized
basal cell or squamous cell carcinoma of the skin, adequately treated superficial
bladder cancer, adequately treated Stage 1 or 2 cancer currently in complete
remission; or any other cancer that has been in complete remission for ≥ 5 years.
4. Subjects with MSI-H pancreatic cancer who have not previously received pembrolizumab.
5. Subjects with any known actionable mutation (e.g. BRCA mutation) who have not been
treated with an approved drug for the mutation (the drug does not have to be approved
for the indication).
6. Radiation to all target lesions within 12 weeks of study baseline.
7. No measurable target lesions.
8. Current use, or up to 14 days prior use, of a restricted medication (see Section 8.7)
or requires any of these medications during treatment phase.
9. Major surgery, defined as any surgical procedure that involves general anesthesia and
a significant incision (i.e. larger than that required for placement of central venous
access, percutaneous feeding tube, or biopsy) within 28 days of the first dose of
study drug.
10. Minor surgical procedures within 7 days of baseline, or not yet recovered from any
prior surgery.
11. Any dysphagia, odynophagia, esophageal dysmotility or stricture, known
gastrointestinal (GI) malabsorption syndrome, or intractable diarrhea that may
significantly alter the absorption of any of the components of SM-88 used with MPS,
e.g., cirrhosis.
12. Known human immunodeficiency (HIV) virus infection. Note: HIV testing is not required
in the absence of clinical suspicion.
13. Known hepatitis B surface antigen (HBsAg) positive.
14. Known hepatitis C (HCV) viral RNA present.
15. Have previously been enrolled in this study or any other study investigating SM-88 or
who have previously received any SM-88, methoxsalen, phenytoin, or sirolimus in a
clinical trial.
16. History of any known drug allergies to any study medication.
17. Are currently enrolled in, or have discontinued within 14 days of screening, from a
clinical trial involving an i nvestigational product or non-approved use of a drug or
device.
18. Subjects must not have any clinically significant and uncontrolled major medical
condition(s) including, but not limited to uncontrolled nausea/vomiting/diarrhea;
active uncontrolled infection; symptomatic congestive heart failure (New York Heart
Association [NYHA] class ≥ II); unstable angina pectoris or cardiac arrhythmia;
psychiatric illness/social situation that would limit compliance with study
requirements.
19. >5% weight loss over the 28 days prior to consent or >5% change in weight from consent
to randomization.
20. Subjects that have a variety of factors influencing oral drugs (such as unable to
swallow, nausea, vomiting, chronic diarrhea and intestinal obstruction, etc.).
21. Subjects with central nervous system metastasis; with the exception of subjects who
have stable brain metastases as defined as off steroids and no CNS progress for 6
months after CNS treatment.
22. Pregnant or lactating women.
23. Substance abuse that cannot be ended, or subjects with mental disorders that will
prevent compliance or evaluation including uncontrolled schizophrenia, uncontrolled
depression or other uncontrolled disorders.
24. Subjects with a history of hypersensitivity to phenytoin, its inactive ingredients, or
other hydantoins; or a history of prior acute hepatotoxicity attributable to
phenytoin.
25. Subjects exhibiting idiosyncratic reactions to psoralen compounds.
26. Subjects with a hypersensitivity to sirolimus.
27. Subjects with a history of the light sensitive diseases for which methoxsalen would be
contraindicated. Diseases associated with photosensitivity include lupus
erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate
porphyria, xeroderma pigmentosum, and albinism.
28. Subjects treated, or anticipated to be treated, with delavirdine (due to potential for
loss of virologic response and possible resistance to delavirdine or to the class of
non-nucleoside reverse transcriptase inhibitors caused by phenytoin).
29. Subjects with cutaneous melanoma or invasive squamous cell carcinomas or a history
thereof, except for those in complete remission for ≥5 years (due to contraindication
for use of methoxsalen).
30. Subjects with prior organ transplant or being treated, or anticipated to be treated,
with cyclosporine (because long-term administration of the combination of cyclosporine
and sirolimus is associated with deterioration of renal function).
31. Subjects with a seizure disorder that is not well controlled or who have required a
change in seizure medications within 60 days of enrollment to the trial.
32. Subjects treated, or anticipated to be treated, with a calcineurin inhibitor (because
concomitant use of sirolimus and a calcineurin inhibitor increases the risk of
calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic
purpura/thrombotic microangiopathy [HUS/TTP/TMA]).
33. Subjects with interstitial lung disease (ILD) [including pneumonitis, bronchiolitis
obliterans organizing pneumonia (BOOP), and pulmonary fibrosis].
34. Baseline repeated prolongation of QT/QTc interval [e.g. > 480 milliseconds (ms)]
(CTCAE Grade 1) using Fredericia's QT correction formula.
35. A family history of Long QT Syndrome or Torsades de Pointes
36. Clinically significant cataracts or aphakia.
37. Presence of ascites or pleural effusion.
