A Randomized Phase 2/3 Multi-Center Study of SM-88 in Patients With Metastatic Pancreatic Cancer

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.